A total of 165 male and female rats that had been exposed during their entire prenatal development to either one of two complex, patterned magnetic fields or to reference (colony) conditions were monitored for emergence of "spontaneous" body tumours until old age (two years after birth). The two patterns were a frequency modulated (FM) field that has been shown to slow malignant cell but not normal cell growth in culture and a complex-sequenced (CSF) field. It was composed of 8 components with 6 of these components containing 8 subcomponents presented for 200 ms for 10 s every 40 s. Significantly greater proportion (33%) of the old rats that had been exposed prenatally to the complex-sequenced field displayed tumors (primarily mammary adenocarcinoma and fibrocarcinoma varieties). Most of these tumors occurred in rats that had been exposed to 30 to ~600 nT strengths but not less than 30 nT or greater than ~600 nT intensities. In comparison 4% of the rats exposed to the single, repeated frequency-modulated field exhibited tumors. The prevalence for normal background colony room conditions was 2%. These data suggest that exposure during prenatal development to weak intensity magnetic fields whose temporal patterns were designed to be convergent with the timing of base sequencing could increase the probability of the development of cancer during the later stages of life. However the frequency-modulated magnetic field pattern that suppress the growth of human breast cells in culture and elicits strong analgesia in rodents produced no significant increase in emergence of tumors in later life compared to non-treated rats.


Increasing attention has been given to vascular tissue engineering in recent years. Although cell seeding onto tubular scaffolds is the first step for constructing three-dimensional vascular grafts, the tubular geometry of the grafts hinders the efficient delivery of cells onto the scaffold. To overcome these limitations, we present here a novel cell-seeding technique using magnetic force and magnetite nanoparticles, termed Mag-seeding. NIH/3T3 fibroblasts (3T3s) were labeled magnetically using our original magnetite cationic liposomes (MCLs), which have a positive surface charge, to improve adsorption onto cell surface. In this study, porcine decellularized common carotid artery (dCCA) was used as one of the most promising scaffolds, because dCCA consists of a mixture of structural and functional proteins that constitute the extracellular matrix. When a cylindrical magnet was inserted into the lumen of dCCA and the dCCA was immersed into a suspension of magnetically labeled 3T3s, almost all the 3T3s attached onto the dCCA, whereas a low cell-seeding efficiency was achieved without using a magnet. When the magnetite uptake rate per cell increased, cell-seeding efficiency by Mag-seeding was enhanced. Furthermore, to construct a vascular graft for humans, the porcine dCCA, which was reseeded with two human cells (smooth muscle cells and dermal fibroblasts), was successfully constructed by Mag-seeding. These results indicate that Mag-seeding can be used for vascular tissue engineering.


The connections among greenhouse-gas emissions scenarios, global warming, and frequencies of hurricanes or tropical cyclones are among the least understood in climate science but among the most fiercely debated in the context of adaptation decisions or mitigation policies. Here we show that a knowledge discovery strategy, which leverages observations and climate model simulations, offers the promise of developing credible projections of tropical cyclones based on sea surface temperatures (SST) in a warming environment. While this study motivates the development of new methodologies in statistics and data mining, the ability to solve challenging climate science problems with innovative combinations of traditional and state-of-the-art methods is demonstrated. Here we develop new insights, albeit in a proof-of-concept sense, on the relationship between sea surface temperatures and hurricane frequencies, and generate the most likely projections with uncertainty bounds for storm counts in the 21st-century warming environment based in turn on the Intergovernmental Panel on Climate Change Special Report on Emissions Scenarios. Our preliminary insights point to the benefits that can be achieved for climate science and impacts analysis, as well as adaptation and mitigation policies, by a solution strategy that remains tailored to the climate domain and complements physics-based climate model simulations with amore » combination of existing and new computational and data science approaches.« less


Gas phase polyethylene reactors are able to produce several different grades of polymer. Adapting to market conditions requires grade transitions, associated with costs in terms of raw material and temporary production of lower priced off-specification products. In this paper, both stationary production and dynamic grade transitions are optimized to maximize profit, i.e., economic process optimization. A cost function for transitions that utilizes product quality variable intervals, specifying premium priced products, and that also gives incentives to produce products having quality variables on target, i.e., equal to a defined grade, is designed. A previously published reactor model is extended with quality variable models and several grade transitions are optimized and shown. (Less)


The high fractional doses, stringent requirements for accuracy and precision, and surgical perspective characteristic of intracranial radiosurgery create considerations for treatment planning which are distinct from most other radiotherapy procedures. This session will introduce treatment planning techniques specific to two popular intracranial SRS modalities: Gamma Knife and MLC-based Linac. The basic treatment delivery characteristics of each device will be reviewed with a focus on how those characteristics determine the paradigm used for treatment planning. Basic techniques for treatment planning will be discussed, including considerations such as isodose selection, target and organ-at-risk definition, quality indices, and protection of critical structures. Future directions for SRS
treatment planning will also be discussed.
Learning Objectives:
1.
Introduce the basic physical principles of intracranial radiosurgery and how they are realized in the treatment planning paradigms for Gamma Knife and Linac
radiosurgery.
2.
Demonstrate basic treatment planning techniques.
3.
Discuss metrics for evaluating SRS treatment plan quality.
4.
Discuss recent and future advances in SRS
treatment planning.
D. Schlesinger receives research support from Elekta, AB


Aim: A model of progressively endocrine-resistant breast cancer was investigated to identify changes that can occur in signaling pathways after endocrine manipulation. Methods: The MCF7 breast cancer model is sensitive to estrogens and anti-estrogens while variant lines previously derived from wild-type MCF7 are either relatively 17β-estradiol (E2 )-insensitive (LCC1) or fully resistant to estrogen and anti-estrogens (LCC9). Results: In LCC1 and LCC9 cell lines, loss of estrogen sensitivity was accompanied by loss of growth response to transforming growth factor alpha (TGFα), heregulin-beta and pertuzumab. LCC1 and LCC9 cells had enhanced AKT phosphorylation relative to MCF7 which was reflected in downstream activation of phospho-mechanistic target of rapamycin (mTOR), phospho-S6, and phospho-estrogen receptor alpha Ser167 [ERα(Ser167)]. Both AKT2 and AKT3 were phosphorylated in the resistant cell lines, but small interfering RNA (siRNA) knockdown suggested that all three AKT isoforms contributed to growth response. ERα(Ser118) phosphorylation was increased by E2 and TGFα in MCF7, by E2 only in LCC1, but by neither in LCC9 cells. Multiple alterations in E2-mediated cell cycle control were identified in the endocrine-resistant cell lines including increased expression of MYC, cyclin A1, cyclin D1, cyclin-dependent kinase 1 (CDK1), CDK2, and hyperphosphorylated retinoblastoma protein (ppRb), whereas p21 and p27 were reduced. Estrogen modulated expression of these regulators in MCF7 and LCC1 cells but not in LCC9 cells. Seliciclib inhibited CDK2 activation in MCF7 cells but not in resistant variants; in all lines, it reduced ppRb, increased p53 associated responses including p21, p53 up-regulated modulator of apoptosis (PUMA), and p53 apoptosis-inducing protein 1 (p53AIP1), inhibited growth, and produced G2/M block and apoptosis. Conclusions: Multiple changes occur with progression of endocrine resistance in this model with AKT activation contributing to E2 insensitivity and loss of ERα(Ser118) phosphorylation being associated with full resistance. Cell cycle regulation is modified in endocrine-resistant breast cancer cells, and seliciclib is effective in both endocrine-sensitive and resistant diseases.


125I-fibrinogen binds to washed rabbit platelets when they ar stimulated wit ADP, and it has previously been observed that fibrinogen binding is prevented by several inhibitors of ADP-induced aggregation. We have now shown that other inhibitors of aggregation, the phosphodiesterase inhibitors caffeine and dipyridamole, and colchicine and cytochalasin B which affect the platelet cytoskeleton, also inhibit specific 125I-fibrinogen binding. A positive correlation was observed between ADP-induced aggregation and fibrinogen binding at limiting concentrations of these inhibitors. Colchicine and cytochalasin B appear to act independently, with no indication of synergism. When any of these inhibitors, as well as those previously tested (EDTA, EGTA, PGE1 and PGI2) was added to platelets that had already been stimulated with ADP and undergone considerable aggregation and fibrinogen binding, it caused rapid deaggregation of the platelets and dissociation of bound fibrinogen, although in some cases the inhibitory effects were not as pronounced as when the inhibitor was added before ADP stimulation. These observations reinforce the concept that fibrinogen plays an essential role in the formation of ADP-induced platelet aggregates.


