Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.

Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.

Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05).

Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics. (C) 2015 Published by Elsevier Inc. on behalf of The Alzheimer's Association.

Hierarchical Demand Response for Peak Reduction using Dantzig‐Wolfe Decomposition

Demand Response (DR) algorithms manipulate the energy consumption schedules of controllable loads so as to satisfy grid objectives. Implementation of DR algorithms using a centralised agent can be problematic for scalability reasons, and there are issues related to the privacy of data and robustness to communication failures. Thus it is desirable to use a scalable decentralised algorithm for the implementation of DR. In this paper, a hierarchical DR scheme is proposed for Peak Minimisation (PM) based on Dantzig-Wolfe Decomposition (DWD). In addition, a Time Weighted Maximisation option is included in the cost function which improves the Quality of Service for devices seeking to receive their desired energy sooner rather than later. The paper also demonstrates how the DWD algorithm can be implemented more efficiently through the calculation of the upper and lower cost bounds after each DWD iteration.

Role played by BRCA1 in transcriptional regulation in response to therapy

BRCA1 (breast-cancer susceptibility gene 1) is a tumour suppressor, implicated in the hereditary predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of cellular processes including DNA repair and recombination, cell cycle checkpoint control, chromatin remodelling and ubiquitination. In addition, substantial data now exist to suggest a role for BRCA1 in transcriptional regulation; BRCA1 has been shown to interact with the Pol II holoenzyme complex and to interact with multiple transcription factors, such as p53 and c-Myc. We have previously identified a range of BRCA1 transcriptional targets and have linked these to specific cellular pathways, including cell cycle checkpoint activation and apoptosis. Current research is focused on the transcriptional mechanisms that underpin the association of BRCA1 deficiency with increased sensitivity to DNA damage-based chemotherapy and resistance to spindle poisons.

Divergent androgen regulation of unfolded protein response pathways drives prostate cancer

The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer (PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor (AR), which is critical for PCa survival. AR bound to gene regulatory sites and activated the IRE1α branch, but simultaneously inhibited PERK signaling. Inhibition of the IRE1α arm profoundly reduced PCa cell growth in vitro as well as tumor formation in preclinical models of PCa in vivo. Consistently, AR and UPR gene expression were correlated in human PCa, and spliced XBP-1 expression was significantly upregulated in cancer compared with normal prostate. These data establish a genetic switch orchestrated by AR that divergently regulates the UPR pathways and suggest that targeting IRE1α signaling may have therapeutic utility in PCa.

Molecular predictors of response to antiangiogenesis therapies

Angiogenesis is a crucial component of tumor growth and metastasis. Targeting the vascular endothelial growth factor pathway represents therapeutic potentials for treating cancer. To date, 3 Food and Drug Administration-approved agents targeting angiogenesis have been developed, bevacizumab, sunitinib, and sorafenib. However, no validated biomarkers are available to identify those patients who are likely to benefit from antiangiogenesis therapy. Molecular biomarker research in antiangiogenesis inhibition is an actively growing field. Although current data are extremely promising, it is still uncertain which biomarker(s) can reliably predict their efficacy. With increasing numbers of inhibitors being developed, the need for biomarkers is more critical than ever. This review will focus on translational research that strives to identify molecular biomarkers (tissue, circulating and genomic) for approved antiangiogenesis therapies that can indicate benefit, resistance, and toxicity.

Parametric study to extract bridge frequencies from the dynamic response of passing vehicles

A conventional way to identify bridge frequencies is utilizing vibration data measured directly from the bridge. A drawback with this approach is that the deployment and maintenance of the vibration sensors are generally costly and time-consuming. One way to cope with the drawback is an indirect approach utilizing vehicle vibrations while the vehicle passes over the bridge. In the indirect approach, however, the vehicle vibration includes the effect of road surface roughness, which makes it difficult to extract the bridge modal properties. One solution may be subtracting signals of two trailers towed by a vehicle to reduce the effect of road surface roughness. A simplified vehicle-bridge interaction model is used in the numerical simulation; the vehicle - trailer and bridge system are modeled as a coupled model. In addition, a laboratory experiment is carried out to verify results of the simulation and examine feasibility of the damage detection by the indirect method.

