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The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput,in vivoscreening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.

Additional file 1: Supplementary Figure 1. Efficiency frontier for C3I programs in Cohort 1 (left) and Cohort 2 (right): reach and effectiveness relative to cost-per-participant. Supplementary Figure 2. Efficiency frontier for C3I programs with (left) and without (right) a point-of-care intervention: reach and effectiveness relative to cost-per-participant. Supplementary Figure 3. Efficiency frontier for C3I programs at centers larger (left) and smaller (right) than median size: reach and effectiveness relative to cost-per-participant. Supplementary Figure 4. Efficiency frontier for C3I programs at centers with higher (left) and lower (right) than median smoking prevalence: reach and effectiveness relative to cost-per-participant.

The research will be to undertake a narrative systematic review of SW-CRTs published after November 2018. We will describe the problems encountered whilst undertaking this design and critically appraise any reported solutions to these problems.

Research methods research project

International audience; Changes to the Earth's biosphere have reached a critical point. It's abundantly clear that we can no longer halt those changes that have resulted from humaninduced modifications to the Earth's systems (1, 2). The climate crisis will fundamentally disrupt weather patterns, raise sea levels, alter biogeographic distributions, and much more. Research across disciplines from archaeology to zoology shows that terrestrial environments comprise irreplaceable archives of past human and evolutionary activity. Our rapidly changing Earth presents a grand challenge for humanity: We must preserve or record our cultural and ecological heritage, along with information about habitats critical for biodiversity, before they are lost completely. But this challenge brings up a profoundly important question: How best do we accomplish this recording, as quickly and with as much detail as possible? Some of this documentation is already underway. For example, there are archives of multi-spectral remote sensing products that are freely open to all, most notably the U.S. Geological Survey (USGS) archives (earthexplorer.usgs.gov) that include Landsat multi-spectral images dating back to the 1970s for much of the Earth's surface, as well as aerial photographs that date to earlier. What's missing from these archives is three-dimensional data that record the structure of the Earth's forest cover as well as the cultural and ecological features found beneath forest canopies. There have been calls to use remote sensing technologies, such as light detection and ranging (Lidar), to fill in this gap and record these broad areas of the

Additional file1 (DOCX 44 kb)

Background The prevalence of obesity is increasing globally and this could partly explain the worldwide increase in the prevalence of atrial fibrillation (AF), as both overweight and obesity are established risk factors. However, the relationship between weight change and risk of incident AF, independent of starting weight, remains uncertain. Methods MEDLINE, Embase, Pubmed, Web of Science, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Trials Register—clinicaltrials.gov, CINAHL and the WHO ICTRP were searched from inception to July 2018. We included randomised controlled trials and cohort studies across all healthcare settings but excluded studies of bariatric surgery. A random effects model was used to calculate pooled hazard ratios. The primary outcome was the risk of incident AF in relation to weight change. Results Ten studies, including 108 996 people, met our inclusion criteria. For a 5% gain in weight, the incidence of AF increased by 13% (HR 1.13, 95% CI 1.04 to 1.23, I2=70%, n>20 411 in five studies; study size was unknown for one study). A 5% loss in body weight was not associated with a significant change in the incidence of AF (HR 1.04, 95% CI 0.94 to 1.16, I2=73%, n=40 704 in five studies). Conclusions Weight gain may increase the risk of AF, but there was no clear evidence that non-surgical weight loss altered AF incidence. Strategies to prevent weight gain in the population may reduce the global burden of AF. Given the lack of studies and methodological limitations, further research is needed.

Walking north along the Homat HaYam Promenade in Jaffa, the entire Tel Aviv skyline comes into view with Mediterranean waves crashing against the old port’s walls. Families with young babies pause for pictures, bronzed 20-somethings play matkot (a popular paddle ball game similar to beach tennis) on the sand, and the occasional vendor hawking ice cream or drinks passes by. To the uncritical tourist eye, this is a veritable paradise; perfect weather, warm sand and cosmopolitan pleasures abound. But what these seaside vignettes of leisure and decadence omit is the historicity of the al-Manshiyya neighborhood upon which these spaces are built, as well as the ongoing dispossession of Palestinians in greater Tel Aviv. Consecutive eras of Zionist colonialism since the late 19th and early 20th century in this coastal city are generative of physical and psychic bordering through present day. The Hassan Bek mosque, Charles Clore Park and the Etzel Museum, all situated in what was historically al-Manshiyya, serve as sites to anchor this understanding of negation and erasure.

H4A Primary Healthcare Research Network scholars programme for support of research. This article was supported by National Funds through FCT - Fundação para a Ciência e a Tecnologia,I.P., within CINTESIS, R&D Unit (reference UIDB/4255/2020) OBJECTIVES: To translate and culturally adapt an English language patient decision aid addressing prostate cancer screening, so it can be used by Portuguese men. DESIGN: Qualitative study. We followed the European Centre for Disease Prevention and Control's (ECDC) five-step, stakeholder-based approach to adapting health communication materials: (1) selection of materials and process coordinators, (2) early review, (3) translation and back translation, (4) comprehension testing with cognitive semi-structured interviews and (5) proofreading. Content analysis was performed using Ligre software. SETTING AND PARTICIPANTS: Cognitive interviews with 15 men to refine a decision aid after its translation. Eligible participants were Portuguese native-speaking men aged 55-69 years old recruited from the local community (urban and suburban) of Oporto district through advertisements in social media and senior universities between January and March 2019. A previous diagnosis of prostate cancer was the single exclusion criterion. RESULTS: Five main themes are presented: informational content, information comprehension, sociocultural appropriateness, feelings and main message and personal perspective concerning prostate cancer screening. Most men found the translated version of the decision aid to be clear, comprehensive and appropriate for its target population, although some suggested that medical terms could be a barrier. The data collected from men's interviews afforded the researchers the opportunity to clarify concepts and expand existing content. CONCLUSIONS: A decision aid was successfully translated and adapted to the Portuguese cultural setting. Our ECDC based approach can be replicated by other workgroups to translate and culturally adapt decision aids. publishersversion published

