Search

Tumor-initiating cells (TIC) are critical yet evasive targets for the development of more effective antitumoral strategies. The cell surface marker CD133 is frequently used to identify TICs of various tumor entities, including hepatocellular cancer and glioblastoma. Here, we describe oncolytic measles viruses (MV) retargeted to CD133. The viruses, termed MV-141.7 and MV-AC133, infected and selectively lysed CD133+ tumor cells. Both viruses exerted strong antitumoral effects on human hepatocellular carcinoma growing subcutaneously or multifocally in the peritoneal cavity of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Notably, the CD133-targeted viruses were more effective in prolonging survival than the parental MV-NSe, which is currently assessed as oncolytic agent in clinical trials. Interestingly, target receptor overexpression or increased spreading kinetics through tumor cells were excluded as being causative for the enhanced oncolytic activity of CD133-targeted viruses. MV-141.7 was also effective in mouse models of orthotopic glioma tumor spheres and primary colon cancer. Our results indicate that CD133-targeted measles viruses selectively eliminate CD133+ cells from tumor tissue, offering a key tool for research in tumor biology and cancer therapy. Cancer Res; 73(2); 865–74. ©2013 AACR.

The genomic landscape of divergence-the distribution of differences among populations or species across the genome-is increasingly characterized to understand the role that microevolutionary forces such as natural selection and recombination play in causing and maintaining genetic divergence. This line of inquiry has also revealed chromosome structure variation to be an important factor shaping the landscape of adaptive genetic variation. Owing to a high prevalence of chromosome structure variation and the strong pressure for local adaptation necessitated by their sessile nature, bivalve molluscs are an ideal taxon for exploring the relationship between chromosome structure variation and local adaptation. Here, we report a population genomic survey of king scallop (

Funding: This study was initiated as part of the European Marine Biological Research Infrastructure Cluster (EMBRIC) project funded by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 654008. The genomic landscape of divergence—the distribution of differences among populations or species across the genome—is increasingly characterized to understand the role that microevolutionary forces such as natural selection and recombination play in causing and maintaining genetic divergence. This line of inquiry has also revealed chromosome structure variation to be an important factor shaping the landscape of adaptive genetic variation. Owing to a high prevalence of chromosome structure variation and the strong pressure for local adaptation necessitated by their sessile nature, bivalve molluscs are an ideal taxon for exploring the relationship between chromosome structure variation and local adaptation. Here, we report a population genomic survey of king scallop (Pecten maximus) across its natural range in the northeastern Atlantic Ocean, using a recent chromosome-level genome assembly. We report the presence of at least three large (12–22 Mb), putative chromosomal inversions associated with sea surface temperature and whose frequencies are in contrast to neutral population structure. These results highlight a potentially large role for recombination-suppressing chromosomal inversions in local adaptation and suggest a hypothesis to explain the maintenance of differences in reproductive timing found at relatively small spatial scales across king scallop populations. Publisher PDF

Background Cardiovascular disease (CVD) is a major cause of morbidity and mortality in Canada. Assessment and management of CVD risk is essential in reducing disease burden. This includes both clinical risk factors and socioeconomic factors, though few studies report on socioeconomic status in relation to CVD risk and treatment. The primary objective of this study was to estimate the cardiovascular risk of patients attending primary care practices across Canada; secondly, to evaluate concordance with care indicators suggested by current clinical practice guidelines for statin prescribing according to patients’ cardiovascular risk and socioeconomic status. Methods This cross-sectional observational study used the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) database, which is comprised of clinical data from primary care electronic medical records. Patients aged 35-75y with at least one visit to their primary care provider between 2012 and 2016 were included. Patients were assigned to a CVD risk category (high, medium, low) and a deprivation quintile was calculated for those with full postal code available. Descriptive analyses were used to determine the proportion of patients in each risk category. Logistic regression was used to evaluate the consistency of statin prescribing according to national clinical guidelines by risk category and deprivation quintile. Results A total of 324,526 patients were included. Of those, 116,947 (36%) of patients were assigned to a high CVD risk category, primarily older adults, males, and those with co-morbidities. There were statistically significant differences between least (quintile 1) and most (quintile 5) deprived socioeconomic quintiles, with those at high CVD risk disproportionately in Q5 (odds ratio 1.4). Overall, 48% of high-risk patients had at least one statin prescription in their record. Patients in the lower socioeconomic groups had a higher risk of statin treatment which deviated from clinical guidelines. Conclusions Primary care patients who are at high CVD risk are more often male, older, have more co-morbidities and be assigned to more deprived SES quintiles, compared to those at low CVD risk. Additionally, patients who experience more challenging socioeconomic situations may be less likely to receive CVD treatment that is consistent with care guidelines.