Irish Power System Primary Frequency Response Metrics during Different System Non Synchronous Penetrations.

This paper discusses the use of primary frequency response metrics to assess the dynamics of frequency disturbance data with the presence of high system non synchronous penetration (SNSP) and system inertia variation. The Irish power system has been chosen as a study case as it experiences a significant level of SNSP from wind turbine generation and imported active power from HVDC interconnectors. Several recorded actual frequency disturbances were used in the analysis. These data were measured and collected from the Irish power system from October 2010 to June 2013. The paper has shown the impact of system inertia and SNSP variation on the performance of primary frequency response metrics, namely: nadir frequency, rate of change of frequency, inertial and primary frequency response.

Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603 838 individuals

Background: Long working hours might increase the risk of cardiovascular disease, but prospective evidence is scarce, imprecise, and mostly limited to coronary heart disease. We aimed to assess long working hours as a risk factor for incident coronary heart disease and stroke. 

Methods We identified published studies through a systematic review of PubMed and Embase from inception to Aug 20, 2014. We obtained unpublished data for 20 cohort studies from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium and open-access data archives. We used cumulative random-effects meta-analysis to combine effect estimates from published and unpublished data. 

Findings We included 25 studies from 24 cohorts in Europe, the USA, and Australia. The meta-analysis of coronary heart disease comprised data for 603 838 men and women who were free from coronary heart disease at baseline; the meta-analysis of stroke comprised data for 528 908 men and women who were free from stroke at baseline. Follow-up for coronary heart disease was 5·1 million person-years (mean 8·5 years), in which 4768 events were recorded, and for stroke was 3·8 million person-years (mean 7·2 years), in which 1722 events were recorded. In cumulative meta-analysis adjusted for age, sex, and socioeconomic status, compared with standard hours (35-40 h per week), working long hours (≥55 h per week) was associated with an increase in risk of incident coronary heart disease (relative risk [RR] 1·13, 95% CI 1·02-1·26; p=0·02) and incident stroke (1·33, 1·11-1·61; p=0·002). The excess risk of stroke remained unchanged in analyses that addressed reverse causation, multivariable adjustments for other risk factors, and different methods of stroke ascertainment (range of RR estimates 1·30-1·42). We recorded a dose-response association for stroke, with RR estimates of 1·10 (95% CI 0·94-1·28; p=0·24) for 41-48 working hours, 1·27 (1·03-1·56; p=0·03) for 49-54 working hours, and 1·33 (1·11-1·61; p=0·002) for 55 working hours or more per week compared with standard working hours (p_trend<0·0001).

Interpretation Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker. These findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours. 

Calibration of BAS-TR image plate response to high energy (3-300 MeV) carbon ions

The paper presents the calibration of Fuji BAS-TR image plate (IP) response to high energy carbon ions of different charge states by employing an intense laser-driven ion source, which allowed access to carbon energies up to 270 MeV. The calibration method consists of employing a Thomson parabola spectrometer to separate and spectrally resolve different ion species, and a slotted CR-39 solid state detector overlayed onto an image plate for an absolute calibration of the IP signal. An empirical response function was obtained which can be reasonably extrapolated to higher ion energies. The experimental data also show that the IP response is independent of ion charge states.