Additional file 3. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015

Additional file 2. List of potential biomarkers. This file contains a non-exhaustive list of possible HF-related biomarkers a prognostic HF model could include at the start of the model development process or retained in the final stage

BACKGROUND: Heart failure (HF) is a chronic and common condition with a rising prevalence, especially in the elderly. Morbidity and mortality rates in people with HF are similar to those with common forms of cancer. Clinical guidelines highlight the need for more detailed prognostic information to optimise treatment and care planning for people with HF. Besides proven prognostic biomarkers and numerous newly developed prognostic models for HF clinical outcomes, no risk stratification models have been adequately established. Through a number of linked systematic reviews, we aim to assess the quality of the existing models with biomarkers in HF and summarise the evidence they present. METHODS: We will search MEDLINE, EMBASE, Web of Science Core Collection, and the prognostic studies database maintained by the Cochrane Prognosis Methods Group combining sensitive published search filters, with no language restriction, from 1990 onwards. Independent pairs of reviewers will screen and extract data. Eligible studies will be those developing, validating, or updating any prognostic model with biomarkers for clinical outcomes in adults with any type of HF. Data will be extracted using a piloted form that combines published good practice guidelines for critical appraisal, data extraction, and risk of bias assessment of prediction modelling studies. Missing information on predictive performance measures will be sought by contacting authors or estimated from available information when possible. If sufficient high quality and homogeneous data are available, we will meta-analyse the predictive performance of identified models. Sources of between-study heterogeneity will be explored through meta-regression using pre-defined study-level covariates. Results will be reported narratively if study quality is deemed to be low or if the between-study heterogeneity is high. Sensitivity analyses for risk of bias impact will be performed. DISCUSSION: This project aims to appraise and summarise the methodological conduct and predictive performance of existing clinically homogeneous HF prognostic models in separate systematic reviews.Registration: PROSPERO registration number CRD42019086990.

ZIP7, a member of the ZIP family of zinc importers, resides on the endoplasmic reticulum membrane and transports zinc from intracellular stores to the cytoplasm after activation by CK2 phosphorylation on two serine residues (S275 and S276). ZIP7 is known to be required for the growth of anti-hormone resistant breast cancer models, especially those with acquired tamoxifen resistance developed from MCF-7. Using our new pS275S276ZIP7 antibody which only recognises activated ZIP7 (pZIP7), we have demonstrated that the hyperactivation of ZIP7 is prevalent in tamoxifen-resistant breast cancer cells. This evidence suggests that pZIP7 might have potential as a biomarker of acquired resistance to such anti-hormones in breast cancer, a current unmet clinical need. In this regard, we have also developed a new immunohistochemical assay for pZIP7 which allowed pZIP7 to be tested on a small clinical series of breast cancer tissues confirming its prevalence in such tumours and relationship to a variety of clinicopathological parameters and biomarkers previously associated with endocrine resistant phenotypes, notably increased activated MAPK signalling, expression of ErbB2, CD71 and the proto-oncogene c-Fos, as well as with increased tumour grade.

Objective: Nightmares are relatively common in patients experiencing psychosis but rarely assessed or treated. Nightmares may maintain persecutory delusions by portraying fears in sensory-rich detail. We tested the potential benefits of imagery-focused cognitive behavioural therapy (CBT) for nightmares on nightmare severity and persecutory delusions. Method: This assessor-blind parallel-group pilot trial randomized 24 participants with nightmares and persecutory delusions to receive CBT for nightmares delivered over 4 weeks in addition to treatment as usual (TAU) or TAU alone. Assessments were at 0, 4 (end of treatment), and 8 weeks (follow-up). Feasibility outcomes assessed therapy uptake, techniques used, satisfaction, and attrition. The primary efficacy outcome assessed nightmare severity at week 4. Analyses were intention to treat, estimating treatment effect with 95% confidence intervals (CIs). Results: All participants offered CBT completed therapy (mean [SD], 4.8 [0.6] sessions) with high satisfaction, and 20 (83%) participants completed all assessments. Compared with TAU, CBT led to large improvements in nightmares (adjusted mean difference = −7.0; 95% CI, –12.6 to –1.3; d = –1.1) and insomnia (6.3; 95% CI, 2.6 to 10.0; d = 1.4) at week 4. Gains were maintained at follow-up. Suicidal ideation was not exacerbated by CBT but remained stable to follow-up, compared with TAU, which reduced at follow-up (6.8; 95% CI, 0.3 to 3.3; d = 0.7). CBT led to reductions in paranoia (–20.8; 95% CI, –43.2 to 1.7; d = –0.6), although CIs were wide. Three serious adverse events were deemed unrelated to participation (CBT = 2, TAU = 1). Conclusions: CBT for nightmares is feasible and may be efficacious for treating nightmares and comorbid insomnia for patients with persecutory delusions. It shows promise on paranoia but potentially not on suicidal ideation.