Chimeric antigen receptor (CAR)-modified T cells have revealed promising results in the treatment of cancer, but they still need to overcome various hurdles, including a complicated manufacturing process. Receptor-targeted lentiviral vectors (LVs) delivering genes selectively to T cell subtypes may facilitate and improve CAR T cell generation, but so far they have resulted in lower gene delivery rates than conventional LVs (vesicular stomatitis virus [VSV]-LV). To overcome this limitation, we studied the effect of the transduction enhancer Vectofusin-1 on gene delivery to human T cells with CD4- and CD8-targeted LVs, respectively, encoding a second-generation CD19-CAR in conjunction with a truncated version of the low-affinity nerve growth factor receptor (ΔLNGFR) as reporter. Vectofusin-1 significantly enhanced the gene delivery of CD4- and CD8-LVs without a loss in target cell selectivity and killing capability of the generated CAR T cells. Notably, delivery rates mediated by VSV-LV were substantially reduced by Vectofusin-1. Interestingly, a transient off-target signal in samples treated with Vectofusin-1 was observed early after transduction. However, this effect was not caused by uptake and expression of the transgene in off-target cells, but rather it resulted from cell-bound LV particles having ΔLNGFR incorporated into their surface. The data demonstrate that gene transfer rates in the range of those mediated by VSV-LVs can be achieved with receptor-targeted LVs. Keywords: transduction enhancer, Vectofusin-1, receptor-targeted viral vectors, LV, Δ, LNGFR, protein transfer

A sizeable body of work has demonstrated that participants have the capacity to show substantial increases in performance on perceptual tasks given appropriate practice. This has resulted in significant interest in the use of such perceptual learning techniques to positively impact performance in real-world domains where the extraction of perceptual information in the service of guiding decisions is at a premium. Radiological training is one clear example of such a domain. Here we examine a number of basic science questions related to the use of perceptual learning techniques in the context of a radiology-inspired task. On each trial of this task, participants were presented with a single axial slice from a CT image of the abdomen. They were then asked to indicate whether or not the image was consistent with appendicitis. We first demonstrate that, although the task differs in many ways from standard radiological practice, it nonetheless makes use of expert knowledge, as trained radiologists who underwent the task showed high (near ceiling) levels of performance. Then, in a series of four studies we show that (1) performance on this task does improve significantly over a reasonably short period of training (on the scale of a few hours); (2) the learning transfers to previously unseen images and to untrained image orientations; (3) purely correct/incorrect feedback produces weak learning compared to more informative feedback where the spatial position of the appendix is indicated in each image; and (4) there was little benefit seen from purposefully structuring the learning experience by starting with easier images and then moving on to more difficulty images (as compared to simply presenting all images in a random order). The implications for these various findings with respect to the use of perceptual learning techniques as part of radiological training are then discussed.

A domain that is often neglected in the assessment of chimeric antigen receptor (CAR) functionality is the extracellular spacer module. However, several studies have elucidated that membrane proximal epitopes are best targeted through CARs comprising long spacers, while short spacer CARs exhibit highest activity on distal epitopes. This finding can be explained by the requirement to have an optimal distance between the effector T cell and target cell. Commonly used long spacer domains are the CH2-CH3 domains of IgG molecules. However, CARs containing these spacers generally show inferior in vivo efficacy in mouse models compared to their observed in vitro activity, which is linked to unspecific Fcγ-Receptor binding and can be abolished by mutating the respective regions. Here, we first assessed a CAR therapy targeting membrane proximal CD20 using such a modified long IgG1 spacer. However, despite these mutations, this construct failed to unfold its observed in vitro cytotoxic potential in an in vivo model, while a shorter but less structured CD8α spacer CAR showed complete tumor clearance. Given the shortage of well-described long spacer domains with a favorable functionality profile, we designed a novel class of CAR spacers with similar attributes to IgG spacers but without unspecific off-target binding, derived from the Sialic acid-binding immunoglobulin-type lectins (Siglecs). Of five constructs tested, a Siglec-4 derived spacer showed highest cytotoxic potential and similar performance to a CD8α spacer in a CD20 specific CAR setting. In a pancreatic ductal adenocarcinoma model, a Siglec-4 spacer CAR targeting a membrane proximal (TSPAN8) epitope was efficiently engaged in vitro, while a membrane distal (CD66c) epitope did not activate the T cell. Transfer of the TSPAN8 specific Siglec-4 spacer CAR to an in vivo setting maintained the excellent tumor killing characteristics being indistinguishable from a TSPAN8 CD8α spacer CAR while outperforming an IgG4 long spacer CAR and, at the same time, showing an advantageous central memory CAR T cell phenotype with lower release of inflammatory cytokines. In summary, we developed a novel spacer that combines cytotoxic potential with an advantageous T cell and cytokine release phenotype, which make this an interesting candidate for future clinical applications.

The so-called 'fatal five' behaviours (drink and drug driving, distraction and inattention, speeding, fatigue, and failure to wear a seat belt) are known to be the major behavioural contributory factors to road trauma. However, little is known about the factors that lead to drivers engaging in each behaviour. This article presents the findings from a study which collected and analysed data on the factors that lead to drivers engaging in each behaviour. The study involved a survey of drivers' perceptions of the causes of each behaviour and a subject matter expert workshop to gain the views of road safety experts. The results were mapped onto a systems ergonomics model of the road transport system in Queensland, Australia, to show where in the system the factors reside. In addition to well-known factors relating to drivers' knowledge, experience and personality, additional factors at the higher levels of the road transport system related to road safety policy, transport system design, road rules and regulations, and societal issues were identified. It is concluded that the fatal five behaviours have a web of interacting contributory factors underpinning them and are systems problems rather than driver-centric problems. The implications for road safety interventions are discussed.