The objective of the study was to analyze the composition of mortar in order to enhance the use of milk serum and its application in earth constructions. Development of the study involved, initially, a bibliographic review and identification of dairy industry producers in the Paraiba Valley, São Paulo, with milk residue storage facilities. The next stage consisted in the preparation of three adobe molds, based on technical reproductions, of the composition of historic constructions. Subsequently, the molds were submitted to laboratory tests: preservation and compression resistance. This was followed by execution of the mortar with milk serum and bacteriological tests, anchoring, and plasticity through the application of mortar. The adobe molds were observed over a period of 15 days, with even the cracked molds shown to be useful for purposes of simulating risk situations. The technical viability analysis of the sample milk serum mortar applied to a historic construction and exposed to the natural elements for a period of 1 year revealed no deformities. After a full year of research, we found the presence of acid milk residue to be a major concern among dairy producers. Further, the difference between acid and sweet milk serum gave rise to a new challenge given the different chemical properties of the two serum types, which can alter the structure of the mortar and its efficacy. To this end, the research work was extended into 2009 with implementation of a new stage aimed at adapting Brazilian technical standards through a technical evaluation of historic mortar and the applicability of acid serum to the residue process.


BACKGROUND: Maximal oxygen uptake (VO2max) obtained from incremental exercise testing is a useful indicator of limited exercise capacity. Several prediction equations have been developed to estimate VO2max in patients with chronic obstructive pulmonary disease (COPD), but agreement studies between estimated and measured VO2max are lacking. This study aims to assess agreement between the 6 estimated VO2max equations and direct measures of VO2max evaluated during maximal incremental exercise testing in male COPD patients. METHODS: Patients with stable COPD, in accordance with GOLD guidelines, were included in the study. Agreement between VO2max obtained during incremental exercise testing and VO2max obtained from 6 prediction equations were studied. To estimate VO2max from anthropometric prediction equations, lung function variables and submaximal exercise testing were used. RESULTS: Of the 60 male patients in the study, 12 were GOLD stage II, 24 GOLD stage III, and 24 GOLD stage IV. Five prediction equations underestimated the value of VO2max in relation to measured VO2max: equations 1, 2, 3, 4, and 6, by 14%, 66%, 42.2%, 35%, and 23.3%, respectively. Conversely, prediction equation 5 overestimated measured VO2max by 76.9%. Agreement between all VO2max prediction equations and measured VO2max was poor. Discrepancy between VO2max prediction equations and measured VO2max varied from 20.857 to 0.736 L/min. CONCLUSIONS: The use of lung function at rest and submaximal exercise testing is inaccurate for determining VO2max, which cannot be estimated by prediction equations in patients with stable COPD.


Small ruminants are important source of income for agricultural community and are one of Ethiopia's major sources of foreign currency through exportation of live animals, meat and skin. Internal parasites are an important cause of disease and lose of production in small ruminants. Gastrointestinal nematodes are recognized as a major constraint to both small and large-scale small ruminant production in developing countries. These could be harmful to the health of infected animals in different regions and causes economic losses due to mortalities, reduce weight gain and other production losses. The gastrointestinal nematode parasites are found livestock health problems including for small ruminants and are responsible for economic losses due to reduced production, morbidity and mortality. Therefore, Strategic treatment of small ruminants with anthelmintic, parasitic control and prevention should be practiced in the study area to minimize the impact of gastrointestinal nematodes on the health of animals.


Landslides triggered by rainfall can possibly be foreseen in real time by jointly using rainfall intensity-duration thresholds and information related to land surface susceptibility. However, no system exists at either a national or a global scale to monitor or detect rainfall conditions that may trigger landslides due to the lack of sufficient ground-based observing network in many parts of the world. Recent advances in satellite remote sensing technology and increasing availability of high-resolution geospatial products around the globe have provided an unprecedented opportunity for such a study. In this paper, a framework for developing an experimental real-time prediction system to identify where rainfall-triggered landslides will occur is proposed by combining two necessary components: surface landslide susceptibility (LS) and a real-time space-based rainfall analysis system. First, a global LS map is derived from a combination of semistatic global surface characteristics (digital elevation topography, slope, soil types, soil texture, land cover classification, etc.) using a geographic information system weighted linear combination approach. Second, an adjusted empirical relationship between rainfall intensity-duration and landslide occurrence is used to assess landslide hazards at areas with high susceptibility. A major outcome of this paper is the availability for the first time of a global assessment of landslide hazards, which is only possible because of the utilization of global satellite remote sensing products. This experimental system can be updated continuously using the new satellite remote sensing products. This proposed system, if pursued through wide interdisciplinary efforts as recommended herein, bears the promise to grow many local landslide hazard analyses into a global decision-making support system for landslide disaster preparedness and mitigation activities across the world


Tuberculosis is a major health problem throughout the world causing large number of deaths, more than that from any other single infectious disease. Estimates till date ascertain the fact that Tuberculosis (TB) is continuing to be the leading cause of death worldwide. The infection from single infectious agent Mycobacterium tuberculosis is killing about 3 million individuals every year and accounts for around 18.5% of all deaths in adults between the age group of 15 and 65. An average of 1.79 billion people, which constitutes roughly one-third of the world's population, is infected with the causative agent M. tuberculosis and is at risk of developing the disease. This situation highlights the relative shortcomings of the current treatment and diagnosis strategies for TB and the limited effectiveness of public health systems, particularly in resource-poor countries where the main TB burden lies. The timely identification of persons infected with Mycobacterium tuberculosis and rapid laboratory confirmation of tuberculosis are two key factors for the treatment and prevention of the disease. Novel molecular assays for diagnosis and drug susceptibility testing offer several potential advantages over the above methods including faster turnaround times, very sensitive and specific detection of nucleic acids, and minimal, or possibly no, prior culture. The need for new technologies for rapid diagnosis of tuberculosis is clear. Most studies of mycobacterial immunity attributes focus on proliferation of T cells, production of cytokines and cytolytic activity. A proper vaccine for tuberculosis can be developed by using a combination of antigens and adjuvants capable of inducing appropriate and long-lasting T cell immunity. Development of new vaccines against TB should include some important aspects learned from BCG use such as mucosal routes of immunization; revaccination of BCG immunized subjects, booster immunization and prime-boost strategy with wild-type BCG, and other vaccine candidates. Here, we review current and future strategies toward the rational design of novel vaccines against TB, as well as the progress made thus far, and the hurdles that need to be overcome in the near and distant future.


Since the introduction of Family Group Conferences (FGCs) in the Netherlands, there has been a steady growth in conferences being organised each year. Government policy emphasises the importance of empowering families to strengthen their ability to take responsibility for their own well-being. A recently adopted amendment in the Dutch Civil Code reflects this commitment and designates FGC as good practice. However, there is little knowledge on the application of FGCs in mental health care, let alone in a setting even more specific, such as public mental health care (PMHC). Clients in PMHC often have a limited network. The starting point of this study is the assumption that conferences promote involvement, expand and restore relationships and generate support. Over the next two years, we will research the applicability of FGCs in PMHC by evaluating forty case studies. The aim of our study is to provide an answer to the question of whether Family Group Conferencing is an effective tool to generate social support, to prevent coercion and to promote social integration in PMHC. Although making contact and gaining trust is a goal of PMHC, it is an aim to study whether FGCs can elevate or replace the work of professionals.


Purpose: Bymobilizing the sociological approach of action logic, this research aims to understand the articulation between the various dimensions of Corporate Social Responsibility (CSR) and the conditions for the emergence of an overallcommitment towards stakeholders in Small and Medium-Sized Enterprises (SMEs) in an emerging country: Tunisia. Design/methodology: A qualitative study was carried out through multiple case studies of Tunisian SMEs. Findings: The research findings tend to reveal that an overall CSR commitment requires an interaction between individual and contextual dimensions. However, predispositions coming from the individual manager dimension would play the role of a catalyst for a proactive CSR approach. As for the SMEs transition from weak to global commitment, this would primarily stem from contextual dimensions. In addition, each of the hedonistic, entrepreneurial or managerial action logic could be conducive to this type of commitment. Research Limitations:The number of explored cases could constitute a limitation of this work as it does not allow a statistical generalization of the results based on the criterion of frequency. Originality: Few of the CSR studies focused on a multi-dimensional commitment in SMEs In this research we aim to avoid an over-representation of the manager, and approach his action logics most conducive to a multi-stakeholder approach to CSR.