Zinc ions serve as second messengers in major cellular pathways, including the regulation pathways of proliferation and their proper regulation is necessary for homeostasis and a healthy organism. Accordingly, expression of zinc transporters can be altered in various cancer cell lines and is often involved in producing elevated intracellular zinc levels. In this study, human B cells were infected with Epstein–Barr virus (EBV) to generate immortalized cells, which revealed traits of tumor cells, such as high proliferation rates and an extended lifespan. These cells showed differentially altered zinc transporter expression with ZIP7 RNA and protein expression being especially increased as well as a corresponding increased phosphorylation of ZIP7 in EBV-transformed B cells. Accordingly, free zinc levels were elevated within these cells. To prove whether the observed changes resulted from immortalization or rather high proliferation, free zinc levels in in vitro activated B cells and in freshly isolated B cells expressing the activation marker CD69 were determined. Here, comparatively increased zinc levels were found, suggesting that activation and proliferation, but not immortalization, act as crucial factors for the elevation of intracellular free zinc., Graphical abstract B cell activation and proliferation increase intracellular zinc levels. Neoplastic transformation of B cells by Epstein–Barr-Virus transformation increased the intracellular free zinc. However, this is not a part of neoplastic transformation, but a physiological response to B cell activation, since B cells activated by CD40 ligand in vitro, as well as in vivo activated B cells from peripheral blood, indicated by CD69 expression, increased intracellular free zinc. This seems to be mediated by phosphorylation of zinc transporter ZIP7.Unlabelled Image

Table S1. Trial Registration Data. All details pertaining to the Australian New Zealand Clinical Trial Registry are provided in this file. (DOCX 23 kb)

Differential privacy is a promising framework for addressing the privacy concerns in sharing sensitive datasets for others to analyze. However differential privacy is a highly technical area and current deployments often require experts to write code, tune parameters, and optimize the trade-off between the privacy and accuracy of statistical releases. For differential privacy to achieve its potential for wide impact, it is important to design usable systems that enable differential privacy to be used by ordinary data owners and analysts. PSI is a tool that was designed for this purpose, allowing researchers to release useful differentially private statistical information about their datasets without being experts in computer science, statistics, or privacy. We conducted a thorough usability study of PSI to test whether it accomplishes its goal of usability by non-experts. The usability test illuminated which features of PSI are most user-friendly and prompted us to improve aspects of the tool that caused confusion. The test also highlighted some general principles and lessons for designing usable systems for differential privacy, which we discuss in depth., Comment: 17 pages

This report is expected to be published in August 2018

Supplemental material, PQJE_A_1307865_SM2227 for The virtual maze: A behavioural tool for measuring trust by Joanna Hale, Madeleine EM Payne, Kathryn M Taylor, Davide Paoletti and Antonia F De C Hamilton in Quarterly Journal of Experimental Psychology

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of > 1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification., This work was supported by Cancer Research UK (grants C13468/A13982 and C13468/A23536), CRIS Cancer Foundation, Abbie’s Army and the DIPG Collaborative, the Cure Starts Now Foundation, Christopher’s Smile, McKenna Claire Foundation, Lyla Nsouli Foundation, National Institutes of Health (grants R01NS085336 and R01NS091620), The Dragon Master Foundation, The Kortney Rose Foundation, The Musella Foundation For Brain Tumor Research & Information, Gray Matters Foundation, Pediatric Brain Tumor Foundation, and the INSTINCT network funded by The Brain Tumour Charity, Great Ormond Street Children’s Charity, and Children with Cancer UK. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the ICR. LTB was recipient of Sa˜ o Paulo Research Foundation fellowships (2011/08523-7 and 2012/08287-4). This study makes use of data generated by the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project, the Hospital for Sick Children, the McGill University-DKFZ Pediatric Brain Tumor Consortium, the International Cancer Genomics Consortium PedBrain Project and the Cancer Research UK Genomics Initiative (C13468/A14078) and supports the Children’s Brain Tumor Tissue Consortium and The Pacific Pediatric Neuro-Oncology Consortium (PNOC) CAVATICA: Project OPEN DIPG initiative., info:eu-repo/semantics/publishedVersion

Expectant management (EM) reduces overtreatment in low-risk but not intermediate-risk localized prostate cancer (PCa). We assessed the use and predictors of EM to understand its uptake in U.S. practice.Using the U.S. SEER-Medicare database, we conducted a retrospective cohort study of men 66 years and older diagnosed with low-risk (N=25,506) or intermediate-risk (N=25,597) localized PCa between 2004 - 2011 and followed through December 31, 2012. We defined EM as no definitive therapy (DT) and at least one prostate-specific antigen (PSA) test or re-biopsy 4 - 12 months post diagnosis; or receiving DT after PSA testing or re-biopsy 7 - 12 months after diagnosis. We performed separate analyses for low-risk and intermediate-risk groups using multiple logistic regressions.For men diagnosed with PCa in 2004-2011, EM increased from 22% to 43% in the low-risk group and from 15% to 18% in the intermediate-risk group. In the low-risk group, EM increased with patients' age (adjusted odds ratio [aOR] = 1.26 for 71-75 years; 2.21 for 76-80 years; 6.33 for older then 80, p0.0001, compared to 66-70 years). EM uptake was higher among men with comorbidities (aOR=1.29), and residing in the Pacific region (aOR=0.56, compared to the East Coast).In U.S. practice, the utilization of EM steadily increased in low-risk PCa and remained low in the intermediate-risk group over time. While patients with advanced age or comorbidities were more likely to receive EM, its use varied substantially by geographic region. Our findings bring attention to the presence of multiple barriers for EM implementation.