Economical design of Ground Heat Exchangers (GHEs) relies significantly on accurate estimations of ground thermal properties, including undisturbed ground temperature, ground thermal conductivity, and GHE thermal resistance. Typically these are measured in situ by a Thermal Response Test (TRT), where the parameters are back-calculated by fitting a heat transfer model to the temperature response. The accuracy of most models relies on an assumption of constant ground temperature with depth, but in reality there are several mechanisms by which this may be invalid, one being seasonal variation in ground temperature. In this paper a study of Infinite Line Source Model performance under different seasonal conditions using a Finite Element model is presented. The study aims to determine the robustness of interpretation of TRTs conducted at different times of the year and the sensitivity of the effect's key influencing variables. Results suggest that there is little variability in effective thermal conductivity but some variation in GHE thermal resistance. A dimensionless parameter was derived and found to be strongly linearly related to the difference in GHE thermal resistance, leading to generalized estimates of the potential impact on design length that were greater than 10% under relatively extreme conditions and for short GHEs.

Closed loop ground-source heat pump (GSHP) systems use ground heat exchangers (GHEs) to transfer heat to and from the ground and efficiently provide clean and renewable energy for heating and cooling purposes. Vertical GHEs contain pipes with circulating fluid (loops), which transfer thermal energy between the ground and the fluid. One very common assumption made in designing GSHP systems is that, when installed, these loops remain evenly separated along the length of the GHE, something that due to the nature of construction is rarely true. This can result in thermal interference not accounted for in the design, leading to a potential negative impact on the performance of the system. This paper investigates the effect of this interference, using detailed numerical simulations to compare different geometries, modelling fixed and variable pipe separations. A comprehensive parametric analysis is conducted to identify some of the most influential design parameters and the potential consequences on running and capital costs. Amongst the key findings of this study is the importance of the borehole filling material, as a highly thermally conductive material can minimise these negative effects from the thermal interference by up to 60%. Moreover, potential increases in drilling (capital) costs of up to 24% are shown, while the potential increases in running costs due to the reduced efficiency were found to be relatively minor.

This work received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland) and their support is gratefully acknowledged. MASTS is funded by the Scottish Funding Council (grant reference HR09011) and contributing institutions. Much attention has been given to insulin-like growth factor (Igf) pathways that regulate the balance of skeletal muscle protein synthesis and breakdown in response to a range of extrinsic and intrinsic signals. However, we have a less complete understanding of how the same signals modulate muscle mass upstream of such signalling, through a family of functionally-diverse Igf-binding proteins (Igfbps) that modify the availability of Igfs to the cell receptor Igf1r. We exposed cultured myotubes from Atlantic salmon (Salmo salar L.) to treatments recapturing three catabolic signals: inflammation (interleukin-1β), stress (dexamethasone) and fasting (amino acid deprivation), plus one anabolic signal: recovery of muscle mass post-fasting (supplementation of fasted myotubes with Igf-I and amino acids). The intended phenotype of treatments was confirmed by significant changes in myotube diameter and immunofluorescent staining of structural proteins. We quantified the mRNA-level regulation of the full expressed Igf and Igfbp gene complement across a post-treatment time course, along with marker genes for muscle structural protein synthesis, as well as muscle breakdown, via the ubiquitin-proteasome and autophagy systems. Our results highlight complex, non-overlapping responses of Igfbp family members to the different treatments, suggesting that the profile of expressed Igfbps is differentially regulated by distinct signals promoting similar muscle remodelling phenotypes. We also demonstrate divergent regulation of salmonid-specific gene duplicates of igfbp5b1 and igfbp5b2 under distinct catabolic and anabolic conditions. Overall, this study increases our understanding of the regulation of Igfbp genes in response to signals that promote remodelling of skeletal muscle. Postprint

This study assesses some economic indicators for residential vertical Ground Source Heat Pump (GSHP) systems in Melbourne, Australia. Publicly available data on the performance and costs associated with such systems is rare. To redress this issue, detailed cost breakdowns are reported herein based on actual installation costs. The average upper bound capital cost is found to be around AUD 31,000, with lower costs possible depending on many factors, particularly when considering the early stage of development of the GSHP industry in Australia. Using the gathered cost data as well as other performance data such as recorded average coefficients of performance of 3.8 and 3.6 for heating and cooling respectively, several economic indicators are used to evaluate alternative heating/cooling systems. The analyses found that for a design life of 20 years, an Air Source Heat Pump (ASHP) system is marginally more financially attractive than a GSHP system; however, for a design life of 40 years, GSHP system provide considerably more savings than other alternatives including ASHP systems. The relatively low rate of return for GSHP systems over the first 20 years is due to current high capital costs as well as the mild weather conditions in Melbourne. Climate change was also factored into the economic analyses, with only minor effects observed. Finally, a scenario with government incentives was found to make GSHP systems much more financially attractive, a tax credit on capital cost of as low as 8% was found as such threshold for a design life of 20 years.