Studying Gender in Conference Talks -- data from the 223rd meeting of the American Astronomical Society

We present a study on the gender balance, in speakers and attendees, at the recent major astronomical conference, the American Astronomical Society meeting 223, in Washington, DC. We conducted an informal survey, yielding over 300 responses by volunteers at the meeting. Each response included gender data about a single talk given at the meeting, recording the gender of the speaker and all question-askers. In total, 225 individual AAS talks were sampled. We analyze basic statistical properties of this sample. We find that the gender ratio of the speakers closely matched the gender ratio of the conference attendees. The audience asked an average of 2.8 questions per talk. Talks given by women had a slightly higher number of questions asked (3.2$\pm$0.2) than talks given by men (2.6$\pm$0.1). The most significant result from this study is that while the gender ratio of speakers very closely mirrors that of conference attendees, women are under-represented in the question-asker category. We interpret this to be an age-effect, as senior scientists may be more likely to ask questions, and are more commonly men. A strong dependence on the gender of session chairs is found, whereby women ask disproportionately fewer questions in sessions chaired by men. While our results point to laudable progress in gender-balanced speaker selection, we believe future surveys of this kind would help ensure that collaboration at such meetings is as inclusive as possible.

Analysis of groundwater-level response to rainfall and recharge estimates in fractured hard rock aquifers, NW Ireland

Despite fractured hard rock aquifers underlying over 65% of Ireland, knowledge of key processes controlling groundwater recharge in these bedrock systems is inadequately constrained. In this study, we examined 19 groundwater-level hydrographs from two Irish hillslope sites underlain by hard rock aquifers. Water-level time-series in clustered monitoring wells completed at the subsoil, soil/bedrock interface, shallow and deep bedrocks were continuously monitored hourly over two hydrological years. Correlation methods were applied to investigate groundwater-level response to rainfall, as well as its seasonal variations. The results reveal that the direct groundwater recharge to the shallow and deep bedrocks on hillslope is very limited. Water-level variations within these geological units are likely dominated by slow flow rock matrix storage. The rapid responses to rainfall (⩽2 h) with little seasonal variations were observed to the monitoring wells installed at the subsoil and soil/bedrock interface, as well as those in the shallow or deep bedrocks at the base of the hillslope. This suggests that the direct recharge takes place within these units. An automated time-series procedure using the water-table fluctuation method was developed to estimate groundwater recharge from the water-level and rainfall data. Results show the annual recharge rates of 42–197 mm/yr in the subsoil and soil/bedrock interface, which represent 4–19% of the annual rainfall. Statistical analysis of the relationship between the rainfall intensity and water-table rise reveal that the low rainfall intensity group (⩽1 mm/h) has greater impact on the groundwater recharge rate than other groups (>1 mm/h). This study shows that the combination of the time-series analysis and the water-table fluctuation method could be an useful approach to investigate groundwater recharge in fractured hard rock aquifers in Ireland.

Fluid strategies and outcomes in patients with acute respiratory distress syndrome, systemic inflammatory response syndrome and sepsis: a protocol for a systematic review and meta-analysis

Background
Fluid administration to critically ill patients remains the subject of considerable controversy. While intravenous fluid given for resuscitation may be life-saving, a positive fluid balance over time is associated with worse outcomes in critical illness. The aim of this systematic review is to summarise the existing evidence regarding the relationship between fluid administration or balance and clinically important patient outcomes in critical illness.

Methods
We will search Medline, EMBASE, the Cochrane Central Register of Controlled Trials from 1980 to the present and key conference proceedings from 2009 to the present. We will include studies of critically ill adults and children with acute respiratory distress syndrome (ARDS), sepsis and systemic inflammatory response syndrome (SIRS). We will include randomised controlled trials comparing two or more fluid regimens of different volumes of fluid and observational studies reporting the relationship between volume of fluid administered or fluid balance and outcomes including mortality, lengths of intensive care unit and hospital stay and organ dysfunction. Two independent reviewers will assess articles for eligibility, data extraction and quality appraisal. We will conduct a narrative and/or meta-analysis as appropriate.

Discussion
While fluid management has been extensively studied and discussed in the critical care literature, no systematic review has attempted to summarise the evidence for post-resuscitation fluid strategies in critical illness. Results of the proposed systematic review will inform practice and the design of future clinical trials.