Study Procedures. (DOCX 20 kb)

Title of Dissertation: COMPAÑEROS DEL EXILIO: UNA CARTOGRAFÍA DE RESISTENCIA CULTURAL DESPUÉS DE LA GUERRA CIVIL ESPAÑOLA Kathryn Taylor, Ph.D., 2017 Dissertation directed by: Professor José María Naharro-Calderón, Department of Spanish and Portuguese This dissertation studies the cultural production of three intellectual couples following the Spanish Civil War. Using a variety of genres, my project explores and problematizes traditional approaches to the study of literary and artistic productions in the Post-Civil War period. While previous studies of women’s texts have often been limited to describing feminine difference and noting the oblivion and exclusion of female voices from the canon, I argue that women’s voices need to be considered as part of a larger cultural discourse. By establishing a dialogue among texts created by literary couples, we see the variety and complexity of experiences and responses both during and after the war. Also, while traditional approaches have studied the texts produced in exile separately from those created in Spain, I include texts written in both territorial Spain and exile. Through an examination of responses and strategies of resistance utilized in both spaces, I challenge both the idea that Inner Spain was left with a cultural void after the exodus of 1939, and the myth that there was no communication between the interior and exterior of Spain. The first chapter reconsiders the works of María Teresa León in relation to her husband, Rafael Alberti. León’s literary persona has long been overshadowed by the very public voice of Alberti, and most studies of her work have focused on this fact rather than on her extensive literary production. By looking at a number of texts by León, some of them completely overlooked by the canon, we see themes similar to Alberti’s, particularly a dedication to their political ideals and the future of Spain. In the second chapter, I question the claim that the exodus of Spanish intellectuals at the end of the Civil War left the country devoid of cultural values by studying the works of Rafael Sánchez Ferlosio and Carmen Martín Gaite. The case of Martín Gaite is notable because she achieved more fame and recognition for her work than her spouse. Although she was writing in a very conservative Spain for women, she used strategies of the fantastic to undermine patriarchal domination that clearly influenced her husband’s works. In the final chapter, I examine the work of Jomí García Ascot and María Luisa Elío, who accompanied their parents into exile in Mexico as children. While a common assumption is that they should have adapted perfectly to their new country, the uprootedness of living in exile and a phantom Spain become central themes in both of their works. Their collaboration in the mythical film on exile, En el balcón vacío, portrays the decisive influence of Juan Ramón Jiménez, an exile and inner Spain icon of his own. KEYWORDS: Spain, exile, inner exile, gender, literary couples

Exclusions of home data. (DOCX 21 kb)

Exclusions of home data. (DOCX 21 kb)

Participant Interpretation Chart. (DOCX 13 kb)

Participant Interpretation Chart. (DOCX 13 kb)

There is growing evidence that zinc and its transporters are involved in cell migration during development and in cancer. In the present study, we show that zinc transporter ZIP10 (SLC39A10) stimulates cell motility and proliferation, both in mammalian cells and in the zebrafish embryo. This is associated with inactivation of GSK-3α and -3ß and downregulation of E-cadherin (CDH1). Morpholino-mediated knock-down of zip10 causes delayed epiboly and deformities of the head, eye, heart and tail. Furthermore, zip10 deficiency results in overexpression of cdh1, zip6 and stat3, the latter gene product driving transcription of both zip6 and zip10. The non-reduntant requirement of Zip6 and Zip10 for epithelial to mesenchymal transition (EMT) is consistent with our finding that they exist as a heteromer. We postulate that a subset of ZIPs carrying PrP-like ectodomains, including ZIP6 and ZIP10, are integral to cellular pathways and plasticity programs, such as EMT.

Zinc plays an essential role in the regulation of pancreatic beta cell function, affecting important processes including proinsulin biosynthesis, glucose-stimulated insulin secretion, and cell viability. Mutations in zinc efflux transport protein ZnT8, have been linked with both type 1 and type 2 diabetes, further supporting an important role for zinc in glucose homeostasis. However, very little is known about how cytosolic zinc is controlled by zinc influx proteins (ZIPs). In the current study, we have examined the beta cell and islet ZIP transcriptome and show consistent high expression of ZIP6 (Slc39a6) and ZIP7 (Slc39a7) genes across human, mouse islets and MIN6 beta cells. Modulation of ZIP6 and ZIP7 expression significantly altered cytosolic zinc influx in pancreatic beta cells, indicating an important role for ZIP6 and ZIP7 in regulating cellular zinc homeostasis. Functionally, this deregulated cytosolic zinc homeostasis led to impaired insulin exocytosis and insulin secretion. In parallel studies, we identified both ZIP6 and ZIP7 as potential interacting proteins with GLP-1R by a membrane yeast-two-hybrid (MYTH) assay. Knock-down of ZIP6 but not ZIP7 in MIN6 beta cells impaired the protective effects of GLP-1 on fatty acid-induced cell death possibly via reduced p-ERK pathway. Thus, our data suggests that ZIP6 and ZIP7 function as two important zinc influx transporters to regulate cytosolic zinc concentrations and insulin secretion in beta cells. In particular, ZIP6 is also capable of directly interacting with GLP-1R to facilitate the protective effect of GLP-1 on beta cell survival.

Graphical abstract, Disulfiram, a clinically used alcohol-deterrent has gained prominence as a potential anti-cancer agent due to its impact on copper-dependent processes. Few studies have investigated zinc effects on disulfiram action, despite it having high affinity for this metal. Here we studied the cytotoxic effects of disulfiram in breast cancer cells, and its relationship with both intra and extracellular zinc. MCF-7 and BT474 cancer cell lines gave a striking time-dependent biphasic cytotoxic response between 0.01 and 10 μM disulfiram. Co-incubation of disulfiram with low-level zinc removed this effect, suggesting that availability of extracellular zinc significantly influences disulfiram efficacy. Live-cell confocal microscopy using fluorescent endocytic probes and the zinc dye Fluozin-3 revealed that disulfiram selectively and rapidly increased zinc levels in endo-lysosomes. Disulfiram also caused spatial disorganization of late endosomes and lysosomes, suggesting they are novel targets for this drug. This relationship between disulfiram toxicity and ionophore activity was consolidated via synthesis of a new disulfiram analog and overall we demonstrate a novel mechanism of disulfiram-cytotoxicity with significant clinical implications for future use as a cancer therapeutic.