Abstract Vasculitides are a heterogeneous group of disorders in which inflammation of blood vessel walls is present at least some time during the course of the disease. Vasculitides can affect any caliber or type of vessel in many anatomic sites; however, the disease can alter more than just vasculature. Given the diversity of vasculitides, in 2012, a revised classification system was proposed to categorize vasculitides by the type of vessel involved including size, function, and structural attributes. In the lung, vasculitis impacts both the pulmonary vessels and parenchyma. Extrapulmonary involvement, particularly with concomitant kidney involvement, is a frequent occurrence. Pulmonary vasculitides often present with hemoptysis, pathologically manifested as diffuse alveolar hemorrhage (DAH) with or without capillaritis and can be life threatening when diffuse throughout the lungs. Etiologies for DAH include both primary and secondary vasculitides, along with collagen-vascular diseases, infection, and drug toxicity. Therefore, diagnosing the specific vasculitic etiology often relies on comprehensive assessment of all clinical, laboratory/serological, imaging, and histopathologic features that may be present. The most common primary pulmonary vasculitides often affect small vessels and are associated with circulating antineutrophilic cytoplasmic antibodies (ANCAs). In the 2012 classification, these include granulomatosis with polyangiitis (formerly Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (formerly Churg–Strauss' syndrome), and microscopic polyangiitis. Other less frequent vasculitides that are non-ANCA associated or affect medium- to large-sized vessels can have pulmonary involvement. These entities are usually associated with extrapulmonary disease and include polyarteritis nodosa, Takayasu's arteritis, Behçet's disease, and antibasement membrane antibody disease (formerly Goodpasture's syndrome). Although all vasculitides have vessel wall inflammation at some phase in the disease process, their histopathologic findings are as diverse as the group of diseases themselves. The characteristic histologic findings of the pulmonary vasculitides will be reviewed here.


Recently, the reduction of pattern collapse in 193nm resists with the help of a surfactinated rinse has been widely reported in the literature [1-6]. This additional step was introduced between the DI rinse that follows the developer puddle, and the final dry spin step. The present work demonstrates that the latitude of 100nm, 90nm and 75nm dense line processes can be significantly extended with an appropriate surfactant rinse through pattern collapse reduction. Simultaneously, a considerable reduction of organic defectivity is reported on blanket resist wafers.


BACKGROUND
Preventing overweight and improving physical fitness in primary school children is a worldwide challenge, and physically active intervention programs usually come with the cost of academic instruction time. This study aimed to investigate effects of physically active academic lessons on body mass index (BMI) and physical fitness in primary school children.

METHODS
Dutch children attending second- or third-grade class from 12 primary schools (N = 376; 8.1 ± 0.7 years) were randomly assigned to a 22-week intervention program or to the control group. In addition to measuring BMI before and after the intervention, physical fitness was measured with 5 items of the Eurofit test battery, measuring cardiovascular and muscular fitness.

RESULTS
Multilevel analysis showed a significant interaction effect between condition (intervention vs control) and grade (B = -0.47; p < .05). For third-grade children, BMI of the intervention group did not change significantly during the intervention period, whereas a significant increase was found in the control group. No significant main or interaction effects were found for cardiovascular or muscular fitness.

CONCLUSIONS
The current physically active academic lessons had positive effects on BMI in third-grade children, but had no effects on cardiovascular and muscular fitness.


Sound triggers an increase in the number of peroxisomes to protect cells in the cochlea from oxidative stress. Individuals with mutations in DFNB59, which is also known as PJVK and which encodes the protein pejvakin, have a form of hearing impairment caused by defects in the neural transmission of auditory signals. The extent of hearing loss in DFNB59 patients is variable. By measuring auditory brainstem response (ABR) thresholds, Delmaghani et al. (see also Mardones and Hetz) found that the hearing sensitivity of Pjvk–/– mice also varied, suggesting that additional factors contributed to the phenotype. The extent of loss in hearing sensitivity correlated to the amount of acoustic energy to which the Pjvk–/– pups were exposed. Inner hair cells in the cochlea are auditory sensory receptors and outer hair cells function as amplifiers. Controlled sound exposure attenuated the responses of the outer and inner hair cells in Pjvk–/– mice. Action potential propagation in the cochlear neurons of these mice in response to controlled sound exposure or electrical stimulation was defective, which was rescued by neuronal expression of pejvakin. Sound-induced hearing loss involves oxidative damage to cochlear tissue by reactive oxygen species (ROS), and the cochleas of Pjvk–/– mice showed decreased expression of genes encoding antioxidant proteins and exhibited evidence of oxidative stress, as demonstrated by increases in the ratio of reduced to oxidized glutathione and in lipid peroxidation. Pejvakin associated with peroxisomes, organelles that contain various antioxidant enzymes, and the outer hair cells of Pjvk–/– mice had fewer peroxisomes than those of Pjvk+/+ mice. Hydrogen peroxide induced peroxisome proliferation in embryonic fibroblasts from Pjvk+/+ mice but not in those from Pjvk–/– mice, and HeLa cells expressing normal mouse pejvakin had more peroxisomes than those expressing forms of mouse pejvakin with some of the mutations corresponding to those found in DFNB59 patients. Sound exposure increased the transcription of Pjvk and peroxisome numbers in the outer hair cells of Pjvk+/+ mice. To determine if reconstitution of hair cells with pejvakin could rescue the phenotype of Pjvk–/– mice, one ear was injected with pejvakin-encoding viruses that transduce only hair cells and the other ear was left untreated. ABR thresholds were improved, responses of outer hair cells to sound exposure were partially improved, and peroxisomal numbers after sound exposure were increased in the treated ear. Thus, sound triggers peroxisomal proliferation mediated by pejvakin to protect cells in the cochlea from oxidative stress. S. Delmaghani, J. Defourny, A. Aghaie, M. Beurg, D. Dulon, N. Thelen, I. Perfettini, T. Zelles, M. Aller, A. Meyer, A. Emptoz, F. Giraudet, M. Leibovici, S. Dartevelle, G. Soubigou, M. Thiry, E. S. Vizi, S. Safieddine, J.-P. Hardelin, P. Avan, C. Petit, Hypervulnerability to sound exposure through impaired adaptive proliferation of peroxisomes. Cell 163, 894–906 (2015). [PubMed] P. Mardones and C. Hetz, Peroxisomes get loud: A redox antidote to hearing loss. Cell 163, 790–791 (2015). [PubMed]


Three patients, men aged 65 and 49 and a woman of 38 years, presented with drug-induced interstitial pneumonitis due to nilutamide, bleomycin and nitrofurantoin usage respectively. The signs and symptoms of drug-induced interstitial pneumonitis occur from within several hours up to months or years after the start of treatment, and sometimes even after the cessation of treatment, and consist of a dry cough, dyspnoea, fever and crackles upon auscultation. The results of further investigations are atypical and consist of abnormalities on the X-ray or CT of the thorax and lymphocytosis in the bronchoalveolar lavage fluid. The mechanisms of damage usually include direct pulmonary toxicity and indirect inflammatory or immunological processes. In most patients, the pulmonary abnormalities disappear after cessation of the drug treatment. Sometimes the disease progresses to pulmonary fibrosis and respiratory failure despite treatment with corticosteroids.


Gruss I., Twardowski J.P., Hurej M. (2018): Influence of 90-year potato and winter rye monocultures under different fertilisation on soil mites. Plant Protect Sci., 54: 31–38. The influence of the cultivation of a single crop (potato or winter rye) on mite assemblages was evaluated. Both crops were cultivated in a long-term monoculture (90 years). The response of mites to fertilisation treatment (mineral with manure or mineral alone) was also studied. It was hypothesised that the density of mites as a community and the density of particular mite groups are higher in winter rye crop in comparison with potato. Secondly, the fertilisation with manure is more beneficial for mites than the use of mineral fertilisers alone, both in winter rye and potato crops. Results showed significantly higher mite abundance in potato, mainly due to Prostigmata dominance. Oribatida and Gamasida groups were significantly more numerous in winter rye. The fertilisation type, except for the suborder Astigmata, had no significant influence on the mite community.


