Building cross-scale models of epigenetic mechanisms

Epigenetic changes correspond to heritable modifications of the chromosome structure, which do not involve alteration of the DNA sequence but do affect gene expression. These mechanisms play an important role in normal cell differentiation, but aberration is associated also with several diseases, including cancer and neural disorders. In consequence, despite intensive studies in recent years, the contribution of modifications remains largely unquantified due to overall system complexity and insufficient data. Computational models can provide powerful auxiliary tools to experimentation, not least as scales from the sub-cellular through cell populations (or to networks of genes) can be spanned. In this paper, the challenges to development, of realistic cross-scale models, are discussed and illustrated with respect to current work.

Large-scale interlaboratory study to develop, analytically validate and apply highly multiplexed, quantitative peptide assays to measure cancer-relevant proteins in plasma

There is an increasing need in biology and clinical medicine to robustly and reliably measure tens-to-hundreds of peptides and proteins in clinical and biological samples with high sensitivity, specificity, reproducibility and repeatability. Previously, we demonstrated that LC-MRM-MS with isotope dilution has suitable performance for quantitative measurements of small numbers of relatively abundant proteins in human plasma, and that the resulting assays can be transferred across laboratories while maintaining high reproducibility and quantitative precision. Here we significantly extend that earlier work, demonstrating that 11 laboratories using 14 LC-MS systems can develop, determine analytical figures of merit, and apply highly multiplexed MRM-MS assays targeting 125 peptides derived from 27 cancer-relevant proteins and 7 control proteins to precisely and reproducibly measure the analytes in human plasma. To ensure consistent generation of high quality data we incorporated a system suitability protocol (SSP) into our experimental design. The SSP enabled real-time monitoring of LC-MRM-MS performance during assay development and implementation, facilitating early detection and correction of chromatographic and instrumental problems. Low to sub-nanogram/mL sensitivity for proteins in plasma was achieved by one-step immunoaffinity depletion of 14 abundant plasma proteins prior to analysis. Median intra- and inter-laboratory reproducibility was <20%, sufficient for most biological studies and candidate protein biomarker verification. Digestion recovery of peptides was assessed and quantitative accuracy improved using heavy isotope labeled versions of the proteins as internal standards. Using the highly multiplexed assay, participating laboratories were able to precisely and reproducibly determine the levels of a series of analytes in blinded samples used to simulate an inter-laboratory clinical study of patient samples. Our study further establishes that LC-MRM-MS using stable isotope dilution, with appropriate attention to analytical validation and appropriate quality c`ontrol measures, enables sensitive, specific, reproducible and quantitative measurements of proteins and peptides in complex biological matrices such as plasma.

Inferring lung cancer risk factor patterns through joint Bayesian spatio-temporal analysis

Background: Preventing risk factor exposure is vital to reduce the high burden from lung cancer. The leading risk factor for developing lung cancer is tobacco smoking. In Australia, despite apparent success in reducing smoking prevalence, there is limited information on small area patterns and small area temporal trends. We sought to estimate spatio-temporal patterns for lung cancer risk factors using routinely collected population-based cancer data. Methods: The analysis used a Bayesian shared component spatio-temporal model, with male and female lung cancer included separately. The shared component reflected exposure to lung cancer risk factors, and was modelled over 477 statistical local areas (SLAs) and 15 years in Queensland, Australia. Analyses were also run adjusting for area-level socioeconomic disadvantage, Indigenous population composition, or remoteness. Results: Strong spatial patterns were observed in the underlying risk factor exposure for both males (median Relative Risk (RR) across SLAs compared to the Queensland average ranged from 0.48-2.00) and females (median RR range across SLAs 0.53-1.80), with high exposure observed in many remote areas. Strong temporal trends were also observed. Males showed a decrease in the underlying risk across time, while females showed an increase followed by a decrease in the final two years. These patterns were largely consistent across each SLA. The high underlying risk estimates observed among disadvantaged, remote and indigenous areas decreased after adjustment, particularly among females. Conclusion: The modelled underlying exposure appeared to reflect previous smoking prevalence, with a lag period of around 30 years, consistent with the time taken to develop lung cancer. The consistent temporal trends in lung cancer risk factors across small areas support the hypothesis that past interventions have been equally effective across the state. However, this also means that spatial inequalities have remained unaddressed, highlighting the potential for future interventions, particularly among remote areas.