The data reported in this article presents actual installation costs and performance data for a selection of residential Ground Source Heat Pump (GSHP) systems in Melbourne, Australia. The installation cost data includes five main cost components: ground loop installation, head pipe installation, heat pump, mechanical room installation, and fittings. The performance data presented here includes timestamp, air temperature and thermal loading. A more comprehensive analysis of this data may be obtained from the article entitled “Economic analysis of vertical ground source heat pump systems in Melbourne” (Q. Lu, G.A. Narsilio, G.R. Aditya, I.W. Johnston, 2017) [1].

Over the past thirty years, research situated in many individual sub-domains of psychology has investigated the potential impact of video game play on behavior. Interestingly, although researchers in the various sub-fields are (presumably) versed in the results of the published research, there nonetheless remain significant individual differences in opinion across researchers regarding what exactly the given literatures “say.” Previous work has suggested that some individual difference factors, such as prior gaming experience, can account for some of this variance. The current study expands this work by examining several additional individual difference factors including field of study (e.g., whether one primarily studies links between video games and aggression, cognitive skill, or well-being) and video game knowledge. Both types of individual differences were associated with differences in belief regarding the state of the literature. In particular, video game knowledge was negatively associated with the belief that video games can lead to addiction and cause aggression and violence, and higher knowledge scores were positively associated with a belief that games can model prosocial behavior. Results are presented in a larger discussion of how researchers’ primary domains of knowledge influence the study of technology of effects, such as those from video game play.

Ground source heat pump (GSHP) systems have the potential to reduce the carbon dioxide footprint of buildings by providing them with sustainable heating and cooling energy from the ground at shallow depths. The financial viability of these systems depends on the adequate sizing of the ground heat exchangers (GHEs), which generally contribute the most to the overall capital costs of GSHP systems. Consideration of the uncertainties in the design of GHEs has the potential to improve GHE design by increasing the confidence in sizing GHEs for particular applications. This paper proposes a methodology for the estimation of the uncertainty in the design length of GHEs by considering the uncertainties involved with the selection of design parameters. By using the proposed methodology, a case study is presented where borehole GHEs are sized following a commonly applied design process recommended in the American Society of Heating, Refrigerating, and Air-Conditioning Engineers (Ashrae) handbook. The uncertainty in the resulting length of GHEs is estimated, and the sensitivity of this uncertainty to the uncertainties in individual design parameters is discussed. In addition, measures to reduce the length uncertainty are considered.

Ground source heat pump (GSHP) systems efficiently heat and cool buildings using geothermal energy accessed via ground heat exchangers (GHEs). The thermal performance of GHEs is usually studied with equivalent groups of linear heat sinks/sources or with more advanced numerical models. In most cases, in regions with common geothermal gradients, the ground temperature is assumed to be constant with depth, a simplification that is reasonable for typical borehole GHEs which are at least 50 m deep. However, the increasing use of piles (and other geo-structures) as GHEs, which are typically shallower than borehole GHEs requires a re-assessment of the thermal effects of the surface air temperature changes on GHEs. This work introduces and addresses such issues using the newly developed 3D detailed numerical model of GHEs and highlights its significant influence on thermal performance. Numerical results show that in the cases studied herein, accounting for the surface air temperature fluctuations may result in up to about 11% shorter GHEs than if these effects are ignored.

Ground source heat pump (GSHP) systems can provide cost effective and sustainable heating and cooling for buildings while using considerably less fossil fuel than conventional heating and cooling systems. This benefit can be further enhanced by adopting hybrid GSHP (HGSHP) systems wherein the GSHP component provides the baseload thermal energy with the balance provided by conventional systems. This study compares the costs of GSHP and HGSHP systems against conventional systems under a variety of climatic conditions, exemplified by those encountered across Australia, but including conditions encountered elsewhere. The results indicate that the comparative performance of GSHP and HGSHP systems depend on many parameters including climatic conditions, ground conditions, drilling prices and prices of electricity and gas in the regions where the systems are installed. Here we show that in general, adopting GSHP or HGSHP systems over conventional systems allow property owners to pay lower lifetime costs under most climatic conditions and gas to electricity energy price ratios. The results also indicate that conventional systems may be preferred in highly heating or cooling dominant climates and at locations with high drilling costs or low energy prices. In contrast, GSHP and HGSHP systems are preferred in locations with a more balanced climate, lower drilling costs and/or higher energy prices. There is no “one size fits all” rule given the many factors that can influence the lifetime costs. The paper shows that climatic conditions, ground conditions, drilling and energy costs must all be carefully considered when assessing the most cost effective sustainable energy technologies for space heating and cooling.