The lactate signaling cascade has recently been linked to mitochondrial energy metabolism and cardiomyocyte apoptosis in several cardiovascular diseases. Asiatic acid (AA) exhibits a variety of pharmacological effects, including antioxidant and anti-apoptotic effects. In this study, we investigated the protective effects of AA against the lactate-induced apoptosis of cardiomyocytes, as well as its mechanisms of action. Neonatal rat cardiomyocytes were pre-treated with 20 µM AA for 24 h, followed by exposure to 20 mM lactate for a further 24 h. Cell viability was determined by a cell counting kit-8 (CCK-8) assay. Cell apoptosis, reactive oxygen species (ROS) levels and mitochondrial membrane potential (Δψm) were evaluated by flow cytometry or fluorescence microscopy. The expression levels of mitochondrial monocarboxylate transporter 1 (MCT1) and cytoplasmic cytochrome c, cleaved caspase-9 and caspase-3 were assayed by western blot analysis. Our results revealed that AA significantly inhibited lactate-induced apoptosis, intracellular ROS generation and the loss of Δψm. AA also increased the expression of mitochondrial MCT1 and reduced the expression of cytoplasmic cytochrome c, cleaved caspase-9 and caspase-3 in the lactate-stimulated cardiomyocytes. To the best of our knowledge, our data demonstrate for the first time that AA plays a cytoprotective role in lactate-induced apoptosis by regulating the lactate signaling cascade, involving the inhibition of oxidative stress and mitochondria-dependent caspase activation, as well as the upregulation of mitochondrial MCT1 expression.


Adaptive clinical trial design has been proposed as a promising new approach that may improve the drug discovery process. Proponents of adaptive sample size re‐estimation promote its ability to avoid 'up‐front' commitment of resources, better address the complicated decisions faced by data monitoring committees, and minimize accrual to studies having delayed ascertainment of outcomes. We investigate aspects of adaptation rules, such as timing of the adaptation analysis and magnitude of sample size adjustment, that lead to greater or lesser statistical efficiency. Owing in part to the recent Food and Drug Administration guidance that promotes the use of pre‐specified sampling plans, we evaluate alternative approaches in the context of well‐defined, pre‐specified adaptation. We quantify the relative costs and benefits of fixed sample, group sequential, and pre‐specified adaptive designs with respect to standard operating characteristics such as type I error, maximal sample size, power, and expected sample size under a range of alternatives. Our results build on others' prior research by demonstrating in realistic settings that simple and easily implemented pre‐specified adaptive designs provide only very small efficiency gains over group sequential designs with the same number of analyses. In addition, we describe optimal rules for modifying the sample size, providing efficient adaptation boundaries on a variety of scales for the interim test statistic for adaptation analyses occurring at several different stages of the trial. We thus provide insight into what are good and bad choices of adaptive sampling plans when the added flexibility of adaptive designs is desired. Copyright © 2012 John Wiley & Sons, Ltd.


A state space model of the stochastic spatio-temporal integro-difference equation (IDE) is derived. Based on multidimensional sampling theory, the dimensions of the state space and parameter space of the model are identified from the spatial bandwidth of the system and the support of the redistribution kernel of the IDE. When both the bandwidth and the kernel support are unknown, a method to propose a number of state space and parameter space dimensions is presented. These chosen dimensions result in a number of candidate model structures. Bayesian model selection, making use of Bayes factor, the data augmentation algorithm and importance sampling, is then used to identify the model best suited to represent the data in a maximum a posteriori sense.


Recent developments in Monte Carlo methods for condensed matter physics are reviewed with the emphasis on the world-line Monte Carlo methods and their applications to quantum spin models.


With the Waxman-Markey Bill passing the House and the Obama administration's push to reduce carbon emissions, the likelihood of the implementation of some form of a carbon policy is increasing. This study estimates the greenhouse gas (GHG) emissions of the six largest crops produced in Arkansas using 63 different production practices as documented by University of Arkansas Cooperative Extension Service. From these GHG estimates a baseline state "carbon footprint" was estimated and a hypothetical cap-and-trade carbon reduction of 5, 10, and 20% was levied on Arkansas agriculture. Results show that while a modest reduction in GHG emissions (5%) would only affect crop allocations amongst certain crops while marginally reducing state net returns, a 20% reduction would cause major cropping pattern shifts with some traditional row crops nearly disappearing.


Raman spectroscopy has been used by various workers to provide a measure of the stresses within the oxides grown on metal substrates at high temperatures. In this paper, we consider thermally grown oxides produced on a Type 316 austenitic stainless steel and an iron 3% silicon ferritic steel. The oxides were grown in air at temperatures of 950oC and 650oC respectively over a range of times. These oxides have been characterised by producing cross-sections using focused ion beam milling. The variation of the Raman spectra wave number (He, Ne laser; λ = 633nm) for the oxides produced on the polycrystalline austenitic stainless steel and the ferritic steel were measured as a function of oxide thickness. This shift in wave number was a function of stress. For a fixed oxide thickness on the stainless steel substrate the specimen has been subject to a bending force. A back face strain gauge fixed to the metal substrate provided a measure of the applied strain. The peak wave number varied with applied strain. The results are discussed with respect to the potential to characterise the stresses produced in thermally grown oxides and as a tool to monitor applied stress.


Deep convective clouds play a key role in regulating the Earth's water and energy cycles and are therefore an important component of the Earth's climate system. Much work has been done on investigating factors such as how aerosols affect these clouds but much less emphasis has been on how the future changes in thermodynamic structure of the atmosphere will affect these clouds. It is vitally important to know how clouds will respond to these changed thermodynamic conditions.

This study explores how modelled deep convective clouds respond to the projected future warmer climate and compares it with past (current) climate. Atmospheric thermodynamic profiles are taken from NCAR CCSM3 global climate model and the modelling study was based on simulations of idealised deep convective clouds using the Weather Research Forecast (WRF) model with a double-moment cloud microphysics scheme.

The modelling study showed that the future thermodynamic environment produced deep convective clouds that are on average 32% lower in cloud base height, 8.5% higher in freezing level and 9% lower in cloud-top height compared to the past climate results. This results in the future clouds having an average of 15% deeper warm-phase cloud layer and 18% shallower cold-phase cloud layer than in the past climate, signifying a strong warm rain process and reduced cold rain process, where the cold rain process is traditionally known to be the dominant precipitation-forming process in the current climate. The strong warm rain process leads to intense heavy rainfall, which reduces the availability of water in the updraught reaching the ice phase, thus reducing the clouds' vertical and horizontal extent.

An in-depth investigation was performed to assess the factors associated with the changes of the future thermodynamic environment influencing the cloud development. Such factors include assessment of the significance of temperature structure, relative humidity structure, both structural changes, and increased moisture due to the warmer mean temperature. It was found that the structural effects of temperature and relative humidity have greater impact on the cloud development compared to the increase in the mean temperature. The temperature structure factor significantly reduces the average total water content and cloud vertical extent by 75% and 8 km, respectively. On the other hand, the relative humidity structure significantly increases the average total water content and cloud vertical extent by 80% and 1.8 km, respectively. Separately assessing these two factors gives significant opposing effects on the cloud's total water content and vertical height. When combined, these two effects cancels out to some extent, but they still produce weaker and smaller deep convective clouds than the effects that arise from the mean temperature increase.

Following from the differences in the cloud development between the past and future environments, the strong warm rain process and weak cold rain process results in the cloud fraction in the future reduced by half of that in the past environment. This reduced cloud horizontal extent results in cloud radiative forcing at the top of the atmosphere that is positive, indicating an increased warming in the future environment. The average local cloud radiative forcing was evaluated to be 43.7 and 54.7 W m^2 for the whole cloud and anvil cloud, respectively. If this is extended to midlatitude deep convective region over land with a coverage of 3% or global coverage of deep convective clouds of less than 1%, a simplistic approximation of the cloud radiative forcing is evaluated to be +1.31 and +0.44 W m^2, respectively. This is opposite to the radiative forcing exerted by aerosol-cloud interaction reported in the Intergovernmental Panel on Climate Change Fifth Assessment Report (IPCC AR5), which was estimated at -0.55 W m^2

The results from this study highlight that the changes in the vertical thermodynamic structure affect the cloud development significantly. This study was based on the output of one global climate model, however, it does suggest that it is important that climate modelling groups pay particular attention to the way their models forecast the thermodynamic structure in both temperature and moisture of the future climate.