Investigating a model of mentoring for effective teaching

This paper investigates a five-factor model of mentoring for effective teaching. A survey was administered to 218 student teachers after student teaching to provide insights into their mentoring experience. Results indicated the five factors, namely, personal attributes, system requirements, pedagogical knowledge, modeling, and feedback, had Cronbach alpha scores of .93, .81, .95, .91, and .91, respectively with mean scale scores ranging from 4.20 to 4.60 (p< .001). Items associated with each factor were analyzed; the lowest percentage response was reviewing lesson plans (71%) and the highest percentage was modeling effective teaching practices (96%). Triangulated data from the survey results suggested that the practices implemented by the mentor teachers were perceived to have supported the student teachers’ development during student teaching. Implications of this study suggest that actively engaging mentor teachers who apply the principles outlined by the five factor areas will serve to ensure highly effective support for the development of student teachers.

Differences in composition of symptom clusters between older and younger oncology patients

Context Older oncology patients have unique needs associated with the many physical, psychological,and social changes associated with the aging process. The mechanisms underpinning and the impact of these changes are not well understood. Identification of clusters of symptoms is one approach that has been used to elicit hypotheses about the biological and/or psychological basis for variations in symptom experiences. Objectives The purposes of this study were to identify and compare symptom clusters in younger (<60 years) and older ($60 years) patients undergoing cancer treatment. Methods. Symptom data from one Australian study and two U.S. studies were combined to conduct this analysis. A total of 593 patients receiving active treatment were dichotomized into younger (<60 years) and older ($60 years) groups. Separate exploratory factor analyses (EFAs) were undertaken within each group to identify symptom clusters from occurrence ratings of the 32 symptoms assessed by the Memorial Symptom Assessment Scale. Results In both groups, a seven-factor solution was selected. Four partially concordant symptom clusters emerged in both groups (i.e., mood/cognitive, malaise, body image, and genitourinary). In the older patients, the three unique clusters reflected physiological changes associated with aging, whereas in the younger group the three unique clusters reflected treatment-related effects. Conclusion The symptom clusters identified in older patients typically included a larger and more diverse range of physical and psychological symptoms. Differences also may be reflective of variations in treatment approaches between age groups. Findings highlight the need for better understanding of variation in treatment and symptom burden between younger and older adults with cancer.

Different correlation of Sphingosine-1-Phosphate receptor 1 with receptor activator of nuclear factor kappa B ligand and regulatory T cells in rat periapical lesions

Introduction Sphingosine-1-phosphate receptor 1 (S1P1) is crucial for regulation of immunity and bone metabolism. This study aimed to investigate the expression of S1P1 in rat periapical lesions and its relationship with receptor activator of nuclear factor kappa B ligand (RANKL) and regulatory T (Treg) cells. Methods Periapical lesions were induced by pulp exposure in the first lower molars of 55 Wistar rats. Thirty rats were killed on days 0, 7, 14, 21, 28, and 35, and their mandibles were harvested for x-ray imaging, micro–computed tomography scanning, histologic observation, immunohistochemistry, enzyme histochemistry, and double immunofluorescence analysis. The remaining 25 rats were killed on days 0, 14, 21, 28, and 35, and mandibles were harvested for flow cytometry. Results The volume and area of the periapical lesions increased from day 0 to day 21 and then remained comparably stable after day 28. S1P1-positive cells were observed in the inflammatory periapical regions; the number of S1P1-positive cells peaked at day 14 and then decreased from day 21 to day 35. The distribution of S1P1-positive cells was positively correlated with the dynamics of RANKL-positive cells but was negatively correlated with that of Treg cells. Conclusions S1P1 expression was differentially correlated with RANKL and Treg cell infiltration in the periapical lesions and is therefore a contributing factor to the pathogenesis of such lesions.

Testing and modifying a tool to measure nurses’ beliefs about aromatherapy

Aromatherapy has been found to have some effectiveness in treating conditions such as postoperative nausea and vomiting, however unless clinicians are aware of and convinced by this evidence, it is unlikely they will choose to use it with their patients. The aim of this study was to test and modify an existing tool, Martin and Furnham’s Beliefs About Aromatherapy Scale in order to make it relevant and meaningful for use with a population of nurses and midwives working in an acute hospital setting. A Delphi process was used to modify the tool and then it was tested in a population of nurses and midwives, then exploratory factor analysis was conducted. The modified tool is reliable and valid for measuring beliefs about aromatherapy in this population.