β-Hemoglobinopathies are among the most common single-gene disorders and are caused by different mutations in the β-globin gene. Recent curative therapeutic approaches for these disorders utilize lentiviral vectors (LVs) to introduce a functional copy of the β-globin gene into the patient's hematopoietic stem cells. Alternatively, fetal hemoglobin (HbF) can reduce or even prevent the symptoms of disease when expressed in adults. Thus, induction of HbF by means of LVs and other molecular approaches has become an alternative treatment of β-hemoglobinopathies. Here, we performed a head-to-head comparative analysis of HbF-inducing LVs encoding for: 1) IGF2BP1, 2) miRNA-embedded shRNA (shmiR) sequences specific for the γ-globin repressor protein BCL11A, and 3) γ-globin gene. Furthermore, two novel baboon envelope proteins (BaEV)-LVs were compared to the commonly used vesicular-stomatitis-virus glycoprotein (VSV-G)-LVs. Therapeutic levels of HbF were achieved for all VSV-G-LV approaches, from a therapeutic level of 20% using γ-globin LVs to 50% for both IGF2BP1 and BCL11A-shmiR LVs. Contrarily, BaEV-LVs conferred lower HbF expression with a peak level of 13%, however, this could still ameliorate symptoms of disease. From this thorough comparative analysis of independent HbF-inducing LV strategies, we conclude that HbF-inducing VSV-G-LVs represent a promising alternative to β-globin gene addition for patients with β-hemoglobinopathies.

Self-esteem research generally focuses on the effects of having over pursuing self-esteem, occasionally blurring the distinctions between these separate concepts. Examination of self-esteem’s pursuit has focused on broad summary states (desired self-esteem) and pathological self-esteem pursuit (narcissism), overlooking possible cognitive mechanisms responsible for variance in people’s self-esteem pursuit. We propose that lay-theoretical beliefs about the important benefits of holding positive self-esteem shape self-esteem pursuit, likely encouraged by self-esteem’s frequent identification as a cultural and personal panacea. To explore these ideas, we examined how lay beliefs about self-esteem’s importance, measured by a novel scale of self-esteem importance (SEIS), were related to but distinct from trait self-esteem (having self-esteem), desired self-esteem (an abstract judgment about valuing self-esteem), and narcissism (a pathological “addiction” to self-esteem). Moderate associations between SEIS with these constructs, and the SEIS’s incremental validity beyond them in three open data sets, suggests that self-esteem importance beliefs represent a novel construct.

We examined the possible adaptation of the dwarf Bleke population of Atlantic salmon Salmo salar from Lake Byglandsfjord in southern Norway to limited food resources. The growth performance and muscle development in juvenile Bleke and farmed S. salar under satiated or restricted (50%) feeding were examined for 10 months, starting 3 weeks after first‐feeding stage. Four‐thousand fish were divided into four replicated groups and random samples of 16–40 fish per group were measured six times during the experiment. The two strains showed no significant difference in mean body mass when fed restricted ration, but the individual variation was considerably higher in the farmed fish. Both Bleke and farmed S. salar grew significantly faster when fed to satiation, but the farmed S. salar showed much higher gain in mass and were three times heavier (201.5 g v. 66.7 g) and possessed twice as many fast muscle fibres (179682 v. 84779) compared with landlocked S. salar after 10 months. Farmed fish fed full ration displayed both hypertrophic and hyperplasic muscle growth, while the increased growth in Bleke S. salar was entirely associated with a larger fibre diameter. The landlocked Bleke strain has apparently adapted to low food availability by minimising the metabolic costs of maintenance and growth through reduced dominance hierarchies and by an increase in average muscle fibre diameter relative to the ancestral condition. Postprint

International audience; Cell and gene therapies are finally becoming viable patient treatment options, with both T cell- and hematopoietic stem cell (HSC)-based therapies being approved to market in Europe. However, these therapies, which involve the use of viral vector to modify the target cells, are expensive and there is an urgent need to reduce manufacturing costs. One major cost factor is the viral vector production itself, therefore improving the gene modification efficiency could significantly reduce the amount of vector required per patient. This study describes the use of a transduction enhancing peptide, Vectofusin-1((R)), to improve the transduction efficiency of primary target cells using lentiviral and gammaretroviral vectors (LV and RV) pseudotyped with a variety of envelope proteins. Using Vectofusin-1 in combination with LV pseudotyped with viral glycoproteins derived from baboon endogenous retrovirus, feline endogenous virus (RD114), and measles virus (MV), a strongly improved transduction of HSCs, B cells and T cells, even when cultivated under low stimulation conditions, could be observed. The formation of Vectofusin-1 complexes with MV-LV retargeted to CD20 did not alter the selectivity in mixed cell culture populations, emphasizing the precision of this targeting technology. Functional, ErbB2-specific chimeric antigen receptor-expressing T cells could be generated using a gibbon ape leukemia virus (GALV)-pseudotyped RV. Using a variety of viral vectors and target cells, Vectofusin-1 performed in a comparable manner to the traditionally used surface-bound recombinant fibronectin. As Vectofusin-1 is a soluble peptide, it was possible to easily transfer the T cell transduction method to an automated closed manufacturing platform, where proof of concept studies demonstrated efficient genetic modification of T cells with GALV-RV and RD114-RV and the subsequent expansion of mainly central memory T cells to a clinically relevant dose.