Introduction: Bruton's Tyrosine Kinase (BTK) is an essential component of normal and malignant B-cell receptor signaling. Covalent BTK inhibitors have transformed the treatment of B-cell malignancies but are limited by off-target toxicity and acquired resistance, leading to eventual treatment discontinuation and disease progression. Emerging evidence suggests that acquired resistance is mediated predominantly by BTK C481 substitution mutations at the covalent BTK inhibitors' binding site. There is significant unmet clinical need for new treatment approaches that overcome acquired resistance and minimize toxicity.
 LOXO-305 is a highly selective, non-covalent, next generation BTK inhibitor. We previously showed that LOXO-305 potently inhibited both wild-type (WT) BTK and BTK C481S -mediated kinase activity in enzyme and cell-based assays with nanomolar potency, caused regression of BTK-dependent lymphoma mouse xenograft models, and was more than 300-fold selective for BTK over 98% of 370 other kinases tested and showed no significant inhibition of non-kinase off targets at 1 mM (Brandhuber et al. SOHO 2018). In addition, ADME and pharmacokinetic experiments in two preclinical species predicted that LOXO-305 will have high human exposure and sustained BTK C481S target coverage in patients at clinically achievable doses.
 Here we describe the activity of LOXO-305 against additional BTK C481 substitution mutations, including mutations identified in patients with acquired resistance to covalent BTK inhibitors. We further determine equilibrium-binding affinities for LOXO-305 for diverse mutant BTK enzymes in comparison to other clinically available BTK inhibitors.
 Methods: To assess cellular BTK inhibitor potency, HEK293T cell lines transiently expressing wild-type BTK and BTK C481 substitution mutations were serum starved and incubated with LOXO-305 overnight. Cells were next incubated with serum and orthovanadate for 5 min and the phosphorylated Y223 BTK was analyzed by immunoblot. Bands were quantified and the IC50 values calculated with GraphPad Prism. The equilibrium-binding affinities for targeted BTK inhibitors to BTK enzyme variants were determined by surface plasmon resonance (SPR) using the Biacore T200. Biotinylated BTK variants were immobilized on a docked streptavidin coated sensor chip. Five concentrations of each inhibitor plus blank controls were analyzed. Association/dissociation rate constants were calculated by global fitting of the data to a 1:1 binding interaction model.
 Results: While BTK C481S possessed similar levels of basal Y223 autophosphorylation as wild-type BTK in cells, BTK C481T autophosphorylation was reduced by ~50%, C481R by ~90%, and mutants C481F, and C481Y were inactive in HEK293T cells. LOXO-305 inhibited Y223 phosphorylation of all active mutants with similar nanomolar potency. In contrast, autophosphorylation of all BTK C481 mutants were resistant to both Ibrutinib and acalabrutinib. Equilibrium-binding affinities of LOXO-305 for select BTK C481 substitution mutations confirmed LOXO-305's superior potency versus commercially available BTK inhibitors (ibrutinib and acalabrutinib).
 Conclusions: The next generation, non-covalent, highly selective BTK inhibitor LOXO-305 potently inhibited the cellular activity of BTK C481S, T and R mutations and displayed strong equilibrium binding to WT BTK and several BTK C481 substitution mutations. Together with high selectivity and significant BTK target coverage in vivo, these results indicate that LOXO-305 may overcome acquired resistance to covalent BTK inhibitors in patients without significant off-target toxicity. A phase 1 clinical trial of LOXO-305 is currently underway.

 Gomez: LOXO Oncology Inc.: Employment, Equity Ownership. Isabel:Loxo Oncology: Employment. Rosendahal:Loxo Oncology: Employment. Rothenberg:LOXO Oncology Inc.: Employment. Andrews:Loxo Oncology: Employment. Brandhuber:LOXO Oncology Inc.: Employment, Equity Ownership.


A 13-year-old epileptic girl took an overdose of acetaminophen (Tylenol) and phenobarbital. Hepatic encephalopathy developed and the patient died eight days later. Necropsy revealed extensive centrilobular necrosis of the liver, degeneration of the renal distal tubules, and infarcted and demyelinated foci throughout the white matter of the cerebral cortex. Electron microscopy of intact hepatocytes showed a proliferation of both smooth and rough endoplasmic reticulum consistent with enzyme induction from phenobarbital. To our knowledge, this is the first reported death in a child in the United States as a result of acetaminophen and should alert physicians to an expected increase in acetaminophen toxicity as the drug becomes more widely available.


Author(s): Teaiwa, Katerina Martina | Abstract: My book, Consuming Ocean Island: Stories of People and Phosphate from Banaba , about the impact of British, Australian, and, New Zealand phosphate mining on one of my ancestral homelands, felt like a mission to Mars. Prolonged sitting, writing, reading, rewriting, and editing are static embodied processes unnatural to human design. And while I'm so pleased the book has been taken up in several anthropology, history, Pacific studies, and Indigenous studies classrooms, the chapter I love most is the one that reviewers and editors had almost nothing to say about. Titled "Remix: Our Sea of Phosphate," it consists of textual and visual fragments from books, journal articles, ethnographic film, and archives. Elsewhere, I have written about my interest in Indigenous remix and how apt it is for Banaban lands, choreographies, histories, and displacement. My goal has never been to produce a neat and well-synthesized master narrative of what happened to Banaba, also known as Ocean Island, but to appropriately present our two-and-a-half-square-mile (six-square-kilometer) ancestral island that was broken, crushed, dried, bagged, and hauled off in ships "in pieces." The remixed forms of research and storytelling about Banaba are in line with the multisited, multisensory, empirical, material, social, and political elements marking the interaction and mutual interference between Banaba and twentieth-century British, Australian, and New Zealand colonial, imperial, agricultural, and food security projects.


During cancer development, host's tumorigenesis and immune signals are released to and informed by circulating molecules, like cell-free DNA (cfDNA) and RNA (cfRNA) in blood. However, these two kinds of molecules are still not systematically compared in gastrointestinal cancer. Here, we profiled 4 types of cell-free omics data from colorectal and stomach cancer patients, and assayed 15 types of genomic, epi-genomic, and transcriptomic variations. First, we demonstrated that the multi-omics data were more capable of detecting cancer genes than the single-omics data, where cfRNAs were more sensitive and informative than cfDNAs in terms of detection ratio, variation type, altered number, and enriched functional pathway. Moreover, we revealed several peripheral immune signatures that were suppressed in cancer patients and originated from specific circulating and tumor-microenvironment cells. Particularly, we defined a γδ-T-cell score and a cancer-associated-fibroblast (CAF) score using the cfRNA-seq data of 143 cancer patients. They were informative of clinical status like cancer stage, tumor size, and survival. In summary, our work reveals the cell-free multi-molecular landscape of colorectal and stomach cancer, and provides a potential monitoring utility in blood for the personalized cancer treatment.


Machine learning promises to accelerate materials discovery by allowing computational efficient property predictions from a small number of reference calculations. As a result, the literature has spent a considerable effort in designing representations that capture basic physical properties so far. In stark contrast, our work focuses on the less-studied learning formulations in this context in order to exploit inner structures in the prediction errors. In particular, we propose to directly optimize basic loss functions of the prediction error metrics typically used in the literature, such as the mean absolute error or the worst case error. In some instances, a proper choice of the loss function can directly reduce reasonably the prediction performance in the desired metric, albeit at the cost of additional computations during training. To support this claim, we describe the statistical learning theoretic foundations, and provide supporting numerical evidence with the prediction of atomization energies for a database of small organic molecules.


Academic literature to date has effectively proven the scale of plastic pollution's harm to the environment. Some scholars have even argued that it should be discussed broadly in society as a crisis (Mæland & Staupe‐Delgado 2019). To reduce plastic pollution, potential policies need widespread support. Existing literature shows framing manipulations can influence opinion and care for plastic pollution but have not been tied to policy support. This study looked to assess the difference in policy support between groups framed with plastic pollution contributing to climate change causing emissions, plastic pollution endangering charismatic animals, or a control framing with simple information regarding how plastic enters the environment. The hypothesis being tested was that a climate change frame would be more impactful than a charismatic animal frame and therefore be associated with higher policy support. This was tested through a survey experiment of 600 respondents on an online survey platform. Analysis was conducted through SPSS using two regression models for accuracy. The hypothesis was not supported; overall, the control framing and charismatic animal frames were associated with higher support of the most outcome variables. This shows that plastic reduction policies with strong framing may trigger strong identities, and therefore simple explanatory information may be more sufficient. Furthermore, this paper discusses the impact of framing on political and sex subgroups, elucidating a clearer understanding of how these identities differ in support of plastic reduction policies and behavior changes.


Automatic gain control using an all-optical feedback loop in in-line erbium-doped fiber amplifiers (EDFA's) used in hybrid analog/digital wavelength division multiplexing (WDM) systems was studied. It is found that the signal level variation for the digital channels can be maintained within a range /spl les/3-dB between the presence and dropout of the analog channel when the narrowband feedback is centered at the amplified spontaneous emission (ASE) peak (/spl sim/1532 nm) with loop loss ranging between 13-22 dB. Robust transmission at 2.5 Gb/s without measurable power penalty was obtained for the digital channels when the EDFA was saturated by either the analog or the control lasing signal.