Limitations of a laboratory scale model in predicting optimal pilot scale conditions for dilute acid pretreatment of sugarcane bagasse

Pilot and industrial scale dilute acid pretreatment data can be difficult to obtain due to the significant infrastructure investment required. Consequently, models of dilute acid pretreatment by necessity use laboratory scale data to determine kinetic parameters and make predictions about optimal pretreatment conditions at larger scales. In order for these recommendations to be meaningful, the ability of laboratory scale models to predict pilot and industrial scale yields must be investigated. A mathematical model of the dilute acid pretreatment of sugarcane bagasse has previously been developed by the authors. This model was able to successfully reproduce the experimental yields of xylose and short chain xylooligomers obtained at the laboratory scale. In this paper, the ability of the model to reproduce pilot scale yield and composition data is examined. It was found that in general the model over predicted the pilot scale reactor yields by a significant margin. Models that appear very promising at the laboratory scale may have limitations when predicting yields on a pilot or industrial scale. It is difficult to comment whether there are any consistent trends in optimal operating conditions between reactor scale and laboratory scale hydrolysis due to the limited reactor datasets available. Further investigation is needed to determine whether the model has some efficacy when the kinetic parameters are re-evaluated by parameter fitting to reactor scale data, however, this requires the compilation of larger datasets. Alternatively, laboratory scale mathematical models may have enhanced utility for predicting larger scale reactor performance if bulk mass transport and fluid flow considerations are incorporated into the fibre scale equations. This work reinforces the need for appropriate attention to be paid to pilot scale experimental development when moving from laboratory to pilot and industrial scales for new technologies.

The pet factor - Companion animals as a conduit for getting to know people, friendship formation and social support

BACKGROUND: While companion animals have been previously identified as a direct source of companionship and support to their owners, their role as a catalyst for friendship formation or social support networks among humans has received little attention. This study investigated the indirect role of pets as facilitators for three dimensions of social relatedness; getting to know people, friendship formation and social support networks. METHODS: A telephone survey of randomly selected residents in four cities, one in Australia (Perth; n = 704) and three in the U.S. (San Diego, n = 690; Portland, n = 634; Nashville, n = 664) was conducted. All participants were asked about getting to know people within their neighborhood. Pet owners were asked additional questions about the type/s of pet/s they owned, whether they had formed friendships as a result of their pet, and if they had received any of four different types of social support from the people they met through their pet. RESULTS: Pet owners were significantly more likely to get to know people in their neighborhood than non-pet owners (OR 1.61; 95%CI: 1.30, 1.99). When analyzed by site, this relationship was significant for Perth, San Diego and Nashville. Among pet owners, dog owners in the three U.S. cities (but not Perth) were significantly more likely than owners of other types of pets to regard people whom they met through their pet as a friend (OR 2.59; 95%CI: 1.94, 3.46). Around 40% of pet owners reported receiving one or more types of social support (i.e. emotional, informational, appraisal, instrumental) via people they met through their pet. CONCLUSION: This research suggests companion animals can be a catalyst for several dimensions of human social relationships in neighborhood settings, ranging from incidental social interaction and getting to know people, through to formation of new friendships. For many pet owners, their pets also facilitated relationships from which they derived tangible forms of social support, both of a practical and emotionally supportive nature. Given growing evidence for social isolation as a risk factor for mental health, and, conversely, friendships and social support as protective factors for individual and community well-being, pets may be an important factor in developing healthy neighborhoods.

Inventory of pedagogy and practice: Confirmatory factor analysis of multiple facets of teaching

Student perceptions of teaching have often been used in tertiary education for evaluation purposes. However, there is a paucity of research on the validity, reliability, and applicability of instruments that cover a wide range of student perceptions of pedagogies and practices in high school settings for descriptive purposes. The study attempts to validate an inventory of pedagogy and practice (IPP) that provides researchers and practitioners with a psychometrically sound instrument that covers the most salient factors related to teaching. Using a sample of students (N = 1515) from 39 schools in Singapore, 14 factors about teaching in English lessons from the students’ perspective were tested with confirmatory factor analysis (classroom task goal, structure and clarity, curiosity and interest, positive class climate, feedback, questioning, quality homework, review of students’ work, conventional teaching, exam preparation, behaviour management, maximizing learning time, student-centred pedagogy, and subject domain teaching). Two external criterion factors were used to further test the IPP factor structure. The inventory will enable teachers to understand more about their teaching and researchers to examine how teaching may be related to learning outcomes.