Shallow geothermal technologies have proven to efficiently provide renewable energy for space heating and cooling. Recently, significant attention has been given to utilising sub-surface structures, primarily designed for stability, to also exchange heat with the ground, converting them into energy geo-structures. This research includes investigations into the feasibility of applying this technology to retaining walls, focusing on the usually neglected interaction between the energy retaining wall and the air inside the underground space it contains (e.g., a building basement, a metro station). Even though soldier pile walls are adopted for the study, the results are applicable for any retaining wall type. Two commonly adopted boundary conditions on the surfaces of the underground structure (thermal insulation and a defined temperature) are used as well as the computationally expensive approach of fully modelling the air inside the underground space. The results show that if these boundaries are not carefully considered, a significant amount of heat can flow into/out of the underground space (up to about 75% in this study). Importantly, adopting inappropriate boundary conditions for these surfaces can result in erroneous and misleading results, a potentially under-designed heating, ventilation and air-conditioning (HVAC) system and subsequently thermal discomfort within these spaces.

Ground-source heat pump (GSHP) systems typically show higher efficiencies than conventional systems for space heating and cooling of buildings. However, the availability of GSHP systems performance data is still limited, especially in Australia due to the small number of GSHP systems installed and monitored. This paper provides some initial results from a GSHP systems monitoring project conducted on ten residential properties in the greater Melbourne region of Australia. The data measured reveals an estimated Coefficient of Performance between 2 and 4.9. The reasons for these variations in measured system efficiency with respect to design expectations are discussed.

This research was funded by European Union’s Horizon 2020 research and innovation programme under grant agreement No 654008. Marine environments account for over 90% of the biosphere and hold tremendous potential for biotechnological applications and drug discovery. To fully exploit this potential and develop interesting discoveries into useful molecular tools and successful products, a multidisciplinary approach is indispensable. Here, we introduce the European Marine Biological Research Infrastructure Cluster (EMBRIC), a novel collaborative initiative that aims to facilitate translational marine science and remove existing bottlenecks that are currently impeding blue innovation. In the context of this initiative, pilot projects have been designed to test the functionality of the cluster focusing on two specific sectors of marine biotechnology: (i) the discovery and exploitation of marine natural products and (ii) the marker-assisted selection of desirable traits in aquaculture. EMBRIC brings together the expertise of six European Research Infrastructures on accessing the potential of marine organisms, specifically on the 99% of bacteria yet to be grown in culture, the microalgae, finfish, and shellfish. It improves the throughput and efficiency of workflows for discovery of novel marine products and facilitates projects that require an interdisciplinary approach. The objective is to develop coherent chains of high quality services for access to biological, analytical, and data resources by deploying common underpinning technologies and practices. The connection of academic science with industry is being strengthened by engaging companies, as well as geographically separated public and private-sector communities in the domain of marine biotechnology, and by federating technology transfer services amongst the players involved. Publisher PDF

The dataset in this article is related to shallow geothermal energy systems, which efficiently provide renewable heating and cooling to buildings, and specifically to the performance of the vertical ground heat exchangers (GHE) embedded in the ground. GHEs incorporate pipes with a circulating (carrier) fluid, exchanging heat between the ground and the building. The data show the average and inlet temperatures of the carrier fluid circulating in the pipes embedded in the GHEs (which directly relate to the performance of these systems). These temperatures were generated using detailed finite element modelling and comprise part of the daily output of various one-year simulations, accounting for numerous design parameters (including different pipe geometries) and ground conditions. An expanded explanation of the data as well as comprehensive analyses on how they were used can be found in the article titled “Ground-source heat pump systems: the effect of variable pipe separation in ground heat exchangers” (Makasis N, Narsilio GA, Bidarmaghz A, Johnston IW, 2018) [1].

Marine biotechnology is the key to harness the huge economic potential of the unique biodiversity of marine organisms. This potential remains largely underexploited due to three major issues: (1) lack of connectivity between research services, (2) practical and cultural difficulties in connecting science with industry and (3) uneven regional development and innovation policies throughout Europe. The European Marine Biological Resource Centre (EMBRC) is a distributed Research Infrastructure (RI) with facilities located in renowned marine biological stations and institutes across Europe. On its way to become a European Research Infrastructure Consortium, EMBRC will be the reference RI for marine biology and ecology research. Yet, EMBRC recognizes the necessity to interface with other RIs to enable specialized workflow services in, e.g. chemical biology, bioinformatics and social sciences. The European Marine Biological Research Infrastructure Cluster (EMBRIC, INFRA DEV 4 2014–2015) was designed to connect EMBRC with cognate RI, i.e. MIRRI, EU-OPENSCREEN, ELIXIR and AQUAEXCEL. The cluster combines the RIs services into discovery pipelines through which academic and private research users can run their projects. EMBRIC also relies on the Integrating Activity of RISIS to analyse regional innovation ecosystems in marine biology and ecology and to develop a methodology to measure the impact of the project. The EMBRIC alliance provides workflows on a variety of marine bioresources, a strategy that will boost EMBRC expert centres into regional innovation clusters. This will reconcile the need for marrying scientific and technological excellence with territorial development, resulting in the promotion of the blue bioeconomy.