Abstract This article explores how power relations are constructed in the governance of higher education institutions. It examines and deconstructs, from a Foucauldian perspective, power relations and mechanisms in the relationship between the state and higher education institutions, and between academic and management staff. This research article originates from a benchmarking project. The data was collected by a structured questionnaire that was developed to allow the research team to map the governance structures and processes on four main governance areas: internal and external stakeholders; decision-making bodies and actors; quality of governance; and key performance indicators. The surprising finding is that governments have used their authority to influence and shape the governance structures of their higher education institutions, but also their decision-making processes. We suggest that, as the external and internal environments of higher education institutions are not the same, there is no 'one-size-fits-all' model of 'good governance' for higher education.


The key idea of this paper is that the relative price of primary commodities in terms of manufactured goods affects the likelihood of actual conflicts. The empirical application focused on a panel of Sub-Saharan African countries for the period 1995-2006. Results are not fully conclusive. However, there is robust evidence that a proxy of world price of manufactured goods is negatively associated with the likelihood of a civil war. The conclusion would be that an increase in world prices of manufactured goods would make civil wars less likely.


This study investigated the effects of size, size distribution, specific surface area, surface roughness, crystallinity, and fine content (< 5 pim fraction) of lactose microcarrier on the pulmonary inhalation profiles of rifampicin encapsulated in polyvinylpyrrolidone nanoparticles (194.77 ± 9.52 ran). The spherical lactose was modified through solvation and reprecipitation processes using aqueous ethanolic solution with different ethanol contents. The reprecipitated lactose had smaller particle size, wider size distribution, larger specific surface area, more elongated shape, smoother surface texture and lower crystallinity than the unprocessed lactose. They contained fine particles of sizes smaller than 5 /an of which none was found in the unprocessed lactose. Cascade impactor and scanning electron microscopy analysis of lactose-nanoparticle blends indicated that unprocessed lactose carried nanoparticles through surface adsorption and pore immersion methods. The small, less crystalline and elongated processed lactose carried nanoparticles through surface adsorption and encapsulation via inter-lactose aggregation. The aggregative tendency of these lactoses increased with reduced size and crystallinity and a increased surface roughness that provided more active sites for particulate interaction. This improved the fine particle dose, fine particle fraction, percent dispersed, percent inhaled of nanoparticles due to their ability to remain attaching to lactose during aerosolization, and detach for deep lung deposition in late time domain unlike those immersed in pores of unprocessed lactose. Overall, a lactose fine content amounting to less than 9 % or more than 12 % was detrimental to aerosolization. Excessive fine reduced nanoparticle attachment. Suboptimal fine content discouraged nanoparticle detachment and deposition.


A prospective study has been carried out to assess the incidence, prevalence and cost implications of drugrelated problems in patients with chronic diseases dwelling in a south Indian rural community setting. Details of patients with chronic diseases were recorded in a suitably designed data collection form and assessed for the potential drug-related problems in the prescriptions with the patient's consent. Hepler and Strand classification was used to categorize the identified drug related problems. Each drug-related problem was assessed for its significance level and graded either as minor, moderate or major based on expected clinical outcome. Cost implications due to drug-related problems were also evaluated. During the study period, the research pharmacist visited 550 houses and interviewed 2370 people. Among the interviewed individuals, 215 (8.36%) people were found with chronic diseases. A total of 90 drug-related problems were observed in the patients' prescriptions who met the study criteria. Noncompliance (22), untreated indications (18) and drug interactions (14) were the most commonly found drug-related problems. Among all drug-related problem's, 9 drug related problems were graded as major, 37 were moderate and 44 were minor in severity. It is estimated that, a sum of 84 64 950 rupees could have been saved through the pharmacist intervention.


Managers face a constant challenge to develop specific capabilities that will assist them to deploy resources which provide positional advantages in an effort to achieve superior financial or customer performance. To address mechanisms to provide solutions for these challenges, this study examines the relationships between marketing planning capability, marketing mix implementation capability, market orientation (MO) and customer-centric performance. The contention is raised and supported that firm resource–capability co-alignment drives towards superiority in customer-centric performance. The results of a survey of senior executives from firms in Australia show that marketing planning capability and MO improve marketing implementation capability, which in turn fosters customer-centric performance (customer attraction and customer retention). In particular, while MO and marketing planning capability do impact marketing mix implementation capability, marketing planning capability does so more significantly than MO. The contribution of this study is in examining marketing across three main domains: marketing as culture; strategy; and tactics in SMEs in Australia.


Cytological analysis of four Serapias L. (Orchidaceae), of which two are Sicilian endemics, is carried out. In particular, the endemic S. intermedia subsp. hyblaea shows a triploid chromosome complement with 2n = 3x = 54, representing natural nothotaxa arising from a hybridization process between supposed parental S. vomeracea (2n = 2x = 36) and Serapias lingua (2n = 4x = 72). For each of them the C-heterochromatin distribution, using Giemsa C-banding and karyotypes, was examined. The other endemic taxon (S. orientalis subsp. siciliensis) is characterized by a diploid chromosome number 2n = 2x = 36, of which the C-heterochromatin distribution is examined as well. The taxonomical relationships among these taxa are discussed in relation to the literature data.


A number of putative transcription factors described in the pituitary have been implicated as key elements in the processes that direct pituitary development. Three recently described proteins, Ptx1, Ptx2, and Ptx3, define a new family of transcription factors, the Ptx subfamily, within the paired-like class of homeodomain factors. In mice, Ptx1 and Ptx2 gene expression has been detected in the area of the pituitary primordium and is maintained throughout development in Rathke pouch and adult pituitary. In the present study, the expression of the Ptx1, Ptx2, and Ptx3 genes was characterized in the normal human pituitary and in the different types of human pituitary adenomas. Although no Ptx3 gene expression could be detected in these tissues, Ptx1 presented with a quite ubiquitous pattern of distribution, being expressed at quite constant levels in normal tissues and in all 60 pituitary tumors analyzed. The pattern of expression of the Ptx2 gene among the different subsets of pituitary adenomas was even more varied. No Ptx2 expression could be detected in corticotroph tumors. In contrast, high levels of Ptx2 messenger ribonucleic acid were measured in the gonadotroph tumors, although no specific correlation to other markers of the gonadotroph lineage differentiation, such as alphaGsu, LHbeta, or FSHbeta, could be evidenced. Finally, Ptx2 was also expressed in pure lactotroph adenomas and not in somatotroph adenomas. Ptx2 is, therefore, the first paired homeodomain pituitary transcription factor differentially expressed in these two lineages, which derive from a common precursor. These results support a role for Ptx2 in the terminal differentiation of somatotroph and lactotroph cell phenotypes.


COVID-19 and arrhythmias. SARSCoV-2 infections have important implications for cardiovascular diseases. Cardiovascular diseases are important risk factors for severe courses of COVID-19 disease and the COVID-19 disease may trigger cardiovascular complications such as myocarditis or arrhythmias. It is of great importance to monitor the interaction of drugs that are used in the treatment of COVID-19 and drugs with the potential for QT prolongation such as antiarrhythmics. J Kardiol 2020; (27): 168–70.


The sol-gel method was employed to prepare the Eu3+-doped TiO2 thin films. The influence of doping concentration and annealing temperature on the structures and photoluminescence (PL) properties was investigated. The result of X-ray diffraction revealed that all the films are of anatase phase. It is shown that the PL intensities of the films increased with Eu3+ concentration and reached the maximum at 1.4 mol%, then decreased with the concentration. Observed anatase phase appeared at temperature above 400 °C, and the luminescence intensity increased with the increase of annealing temperature.


PURPOSE
We report results of a randomized trial comparing ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy alone with treatment that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma.

PATIENTS AND METHODS
Patients with nonbulky clinical stage I to IIA Hodgkin's lymphoma were stratified into favorable and unfavorable risk cohorts. Patients allocated to radiation-containing therapy received subtotal nodal radiation if favorable risk or combined-modality therapy if unfavorable risk. Patients allocated to ABVD received four to six treatment cycles.

RESULTS
We evaluated 399 patients. Median follow-up is 4.2 years. In comparison with ABVD alone, 5-year freedom from disease progression is superior in patients allocated to radiation therapy (P = .006; 93% v 87%); no differences in event-free survival (P = .06; 88% v 86%) or overall survival (P = .4; 94% v 96%) were detected. In a subset analyses comparing patients stratified into the unfavorable cohort, freedom from disease progression was superior in patients allocated to combined-modality treatment (P = .004; 95% v 88%); no difference in overall survival was detected (P = .3; 92% v 95%). Of 15 deaths observed, nine were attributed to causes other than Hodgkin's lymphoma or acute treatment-related toxicity.