Systematic review registration
PROSPERO CRD42013005608. (http://​www.​crd.​york.​ac.​uk/​PROSPERO/​)

Validation of a 3D damage model for predicting the response of composite structures under crushing loads

A 3D intralaminar continuum damage mechanics based material model, combining damage mode interaction and material nonlinearity, was developed to predict the damage response of composite structures undergoing crush loading. This model captures the structural response without the need for calibration of experimentally determined material parameters. When used in the design of energy absorbing composite structures, it can reduce the dependence on physical testing. This paper validates this model against experimental data obtained from the literature and in-house testing. Results show that the model can predict the force response of the crushed composite structures with good accuracy. The simulated energy absorption in each test case was within 12% of the experimental value. Post-crush deformation and the damage morphologies, such as ply splitting, splaying and breakage, were also accurately reproduced. This study establishes the capability of this damage model for predicting the responses of composite structures under crushing loads.

An evaluation of the Socrative (personal response system) app for increasing student engagement and learning in an undergraduate psychology curriculum.

Personal response systems using hardware such as 'clickers' have been around for some time, however their use is often restricted to multiple choice questions (MCQs) and they are therefore used as a summative assessment tool for the individual student. More recent innovations such as 'Socrative' have removed the need for specialist hardware, instead utilising web-based technology and devices common to students, such as smartphones, tablets and laptops. While improving the potential for use in larger classrooms, this also creates the opportunity to pose more engaging open-response questions to students who can 'text in' their thoughts on questions posed in class. This poster will present two applications of the Socrative system in an undergraduate psychology curriculum which aimed to encourage interactive engagement with course content using real-time student responses and lecturer feedback. Data is currently being collected and result will be presented at the conference.
The first application used Socrative to pose MCQs at the end of two modules (a level one Statistics module and level two Individual Differences Psychology module, class size N≈100), with the intention of helping students assess their knowledge of the course. They were asked to rate their self-perceived knowledge of the course on a five-point Likert scale before and after completing the MCQs, as well as their views on the value of the revision session and any issues that had with using the app. The online MCQs remained open between the lecture and the exam, allowing students to revisit the questions at any time during their revision.
This poster will present data regarding the usefulness of the revision MCQs, the metacognitive effect of the MCQs on student's judgements of learning (pre vs post MCQ testing), as well as student engagement with the MCQs between the revision session and the examination. Student opinions on the use of the Socrative system in class will also be discussed.
The second application used Socrative to facilitate a flipped classroom lecture on a level two 'Conceptual Issues in Psychology' module, class size N≈100). The content of this module requires students to think critically about historical and contemporary conceptual issues in psychology and the philosophy of science. Students traditionally struggle with this module due to the emphasis on critical thinking skills, rather than simply the retention of concrete knowledge. To prepare students for the written examination, a flipped classroom lecture was held at the end of the semester. Students were asked to revise their knowledge of a particular area of Psychology by assigned reading, and were told that the flipped lecture would involve them thinking critically about the conceptual issues found in this area. They were informed that questions would be posed by the lecturer in class, and that they would be asked to post their thoughts using the Socrative app for a class discussion. The level of preparation students engaged in for the flipped lecture was measured, as well as qualitative opinions on the usefulness of the session. This poster will discuss the level of student engagement with the flipped lecture, both in terms of preparation for the lecture, and engagement with questions posed during the lecture, as well as the lecturer's experience in facilitating the flipped classroom using the Socrative platform.

Towards the 2021 UK Census imputation strategy: Response mode as a matching variable in a donor-based approach?

Since July 2014, the Office for National Statistics has committed to a predominantly online 2021 UK Census. Item-level imputation will play an important role in adjusting the 2021 Census database. Research indicates that the internet may yield cleaner data than paper based capture and attract people with particular characteristics. Here, we provide preliminary results from research directed at understanding how we might manage these features in a 2021 UK Census imputation strategy. Our findings suggest that if using a donor-based imputation method, it may need to consider including response mode as a matching variable in the underlying imputation model.