The study of dopaminergic influences on acetylcholine release is especially useful for the understanding of a wide range of brain functions and neurological disorders, including schizophrenia, Parkinson's disease, Alzheimer's disease, and drug addiction. These disorders are characterized by a neurochemical imbalance of a variety of neurotransmitter systems, including the dopamine and acetylcholine systems. Dopamine modulates acetylcholine levels in the brain by binding to dopamine receptors located directly on cholinergic cells. The dopamine D5 receptor, a D1-class receptor subtype, potentiates acetylcholine release and has been investigated as a possible substrate underlying a variety of brain functions and clinical disorders. This receptor subtype, therefore, may prove to be a putative target for pharmacotherapeutic strategies and cognitive-behavioral treatments aimed at treating a variety of neurological disorders. The present study investigated whether cholinergic cells in the dopamine targeted areas of the cerebral cortex, striatum, basal forebrain, and diencephalon express the dopamine D5 receptor. These receptors were localized on cholinergic neurons with dual labeling immunoperoxidase or immunofluorescence procedures using antibodies directed against choline acetyltransferase (ChAT) and the dopamine D5 receptor. Results from this study support previous findings indicating that striatal cholinergic interneurons express the dopamine D5 receptor. In addition, cholinergic neurons in other critical brain areas also show dopamine D5 receptor expression. Dopamine D5 receptors were localized on the somata, dendrites, and axons of cholinergic cells in each of the brain areas examined. These findings support the functional importance of the dopamine D5 receptor in the modulation of acetylcholine release throughout the brain.

Genes involved in normal developmental processes attract attention as mediators of tumour progression as they facilitate migration of tumour cells. Epithelial-mesenchymal transition (EMT), an essential part of embryonic development, tissue remodelling and wound repair, is crucial for tumour metastasis. Previously zinc transporter ZIP6 (SLC39A6, LIV-1) was linked to EMT in zebrafish gastrulation through a STAT3 mechanism resulting in nuclear localisation of transcription factor Snail. Here we show that zinc transporter ZIP6 is transcriptionally induced by STAT3 and unprecedented among zinc transporters is activated by N-terminal cleavage which triggers ZIP6 plasma membrane location and zinc influx. This zinc influx inactivates GSK-3β, either indirectly or directly via AKT or GSK-3β, respectively, resulting in activation of Snail, which remains in the nucleus and acts as a transcriptional repressor of E-cadherin, CDH1, causing cell rounding and detachment. This was mirrored by ZIP6-transfected cells which underwent EMT, detached from monolayers and exhibited resistance to anoikis by their ability to continue proliferating even after detachment. Our results indicate a causative role for ZIP6 in cell motility and migration, providing ZIP6 as a new target for prediction of clinical cancer spread and also suggesting a ZIP6-dependant mechanism of tumour metastasis.

Background: Pesticide use has been consistently associated with the risk of Parkinson’s disease (PD). While household use of pesticides is widespread, the contribution of household pesticide use to...

UnlabelledChildren and young adults with glioblastoma (GBM) have a median survival rate of only 12 to 15 months, and these GBMs are clinically and biologically distinct from histologically similar cancers in older adults. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A , occurring either at or close to key residues marked by methylation for regulation of transcription—K27 and G34. Here, we show that the cerebral hemisphere-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem-cell maintenance, cell-fate decisions, and self-renewal.Critically, H3F3A G34 mutations cause profound upregulation of MYCN , a potent oncogene that is causative of GBMs when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population through inhibiting kinases responsible for stabilization of the protein.SignificanceWe provide the mechanistic explanation for how the fi rst histone gene mutation inhuman disease biology acts to deliver MYCN, a potent tumorigenic initiator, into a stem-cell compartment of the developing forebrain, selectively giving rise to incurable cerebral hemispheric GBM. Using synthetic lethal approaches to these mutant tumor cells provides a rational way to develop novel and highly selective treatment strategies

BACKGROUND AND OBJECTIVES: Shared decision making (SDM) for prostate cancer screening (PCS) is recommended for physicians and patients due to the uncertainty regarding the risks and benefits of screening. METHODS: We assessed primary care physicians’ attitudes and specific factors that may influence the SDM process, including level of training and practice setting. Participants included academic clinicians (n=16), interns/residents (n=84) and community clinicians (n=35). Physicians completed a 26-item survey that assessed attitudes about the SDM process for PCS. RESULTS: More physicians endorsed SDM (47.4%) or the patient deciding (35.6%), while few physicians wanted to decide for their patients about screening. However, 54.8% endorsed an annual PSA as the standard of care. Most felt that decisions should be based on full disclosure of the risks and benefits of testing (93.3%), and few believed that the sensitivity and specificity of the PSA was adequate (36.6%). Across all physicians, lack of time, competing health demands, malpractice fears, and patient interest were all commonly cited as potential factors that influence the SDM process. Compared to academic clinicians and interns/residents, community clinicians were more likely to endorse annual screening, to be concerned about malpractice, and to agree that PSA sensitivity and specificity are acceptable. CONCLUSIONS: Our findings demonstrate physician, patient and systemic factors regarding the PCS decision. Further effort is needed to overcome the barriers of engaging patients in SDM if we want to truly promote effective SDM for PCS, as espoused by national guidelines.