This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 654008. Accurate parentage assignment is key for the development of a successful breeding program, allowing pedigree reconstruction from mixed families and control of inbreeding. In the present study we developed a workflow for the design of an efficient single nucleotide polymorphism (SNP) panel for paternity assignment and validated it in Atlantic salmon (Salmo salar L.). A total of 86,468 SNPs were identified from Restriction Site Associated DNA Sequencing (RAD-seq) libraries, and reduced to 1517 following the application of quality control filters and stringent selection criteria. A subsample of SNPs were chosen for the design of high-throughput SNP assays and a training set of known parents and offspring was then used to achieve further filtering. A panel comprising 94 SNPs balanced across the salmon genome were identified, providing 100% assignment accuracy in known pedigrees. Additionally, the panel was able to assign individuals to one of three farmed salmon populations used in this study with 100% accuracy. We conclude that the workflow described is suitable for the design of cost effective parentage assignment and traceability tools for aquaculture species. Postprint

Background: Bile acids [BA] are usually reabsorbed by the terminal ileum, but this process is frequently abnormal in Crohn’s disease [CD]. BA malabsorption occurs, and excess colonic BA cause secretory diarrhea. Furthermore, the hormone fibroblast growth factor 19 [FGF19] is synthesized in the ileum in response to BA absorption and regulates BA synthesis. We hypothesized that reduced serum FGF19 levels will be associated with diarrheal symptoms and disease activity in both ileal-resected [IR-CD] and non-resected CD [NR-CD] patients. Methods: Fasting serum FGF19 levels were measured in 58 patients [23 IR-CD patients and 35 NR-CD patients]. Disease activity was assessed using the Harvey Bradshaw Index and C-reactive protein [CRP]. Stool frequency, Bristol Stool Form Scale and length of previous ileal resection were recorded. FGF19 levels were also compared with healthy and diarrhea control patients. Results: FGF19 levels were inversely correlated with ileal resection length in IR-CD patients [r = -0.54, p = 0.02]. In NR-CD patients, median FGF19 levels were significantly lower in patients with active disease compared with inactive disease [103 vs 158 pg/ml, p = 0.04] and in those with symptoms of diarrhea compared with those without [86 vs 145 pg/ml, p = 0.035]. FGF19 levels were inversely correlated with stool frequency, Bristol stool form and CRP in NR-CD patients with ileal disease. Conclusions: Reduced FGF19 levels are associated with ileal resection, diarrhea and disease activity. FGF19 may have utility as a biomarker for functioning ileum in CD. This study supports a potential role of FGF19 in guiding treatments for diarrhea in Crohn’s disease.

Research is beginning to demonstrate the merits of considering the broader road transport system when attempting to understand and prevent road trauma. This study involved the use of Work Domain Analysis, a systems analysis method, to develop a model of a road transport system based on Queensland, Australia. The model was subsequently used to identify the system wide contributory factors that play a role in road crashes, and to identify aspects of road transport systems that could be exploited when developing road safety interventions. The findings show that there are a set of crash contributory factors relating to the raison d'etre, values, and functions of road transport systems. This suggests that further significant reductions in road trauma will only be achieved through fundamental changes to the road transport system itself. Examples discussed include reducing the emphasis on the use of road transport for economic growth, reducing motor vehicle use and increasing active transport modes, and overhauling road safety strategies.

The recent successes in gene therapy for the treatment of rare blood disorders such as primary immunodeficiencies and hemoglobinopathies have highlighted the need to generate robust and scalable manufacturing processes. Here we compare large scale lentiviral transductions of hemopoietic stem cells performed on the CliniMACS Prodigy® to manual processes in terms of efficacy and viability of the end product. In our first series of experiments, we used a low, non-saturating MOI of 30 and the results showed that transduction efficiency on the CliniMACS Prodigy® was significantly increased from an average of 23.3% (manual) to 50.5% (CliniMACS Prodigy®). These results were further confirmed when we employed an MOI of 100 and showed that the average transduction efficiency was 74% from the CliniMACS Prodigy® compared to 54.1% from the manual steps. Moreover, the total viability of the cells cultured on the CliniMACS Prodigy® remained unaffected after two days of cultivation with an average recovery of 105% but with significantly less variability (SD: 15.4) compared to the manual steps (SD: 35.7). Finally there was no difference to the average VCN which was 2.2 from the manual steps and 2.4 from the CliniMACS Prodigy®. Overall, our results indicate that the CliniMACS Prodigy® generates higher transduction rates, combined with high viability compared to the manual process, but most importantly, with significantly lower variability, suggesting that it represents a closed system able to automatically perform complex processes as successfully as when manual handling steps are performed, but with higher predictability, efficiency and with minimal user interaction. Disclosures Papanikolaou: Miltenyi Biotec: Employment. Bissels:Miltenyi Biotec: Employment. Johnston:Miltenyi Biotec: Employment. Reinartz:Miltenyi Biotec: Employment. Brams:Miltenyi Biotec: Employment. Aivazidou:Miltenyi Biotec: Employment. Krenz:Miltenyi Biotec: Employment. Bomhard:Miltenyi Biotec: Employment. Knöbel:Miltenyi Biotec: Employment. Bosio:Miltenyi Biotec: Employment.