CONCLUSION
In patients with limited-stage Hodgkin's lymphoma, no difference in overall survival was detected between patients randomly assigned to receive treatment that includes radiation therapy or ABVD alone. Although 5-year freedom from disease progression was superior in patients receiving radiation therapy, this advantage is offset by deaths due to causes other than progressive Hodgkin's lymphoma or acute treatment-related toxicity.


This paper reports on two case-studies on the impact of Open Educational Resources taken from an investigation carried out on OpenLearn, the UK Open University Open Content Initiative funded by the Flora and Hewlett Foundation between April 2006 and April 2008. The project has re-purposed several thousand hours of learning materials selected from the university's course provision into freely available units of study on a pair of twin sites, the LearningSpace (aimed primarily at learners) and the LabSpace (the experimental space aimed primarily at other educators). The case-studies form part of a broader investigation into engagement with communication and discussion tools provided by OpenLearn.
Each of the case-studies revolves around a collaborative mini-project involving OpenLearn staff and a subject-specialist. The mini-projects were set up with the twofold aim of providing a test bed for the use of resources and tools provided on the OpenLearn Web site whilst providing a context at the boundary between 'formal' and 'informal' learning. Each mini-project was structured around a series of videoconferences supported with a study unit on the LabSpace (containing resources as well as further communication tools), the first focusing on the area of ethics and technology for practitioners, and the other focusing on the area of collaborative design at introductory level.
This paper describes the process of organising and supporting the mini-projects as one of co-creating new spaces and roles for stakeholders involved in teaching and learning. The learning situations created in the mini-projects are located as samples from the 'informal learningi?½/i?½formal learning' continuum afforded by OpenLearn, which suggests a number of boundary issues in relation to curriculum and pedagogy for online learning as well as discourses and technologies of 'opennessi?½


Relative expression quantitative real-time polymerase chain reaction (RT-qPCR) experiments are a common means of estimating transcript abundances across biological groups and experimental treatments. One of the most frequently used expression measures that results from such experiments is the relative expression ratio (RE), which describes expression in experimental samples (i.e., RNA isolated from organisms, tissues, and/or cells that were exposed to one or more experimental or nonbaseline condition) in terms of fold change relative to calibrator samples (i.e., RNA isolated from organisms, tissues, and/or cells that were exposed to a control or baseline condition). Over the past decade, several models of RE have been proposed, and it is now clear that endogenous reference gene stability and amplification efficiency must be assessed in order to ensure that estimates of RE are valid. In this review, we summarize key issues associated with estimating RE from cycle threshold data. In addition, we describe several methods based on linear modeling that enable researchers to estimate model parameters and conduct quality control procedures that assess whether model assumptions have been violated.


In this paper, a systematic method for the tuning of multiple power system controllers using symbolic eigensensitivity analysis and linear programming is presented. The concept of eigenvalue sensitivity is used here to formulate the linear first-order variation of the real part of the dominant system eigenvalue as a symbolic function of controller parameters. This eigenvalue variation is minimized iteratively subject to linear equality and inequality constraints. All controller parameters are tuned correctly when the objective function meets the desired performance criteria. In this method, no special assumptions are made on the type of power devices and linear feedback controllers present in the system. The proposed method is illustrated with three examples of a single-machine system with a power system stabilizer and a controller for a thyristor-controlled series capacitor. The tested configurations are supplemented with nonlinear time-domain simulations validating the small-signal stability results. >


While previous studies suggested that regressive forms of onset were not common in autism spectrum disorder (ASD), more recent investigations suggest that the rates are quite high and may be under‐reported using certain methods. The current study undertook a systematic investigation of how rates of regression differed by measurement method. Infants with (n = 147) and without a family history of ASD (n = 83) were seen prospectively for up to 7 visits in the first three years of life. Reports of symptom onset were collected using four measures that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective). Latent class growth models were used to classify individual trajectories to see whether regressive onset patterns were infrequent or widespread within the ASD group. A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings. Rates of regression were much lower using retrospective or categorical measures (from 29 to 47%). Agreement among different measurement methods was low. Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The accuracy of widely used methods of measuring onset is questionable and the present findings argue against their widespread use. Autism Res 2018, 11: 788–797. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.


Evacuation of abattoir waste waters into water bodies results in excessive proliferation of decomposers, thus causing oxygen depletion and eutrophication. This study is designed to find means of effectively treating the abattoir waste water before they are reused or discharged into water bodies. The waste water was taken from open drainage before it discharges into Ikpoba river water body and subjected to physicochemical and thermal treatment prior to adsorption by granulated activated charcoal (GAC). The waste water and treated water were analysed for chemical oxygen demand (COD), biochemical oxygen demand (BOD5), total nitrogen (TN), ammonium nitrogen, total phosphate (TP), total solid content (TSC), dissolved solid content (DSC), suspended solid and pH to ascertain the removal efficiency of the treatment procedure. The study revealed that the removal efficiency using a combination of adsorption, physicochemical and thermal treatment in treating waste water from an abattoir was most efficient for total phosphate (95.78%) and least efficient for dissolved solid content (64.80%). Keywords : Heat, Coagulant, Adsorption, Treatment, Abattoir, Wastewater.


Thermal diffusivity of the composites of camphor sulphonic acid (CSA) doped polyaniline (PANI) and its composites with cobalt phthalocyanine (CoPc) has been measured using open cell photoacoustic technique. Analysis of the data shows that the effective thermal diffusivity value can be tuned by varying the relative volume fraction of the constituents. It is seen that polaron assisted heat transfer mechanism is dominant in CSA doped PANI and these composites exhibit a thermal diffusivity value which is intermediate to that of CSA doped PANI and CoPc. The results obtained are correlated with the electrical conductivity and hardness measurements carried out on the samples.


Vascular calcification (VC) is a critical complication in patients with chronic kidney disease (CKD). The effects of spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, on VC have not been fully investigated in CKD. The present in vivo study determined the protective effects of SPL on VC in CKD rats. Rats were divided into a control group and four groups of rats with adenine-induced CKD. Three groups were treated with 0, 50, and 100 mg·kg(-1)·day(-1) SPL for 8 wk, and one group was treated with 100 mg·kg(-1)·day(-1) SPL for the last 2 wk of the 8-wk treatment period. After 8 wk, CKD rats developed azotemia and hyperphosphatemia, with increases in the expression of serum and glucocorticoid-regulated kinase-1 and sodium-phosphate cotransporter, in inflammation and oxidative stress level, in osteogenic signaling and apoptosis, and in aortic calcification, compared with control rats. SPL dose dependently decreased these changes in the aortas, concomitant with improvements in renal inflammation, tubulointerstitial nephritis, and kidney function. SPL neither lowered blood pressure level nor induced hyperkalemia. Treatment of CKD rats for the last 2 wk with 100 mg·kg(-1)·day(-1) SPL attenuated VC compared with CKD rats with the same degree of kidney function and hyperphosphatemia. In conclusion, SPL dose dependently inhibits the progression of VC by suppressing MR signaling, local inflammation, osteogenic transition, and apoptosis in the aortas of CKD rats.


Microstructural characterization and temperature analysis have been performed in friction stir welding (FSW) of A383 and 5052 dissimilar aluminum alloys. Marked difference in microstructure was observed between joints with different arrangements of materials. The temperature at four points on each side of the joint line was measured during FSW in various conditions. In addition, an analytical model assumed that the work generated by the rotation of the tool led to the work for stirring materials and heat generation of the material and the tool. The temperature of the retreating side (RS) for the joint of the advancing side (AS):A383/RS:5052 was about 50K higher than that of AS, while the temperatures of AS and RS for the joint of AS:5052/RS:A383 were almost the same. The experimental temperature could be calculated reasonably by using the model with assumption of the work for stirring the material.


AIMS
Our objective was to explore the functional interdependence of protein kinase A (PKA) phosphorylation with binding of modulatory FK506 binding proteins (FKBP12/12.6) to the ryanodine receptor (RyR). RyR type 1 or type 2 was prepared from rabbit skeletal muscle or pig cardiac muscle, respectively. In heart failure, RyR2 dysfunction is implicated in fatal arrhythmia and RyR1 dysfunction is associated with muscle fatigue. A controversial underlying mechanism of RyR1/2 dysfunction is proposed to be hyperphosphorylation of RyR1/2 by PKA, causing loss of FKBP12/12.6 binding that is reversible by the experimental inhibitory drug K201 (JTV519). Phosphorylation is also a trigger for fatal arrhythmia in catecholaminergic polymorphic ventricular tachycardia associated with point mutations in RyR2.