A homogeneous surface-enhanced Raman scattering platform for ultra-trace detection of trinitrotoluene in the environment

A facile and sensitive surface-enhanced Raman scattering substrate was prepared by controlled potentiostatic deposition of a closely packed single layer of gold nanostructures (AuNS) over a flat gold (pAu) platform. The nanometer scale inter-particle distance between the particles resulted in high population of ‘hot spots’ which enormously enhanced the scattered Raman photons. A renewed methodology was followed to precisely quantify the SERS substrate enhancement factor (SSEF) and it was estimated to be (2.2 ± 0.17) × 105. The reproducibility of the SERS signal acquired by the developed substrate was tested by establishing the relative standard deviation (RSD) of 150 repeated measurements from various locations on the substrate surface. A low RSD of 4.37 confirmed the homogeneity of the developed substrate. The sensitivity of pAu/AuNS was proven by determining 100 fM 2,4,6-trinitrotoluene (TNT) comfortably. As a proof of concept on the potential of the new pAu/AuNS substrate in field analysis, TNT in soil and water matrices was selectively detected after forming a Meisenheimer complex with cysteamine.

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.

Parallel streaming signature EM-tree: A clustering algorithm for web scale applications

The proliferation of the web presents an unsolved problem of automatically analyzing billions of pages of natural language. We introduce a scalable algorithm that clusters hundreds of millions of web pages into hundreds of thousands of clusters. It does this on a single mid-range machine using efficient algorithms and compressed document representations. It is applied to two web-scale crawls covering tens of terabytes. ClueWeb09 and ClueWeb12 contain 500 and 733 million web pages and were clustered into 500,000 to 700,000 clusters. To the best of our knowledge, such fine grained clustering has not been previously demonstrated. Previous approaches clustered a sample that limits the maximum number of discoverable clusters. The proposed EM-tree algorithm uses the entire collection in clustering and produces several orders of magnitude more clusters than the existing algorithms. Fine grained clustering is necessary for meaningful clustering in massive collections where the number of distinct topics grows linearly with collection size. These fine-grained clusters show an improved cluster quality when assessed with two novel evaluations using ad hoc search relevance judgments and spam classifications for external validation. These evaluations solve the problem of assessing the quality of clusters where categorical labeling is unavailable and unfeasible.

Mobile app rating scale: A new tool for assessing the quality of health mobile apps

Background The use of mobile apps for health and well being promotion has grown exponentially in recent years. Yet, there is currently no app-quality assessment tool beyond “star”-ratings. Objective The objective of this study was to develop a reliable, multidimensional measure for trialling, classifying, and rating the quality of mobile health apps. Methods A literature search was conducted to identify articles containing explicit Web or app quality rating criteria published between January 2000 and January 2013. Existing criteria for the assessment of app quality were categorized by an expert panel to develop the new Mobile App Rating Scale (MARS) subscales, items, descriptors, and anchors. There were sixty well being apps that were randomly selected using an iTunes search for MARS rating. There were ten that were used to pilot the rating procedure, and the remaining 50 provided data on interrater reliability. Results There were 372 explicit criteria for assessing Web or app quality that were extracted from 25 published papers, conference proceedings, and Internet resources. There were five broad categories of criteria that were identified including four objective quality scales: engagement, functionality, aesthetics, and information quality; and one subjective quality scale; which were refined into the 23-item MARS. The MARS demonstrated excellent internal consistency (alpha = .90) and interrater reliability intraclass correlation coefficient (ICC = .79). Conclusions The MARS is a simple, objective, and reliable tool for classifying and assessing the quality of mobile health apps. It can also be used to provide a checklist for the design and development of new high quality health apps.

Information technology investment governance: What is it and does it matter?

While the growth in the number of IT investments remains strong, research in the IT investment field is limited, resulting in suboptimal practical guidance on effectively governing IT investments. Based on resource-based theory, this paper reports the initial work involved in developing a construct names IT investment governance (ITIG), because it can be used to measure organizations' capability to govern their IT investments. This paper then empirically examines the association of ITIG and corporate performance. The preliminary result is a four-factor, 16-item instrument for assessing the ITIG construct. This method's factors are IT investment value governance, IT investment value monitoring, IT investment appraisals and IT investment project management. The impact of ITIG on corporate performance was demonstrated with a significant and positive relationship found to exist between the ITIG construct and corporate performance, thus supporting the effectiveness of the ITIG construct. Corporations with higher levels of ITIG capability are more likely to maximize the contribution of their IT investments to firm value.