Despite its common application and widely reported health benefits, walking, in relation to pace and intensity, is under-researched. Few studies have addressed whether people normally walk at a pace which meets the public health recommendations for moderate intensity physical activity (1.34-1.79 ms-1) and there is no known research on individuals’ perceptions of factors which influence walking pace. This study aimed to objectively assess if participants were reaching the pace required for moderate intensity physical activity during ‘normal’ walking. This was examined via a Global Positioning System (GPS) over a 1 km outdoor walk and a timed 150 m trial. In both tests participants (n=10, 3 men, 7 women mean age 54 years (SD 8 years)) were instructed to walk at their ‘normal’ pace. Through short interviews, the study also investigated the factors that participants thought influenced their pace. All participants successfully walked at a pace considered as moderate intensity (≥1.34ms-1). Height was significantly correlated with ‘normal’ walking pace,. The interviews provided an in depth insight into factors that affect walking pace; ground surface and footwear were mentioned frequently and the influence of the weather provided conflicting views, prompting a need for further research in the area. The GPS device showed enormous potential as a human locomotion measurement tool, enabling participants to walk unobstructed and unobserved in an outdoor setting, making the results relevant to real life situations.

This dissertation describes the use of several different types of nanoparticles for biomedical applications including imaging, drug delivery, and sensing. Several novel contrast agents for magnetic resonance imaging have been developed using different nanoparticle platforms. First, highly efficient T1-weighted contrast agents were developed using mesoporous silica nanoparticles. This system was also extended to form a biodegradable contrast agent based on the same mesoporous silica nanoparticle platform. By incorporating paramagnetic metal ions Gd3+ and Mn2+ into nanoscale metal-organic frameworks, new contrast agents for magnetic resonance imaging have also been developed. All of these systems can also be modified to include either an organic fluorophore or luminescent lanthanide ion, forming multimodal contrast agents that can be used for both optical and magnetic resonance imaging. The use of nanoscale metal-organic frameworks for drug delivery will also be presented. Highly porous nanoscale metal-organic frameworks were synthesized using Fe 3+ and an organic bridging ligand. After the nanoparticles were synthesized, a platinum based anticancer drug was covalently attached to the porous framework. These nanoparticles have also been functionalized with organic fluorophores to create optical contrast agents. Finally, the use of a nanoparticle sensor for the detection of dipicolinic acid, a chemical marker for bacterial endospores (such as Anthrax), is demonstrated. Several different nanoparticle sensors were developed, and they are advantageous over the molecular complexes because they allow for the incorporation of an internal standard, which eliminates the need for instrument specific calibration curves.

Fourteen Prunus rootstock cultivars and selections budded with either ‘Redtop’, ‘Redhaven’ or ‘Cresthaven’ peach were planted at 10 locations in North America in 2001 in a randomized block design with a tree spacing of 5 by 6 m and 8 replicates. This test planting was a NC-140 Cooperative Regional Rootstock Project (www.nc140.org). There were 14 rootstocks total, which included three peach seedling rootstocks: Lovell, Bailey, and Guardian® BY520-9 [selection SC-17]. Clonal rootstocks included peach x almond hybrids BH-4 and SLAP (Cornerstone); peach x plum hybrids K146-43 (Controller 5), K146-44, and P30-135 (Controller 9); interspecific plum hybrids Hiawatha, Jaspi and Julior; interspecific Prunus hybrids Cadaman® and VVA-1 (Krymsk® 1); and Prunus pumila selection Pumiselect®. The largest trees were from Georgia, Maryland, and South Carolina. BH-4, SLAP, SC-17, Lovell, and Cadaman® were the most vigorous rootstocks. Jaspi, K146-43, K146-44 and VVA-1 were the least vigorous, having trunk circumferences 30-40% smaller than Lovell. No rootstock had a significantly higher survival rate than Lovell at all locations. Julior, Jaspi, and VVA-1 had significantly more root suckers. Cumulative fruit yields were highest on the peach seedling, peach x almond, and Cadaman® rootstocks. Lowest cumulative yields were from trees on Jaspi, VVA-1, and K146-44 rootstocks. Fruit weight was significantly larger on BH-4, SLAP and Bailey rootstocks. Bailey and Jaspi had the highest and... [to full text] 2001 m. ‘Redtop’, ‘Redhaven’ arba ‘Cresthaven’ veislių persikų vaismedžiai su keturiolika Prunus poskiepių ir selekcinių numerių buvo pasodinti dešimtyje Šiaurės Amerikos vietovių. Bandymas įrengtas 8 atsitiktine tvarka parinktų blokų pakartojimais, vaismedžių sodinimo schema – 5 x 6 m. Tyrimas buvo NC-140 kooperacinio regioninio poskiepių projekto dalis (www.nc140.org). Tirti sėkliniai persikų poskiepiai Lovell, Bailey, ir Guardian® BY520-9 (selekcinis Nr. SC-17), kloniniai poskiepiai BH-4 ir SLAP (Cornerstone) (persiko ir migdolo hibridai), K146-43 (Controller 5), K146-44 ir P30-135 (Controller 9) (persiko ir slyvos hibridai), Hiawatha, Jaspi ir Julior (tarprūšiniai slyvų hibridai), Cadaman® ir VVA-1 (Krymsk® 1) (tarprūšiniai Prunus hibridai) bei Pumiselect® (Prunus pumila). Augiausi vaismedžiai buvo Džordžijoje, Merilende ir Pietų Karolinoje, augiausi poskiepiai ��� BH-4, SLAP, SC-17, Lovell, ir Cadaman®. Mažiausiai augūs buvo Jaspi, K146-43, K146-44 ir VVA-1 poskiepiai. Vaismedžių su šiais poskiepiais kamienų skersmuo buvo 30–40% mažesnis negu su Lovell. Visose vietovėse daugiausia vaismedžių išgyveno su Lovell poskiepiu. Julior, Jaspi ir VVA-1 poskiepiai išaugino daugiausia šaknų atžalų. Didžiausią suminį derlių davė vaismedžiai su persikų sėjinukais, persiko ir migdolo hibridais ir Cadaman®, mažiausią – su Jaspi, VVA-1 ir K146-44. Didžiausius vaisius išaugino vaismed��iai su BH-4, SLAP ir Bailey poskiepiais. Produktyviausi buvo vaismedžiai su Bailey poskiepiu... [toliau žr. visą tekstą]