Plasmacytoid dendritic cells (pDCs) play an important role in innate and adaptive immunity and were shown to be identical to previously described natural interferon (IFN)-α-producing cells. Here, we describe two functionally distinct pDC subpopulations that are characterized by the differential expression of stem cell antigen-1 (Sca-1; Ly-6A/E). Sca-1(-) pDCs are mainly found in the BM, appear first during development, show a higher proliferative activity, and represent the more precursor phenotype. Sca-1(+) pDCs are mostly located in secondary lymphoid organs and represent a later developmental stage. Sca-1(-) pDCs give rise to an Sca-1(+) subset upon activation or in response to endogenous type I IFN. Interestingly, in contrast to Sca-1(-) pDCs, Sca-1(+) pDCs are defective in IFN-α production upon endosomal TLR9 stimulation, whereas lysosomal signaling via TLR9 is functional in both subsets. Gene expression analysis revealed that osteopontin is strongly upregulated in Sca-1(-) pDCs. These data provide evidence for the molecular basis of the observed functional heterogeneity, as the intracellular isoform of osteopontin couples TLR9 signaling to IFN-α expression. Taken together, our results indicate that Sca-1(-) pDCs are an early developmental stage of pDCs with distinct innate functions representing the true murine natural IFN-α-producing cells.

Enhanced production of high quality and healthy fry is a key target for a successful and competitive expansion of the aquaculture industry. Although large quantities of fish larvae are produced, survival rates are often low or highly variable and growth potential is in most cases not fully exploited, indicating significant gaps in our knowledge concerning optimal nutritional and culture conditions. Understanding the mechanisms that control early development and muscle growth are critical for the identification of time windows in development that introduce growth variation, and improve the viability and quality of juveniles. This literature review of the current state of knowledge aims to provide a framework for a better understanding of fish skeletal muscle ontogeny, and its impact on larval and juvenile quality as broadly defined. It focuses on fundamental biological knowledge relevant to larval phenotype and quality and, in particular, on the factors affecting the development of skeletal muscle. It also discusses the available methodologies to assess growth and larvae/juvenile quality, identifies gaps in knowledge and suggests future research directions. The focus is primarily on the major farmed non-salmonid fish species in Europe that include gilthead sea bream, European sea bass, turbot, Atlantic cod, Senegalese sole and Atlantic halibut.

Fibroblast growth factor 19 (FGF19) is proposed to be a negative feedback regulator of hepatic bile acid (BA) synthesis. We aimed to clarify the distribution of FGF19 expression in human intestine and to investigate induction in a novel explant system. Ileal and colonic mucosal biopsies were obtained at endoscopy and analyzed for FGF19 transcript expression. Primary explants were incubated with physiological concentrations of various BA for up to 6 h, and expression of FGF19 and other genes was determined. FGF19 transcripts were detected in ileum but were unquantifiable in colon. No loss of FGF19 mRNA occurred as a consequence of the explant system. Ileal FGF19 transcript expression was induced 350-fold by 50 μM chenodeoxycholate (CDCA, n = 24, P < 0.0001) and 161-fold by 50 μM glycochenodeoxycholate (GCDCA, n = 12, P = 0.0005). The responses of other genes to CDCA or GCDCA (50 μM) were smaller: median increases of ileal bile acid binding protein, organic solute transporter-α and -β, and short heterodimer partner were 2.4- to 4.0-fold; apical membrane sodium bile acid transporter and farnesoid X receptor (FXR) showed little change. The EC50 for FGF19 transcript induction by CDCA was 20 μM. FGF19 protein concentrations were significantly higher in the culture fluid from BA-stimulated explants. FGF19 induction with cholate was 81% of that found with CDCA, but deoxycholate (40%) and lithocholate (4%) were significantly less potent. The synthetic FXR agonist obeticholic acid was much more potent than CDCA with a 70-fold FGF19 stimulation at 1 μM. We concluded that FGF19 expression in human ileum is very highly responsive to BA. Changes in FGF19 induction are a potential mechanism involved in disorders of BA homeostasis.

Tumor-initiating cells (TIC) are critical yet evasive targets for the development of more effective antitumoral strategies. The cell surface marker CD133 is frequently used to identify TICs of various tumor entities, including hepatocellular cancer and glioblastoma. Here, we describe oncolytic measles viruses (MV) retargeted to CD133. The viruses, termed MV-141.7 and MV-AC133, infected and selectively lysed CD133+ tumor cells. Both viruses exerted strong antitumoral effects on human hepatocellular carcinoma growing subcutaneously or multifocally in the peritoneal cavity of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Notably, the CD133-targeted viruses were more effective in prolonging survival than the parental MV-NSe, which is currently assessed as oncolytic agent in clinical trials. Interestingly, target receptor overexpression or increased spreading kinetics through tumor cells were excluded as being causative for the enhanced oncolytic activity of CD133-targeted viruses. MV-141.7 was also effective in mouse models of orthotopic glioma tumor spheres and primary colon cancer. Our results indicate that CD133-targeted measles viruses selectively eliminate CD133+ cells from tumor tissue, offering a key tool for research in tumor biology and cancer therapy. Cancer Res; 73(2); 865–74. ©2013 AACR.