A number of international studies reveal high prevalence rates of posttraumatic stress disorder (PTSD) within homeless populations. Recent research on PTSD indicates that cognitive responses to trauma are critical in determining who develops the disorder. In Australia, a number of studies indicate exceptionally high rates of trauma experience among homeless adults, yet PTSD has not been investigated in this cohort. Therefore, the primary aim of this project was to improve understanding of PTSD and related cognitions in a sample of homeless adults in Sydney. The project attempts to determine the prevalence of PTSD and its onset in relation to homelessness (Study One) and also explores the role of cognitions in PTSD (Study Two). The sample consisted of seventy homeless men and women aged 18 to 73 years, who were randomly sampled through eight homeless services. A computer-assisted face-to-face structured clinical interview was conducted for each participant. The majority of the sample stated that they had experienced at least one traumatic event in their lifetime (98.2%). The twelve-month prevalence of PTSD was higher among homeless adults in Sydney in comparison to the Australian general population (41.1% versus 1.5%). In 59.1% of cases, the onset of PTSD was found to have occurred before the age of the first reported homeless episode. In a comparison of those with and without a current diagnosis of PTSD, it was found that those with PTSD scored significantly higher overall on measures of posttraumatic cognitions and early maladaptive schemas. In particular, this group scored higher on schemas that centre on the world being entirely dangerous and the self being totally inept. A mediational analysis showed that when trauma and mental health care were controlled, the relationship between early maladaptive schemas and PTSD symptom severity was mediated by posttraumatic cognitions. It was concluded that homeless adults in Sydney frequently experience trauma and PTSD, which typically precedes homelessness. It was also concluded that among homeless adults, posttraumatic cognitions and early maladaptive schemas appear to play an important role in PTSD and may be associated with symptom severity. These findings have implications for public policy on homelessness and mental health, homeless service provision, PTSD theory, and PTSD treatment for homeless adults.

The shift in the balance between the primary, secondary and tertiary levels of the National Health Service is an established trend in health care. This has been motivated by various factors, including the desire to improve access to services. However, service shifts can stimulate further demand and thus undermine efforts to improve services overall. There is a need for "joined-up thinking" in respect of service shifts since existing analyses have been limited to isolated parts of the system, and little attention has been given to the actual mechanisms of the feedback or knock-on effects. The model-based methodology of system dynamics could be useful as it is designed for the study of the connections between different parts of systems and feedback effects. This thesis assesses the usefulness of system dynamics as a planning and evaluation tool for service shifts. A case study approach is followed, based upon a shift in cardiac catheterisation services from the established tertiary level to the secondary level involving three hospitals in England. The factors involved in service shifts are described, and the processes and causative forces at play across the different health service boundaries are captured by means of the system dynamics-based model procedure. The study reveals several interacting feedback mechanisms underlying changes in demand. It also demonstrates that by understanding the feedback structure, "joined-up solutions to joined-up problems" may be designed. For example, a more effective policy would be the service shift (to improve access) combined with the use of clinical guidelines (to suppress demand) and with changes to the forces that drive activity rates (to ensure that both the average waiting time and the waiting list length are controlled), In feedback terms, using clinical guidelines weakens existing feedback mechanisms whilst changing the forces that drive activity rates creates new feedback mechanisms.

Nine human mucin genes have been described, which express glycoproteins MUCJ,2,3,4 ,5AC,5B,6, 7, and 8 in various tissues. It has been shown that different mucins are expressed in various gastric disease states as compared to the normal. In this study histochemical and immunohistochemical methods were used to determine the type of mucin and the pattern of staining in 54 patients with a variety of gastric conditions [i.e. normal controls, foetal stomachs, chronic active gastritis, low grade dysplasia, intestinal metaplasia (associated with gastritis, benign ulcers, dysplasia and cancer), early and advanced intestinal type adenocarcinoma, and diffuse adenocarcinoma]. MUCJ-7 antibodies were used in the study, this being the first study to all assess seven MUC antibodies in the various conditions. It is also the first study to assess the pattern of mucin staining in foetal stomachs. Normal controls were immunoreactive for MUC4, 5 and 6, and gastritis specimens showed similar results, although the latter showed more MUCJ immunoreactivity. Whereas early foetal stomach showed no MUC immunoreactivity, MUC4, 5 and 6 were present from the early second trimester onwards. There was no significant difference between dysplasia and intestinal metaplasia, both categories showing expression of MUC2 and 3 predominantly. Early intestinal type adenocarcinomas did not show any mucins in the majority of cases. Advanced intestinal type adenocarcinomas showed immunoreactivity predominantly for MUCJ, 5 and 6, as well as MUC2 in some cases. Diffuse adenocarcinomas showed strong positive MUC2 and MUC6 staining, and in some cases MUC5 and 7. In conclusion this study has shown different patterns of mucin immunoreactivity in various gastric disease states. Specimens with dysplasia, intestinal metaplasia, late intestinal type adenocarcinoma and diffuse gastric cancer were characterized by increased diversity of mucin gene expression, whereas early intestinal cancer showed loss of mucin immunoreactivity.

Supplemental Material, 847422_Supplementary_materials for Cognitive Behavioural Therapy for Nightmares for Patients with Persecutory Delusions (Nites): An Assessor-Blind, Pilot Randomized Controlled Trial by Bryony Sheaves, Emily A. Holmes, Stephanie Rek, Kathryn M. Taylor, Alecia Nickless, Felicity Waite, Anne Germain, Colin A. Espie, Paul J. Harrison, Russell Foster and Daniel Freeman in The Canadian Journal of Psychiatry

This thesis presents an investigation into the influence of magnetic cohesion on the stability of granular slopes. We consider magnetic cohesion that results from the interaction between dipole moments induced in grains by a uniform magnetic field. The repose angle of spheres is known to increase much more slowly with magnetic cohesion than in experiments with liquid-bridge cohesion. To our knowledge, nowhere in the literature has anyone offered a satisfactory explanation of this discrepancy. Our two-dimensional molecular dynamics simulations of granular piles show that shear occurs deep in the pile. The addition of a magnetic field causes the motion to shift farther down into the pile, preventing the angle from increasing substantially. We investigate different models of wall friction, and discover that wall interactions have a significant influence on the rate of increase of the slope angle with magnetic cohesion. In three-dimensional simulations we observe an initial decrease in the repose angle as the cohesion is increased, contrary to expectations. We explain this effect by considering how the transverse magnetic force influences the particle distribution of the pile. In contrast, draining-crater experiments reveal that the angle of repose of diamagnetic bismuth grains increases dramatically with cohesion in a vertical field. We argue that this difference is due to the non-spherical shape of the grains, and investigate further the influence of grain shape by using non-magnetic `voids' of different shapes in a paramagnetic solution. We discover a strong positive correlation between the grain aspect ratio and the size of the effect of magnetic cohesion on the slope angle. This is because a non-spherical grain accumulates magnetic charge on sharp edges and corners, increasing the magnetic field in its immediate vicinity and leading to stronger interactions with neighbouring grains. Also, in piles of grains with larger aspect ratios, avalanches occur closer to the surface, thus increasing the stability of the pile.

Supplemental Material, 847422_Supplementary_materials for Cognitive Behavioural Therapy for Nightmares for Patients with Persecutory Delusions (Nites): An Assessor-Blind, Pilot Randomized Controlled Trial by Bryony Sheaves, Emily A. Holmes, Stephanie Rek, Kathryn M. Taylor, Alecia Nickless, Felicity Waite, Anne Germain, Colin A. Espie, Paul J. Harrison, Russell Foster and Daniel Freeman in The Canadian Journal of Psychiatry

Supplemental Material, 847422_Supplementary_materials for Cognitive Behavioural Therapy for Nightmares for Patients with Persecutory Delusions (Nites): An Assessor-Blind, Pilot Randomized Controlled Trial by Bryony Sheaves, Emily A. Holmes, Stephanie Rek, Kathryn M. Taylor, Alecia Nickless, Felicity Waite, Anne Germain, Colin A. Espie, Paul J. Harrison, Russell Foster and Daniel Freeman in The Canadian Journal of Psychiatry

Highlights • There is no licensed vaccine to prevent severe disease caused by respiratory syncytial virus (RSV) infection. • RSV is a major cause of hospitalisation and death in the elderly. • The novel viral-vectored vaccines PanAd3-RSV and MVA-RSV appeared safe and boosted both humoral and cellular RSV-specific immune responses in healthy older adults. • The magnitude of immune responses to vaccination appeared similar to what was observed in younger adults., Objectives Respiratory syncytial virus (RSV) causes respiratory infection across the world, with infants and the elderly at particular risk of developing severe disease and death. The replication-defective chimpanzee adenovirus (PanAd3-RSV) and modified vaccinia virus Ankara (MVA-RSV) vaccines were shown to be safe and immunogenic in young healthy adults. Here we report an extension to this first-in-man vaccine trial to include healthy older adults aged 60–75 years. Methods We evaluated the safety and immunogenicity of a single dose of MVA-RSV given by intra-muscular (IM) injection (n = 6), two doses of IM PanAd3-RSV given 4-weeks apart (n = 6), IM PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), intra-nasal (IN) spray of PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), or no vaccine (n = 6). Safety measures included all adverse events within one week of vaccination and blood monitoring. Immunogenicity measures included serum antibody responses (RSV- and PanAd3-neutralising antibody titres measured by plaque-reduction neutralisation and SEAP assays, respectively), peripheral B-cell immune responses (frequencies of F-specific IgG and IgA antibody secreting cells and memory B-cells by ex vivo and cultured dual-colour ELISpot assays respectively), and peripheral RSV-specific T-cell immune responses (frequencies of IFNγ-producing T-cells by ex vivo ELISpot and CD4+/CD8+/Tfh-like cell frequencies by ICS/FACS assay). Results The vaccines were safe and well tolerated. Compared with each individual baseline immunity the mean fold-changes in serum RSV-neutralising antibody, appearance and magnitude of F-specific IgG and IgA ASCs and expansion of CD4+/CD8+ IFNγ-producing T-cells in peripheral circulation were comparable to the results seen from younger healthy adults who received the same vaccine combination and dose. There were little/no IgA memory B-cell responses in younger and older adults. Expansion of IFNγ-producing T-cells was most marked in older adults following IM prime, with balanced CD4+ and CD8+ T cell responses. The RSV-specific immune responses to vaccination did not appear to be attenuated in the presence of PanAd3 (vector) neutralising antibody. Conclusions PanAd3-RSV and MVA-RSV was safe and immunogenic in older adults and the parallel induction of RSV-specific humoral and cellular immunity merits further assessment in providing protection from severe disease.