METHODS AND RESULTS
Equilibrium binding kinetics of RyR1/2 to FKBP12/12.6 were measured using surface plasmon resonance (Biacore). Free Ca(2+) concentration was used to modulate the open/closed conformation of RyR1/2 channels measured using [(3)H]ryanodine binding assays. The affinity constant-K(A), for RyR1/2 binding to FKBP12/12.6, was significantly greater for the closed compared with the open conformation. The effect of phosphorylation or K201 was to reduce the K(A) of the closed conformation by increasing the rate of dissociation k(d). K201 reduced [(3)H]ryanodine binding to RyR1/2 at all free Ca(2+) concentrations including PKA phosphorylated preparations.

CONCLUSION
The results are explained through a model proposing that phosphorylation and K201 acted similarly to change the conformation of RyR1/2 and regulate FKBP12/12.6 binding. K201 stabilized the conformation, whereas phosphorylation facilitated a subsequent molecular event that might increase the rate of an open/closed conformational transition.


Current methods of determining the specific gravity, moisture content, and absorption of concrete aggregates (ASTM Test Method for Specific Gravity and Absorption of Coarse Aggregate [C 127], ASTM Test Method for Specific Gravity and Absorption of Fine Aggregate [C 128], and ASTM Test Method for Total Moisture Content of Aggregate by Drying [C 566]) are slow and dependent upon subjective "end-point" determinations as well as requiring elaborate and cumbersome equipment. Presented here is a method using simple equipment, the siphon can, to accomplish all three tests. This technique has an objective "end-point" and statistical error of measurement one-quarter that of ASTM C 127 or C 128. Derivation of formulae and method of application are discussed. The use of this technique in routine concrete production can result in large savings to concrete producers.


Income assistance programs (e.g., Temporary Assistance to Needy Families; TANF) and child welfare service (CWS) programs have implicit intentions to prepare children for an adulthood that is free from serious criminal activity. This cross-sectional study compares the felonious arrests as adults of youth who were involved with TANF (n = 6,596) with those who were involved with CWS (n = 1316). In the CWS population, we compare youth who emancipated from foster care (n = 841), those who reunified (n =278), and those with other exits (n = 197). Outcomes of interest include the severity of the felony an individual was charged with as an adult as well as the hazard of being arrested after age 16 years. Findings show that as adults, TANF-involved youth are less likely than former foster youth to be charged with a felony; moreover, when former TANF youth are charged with felonies as adults, the felonies are less severe than felony charges incurred by former foster youth. Overall, as young adults, males and African American youth are not only more likely to be charged with felonies than other race youth or females but also are more likely to be charged with felonies of higher severity ratings than other race youth or females. Entering foster care as an adolescent and having multiple placements in care are associated with poorer outcomes in adulthood. However, youth who remain in foster care longer are less likely to be charged with a felony. The study confirms earlier work on adverse criminal justice-related outcomes for former foster youth and clarifies the need for specific interventions to reduce subsequent criminal involvement.


The main goal of this research is to describe the role of spiritual leadership or prophetic leadership for development Islamic education. Research conducted in five schools that implement the prophetic leadership and his school well developed. The conclusions of this research are: first, spiritual leadership is very effective for building organizational culture of the school. Secondly, spiritual leadership is the leadership based on piety, leadership by holy war spirit and total leadership. Their hearts, heads, and hands are used for serving and obedience for the sake of God (mardlôtillah). Third, Spiritual leadership proves to be able to make effective school: conducive school organization culture, effective school organization process and learning innovation. Fourth, spirituality that develops in the leadership is ascetic spirituality. Ascetic spirituality is intensive obedience to God resulting in good deed.


It was shown that an increase of temperature (from 0 to 37 degrees C) did not affect the maximum position of the myosin fluorescence spectrum and relative contribution of tyrosine to fluorescence intensity. The spectral band width increases to 2-3 nm. The I (t-o) relationship permits us to sugges that the temperature change causes structural changes of myosine molecules.


PURPOSE
To evaluate the efficacy of CO2 in aortobifemoral DSA with a pressure- and volume-controlled injector.

MATERIALS AND METHODS
In an intraindividual prospective study, 42 patients with arterial occlusive disease underwent stepwise aortobifemoral DSA with CO2 and with iopromid 300.

RESULTS
With Co2, diagnostic images were obtained in 74% of the iliac, 98% of the femoral, 89% of the popliteal arteries, but in only 36% of the arteries of the lower leg. 73% of the stenoses were correctly identified. With therapeutic relevance 8% of the stenoses were overestimated. The length of 1 of 53 occlusions was overestimated and 3 occlusions were simulated. No stenoses or occlusion was missed. There were no severe side-effects. The injector proved to be safe and easy to handle. Fragmentation of the CO2 bolus could be compensated by postprocessing with a minimum opacification summation mode.

CONCLUSIONS
With the equipment used, CO2 was a safe alternative to iodinated CM in routine stepwise aortobifemoral DSA of the iliac, femoral, and popliteal arteries. Because of the risk of overestimation, occlusions and high grade stenoses should be verified with selective injections or iodinated CM before PTA or operations.


Results of wind-tunnel tests of a semispan model of a triangular wing of aspect ratio 2 with a skewed wing-tip flap are presented. Lift, drag, pitching-moment, and hinge-moment data are included for subsonic Mach numbers up to 0.95. The flap showed extremely high hinge moments and low effectiveness as a longitudinal control. Although less affected by compressibility, this flap is indicated to be inferior to a constant-chord flap when applied to this triangular wing.


Peaches are a popular fruit appreciated by consumers due to their eating quality. Quality evaluation of peaches is important for their processing, inventory control, and marketing. Eleven quality indicators (shape index, volume, mass, density, firmness, color, impedance, phase angle, soluble solid concentration, titratable acidity, and sugar–acid ratio) of 200 peach fruits (Prunus persica (L.) Batsch "Spring Belle") were measured within 48 h. Quality indicator data were normalized, outliers were excluded, and correlation analysis showed that the correlation coefficients between dielectric properties and firmness were the highest. A back propagation (BP) neural network was used to predict the firmness of fresh peaches based on their dielectric properties, with an overall fitting ratio of 86.9%. The results of principal component analysis indicated that the cumulative variance of the first five principal components was 85%. Based on k-means clustering analysis, normalized data from eleven quality indicators in 190 peaches were classified into five clusters. The proportion of red surface area was shown to be a poor basis for picking fresh peaches for the consumer market, as it bore little relationship with the comprehensive quality scores calculated using the new grading model.


In response to the murals painted by William Bell Scott in the National Trust property Wallington House in Northumberland, McIntyre's research speculated on how to use mural scale drawing to revisit some of the locations featured in the original Northumbrian landscape. 3 large ink on Fabriano paper line drawings were developed that examine ideas around 'Lines of Desire'. These interrogated and eulogised the geology and physical contours of key locations including Steel Rig on Hadrian's Wall and Lindisfarne Castle on the coast.

The works were then site specifically installed in one of the public meeting rooms at Wallington to create 'The Withdrawing Room' inviting a new and novel interpretation for audiences on the concept of a space in a stately house where visitors are entertained and informed.

The 'Unfinished Business' group exhibition at Wallington House during the summer of 2011 was curated by Dorsett and featured other Northumbria academic staff and graduates.


Titin, the largest protein known to date, has been linked to sarcomere assembly and function through its elastic adaptor and signaling domains. Titin's M-line region contains a unique kinase domain that has been proposed to regulate sarcomere assembly via its substrate titin cap (T-cap). In this study, we use a titin M line–deficient mouse to show that the initial assembly of the sarcomere does not depend on titin's M-line region or the phosphorylation of T-cap by the titin kinase. Rather, titin's M-line region is required to form a continuous titin filament and to provide mechanical stability of the embryonic sarcomere. Even without titin integrating into the M band, sarcomeres show proper spacing and alignment of Z discs and M bands but fail to grow laterally and ultimately disassemble. The comparison of disassembly in the developing and mature knockout sarcomere suggests diverse functions for titin's M line in embryonic development and the adult heart that not only involve the differential expression of titin isoforms but also of titin-binding proteins.


The pod and yield characteristics of Moringa oleifera plants grown in Ibadan (Rainforest vegetation), Nsukka (Forest-derived savannah vegetation) and Jos (arid derived savannah vegetation) were evaluated from 2007- 2009 to assess adaptability of the plant to climate change threats. The rainfall and temperature distribution in the three locations varied over the years. The Moringa oleifera plants grown at Ibadan had the greatest pod and seed yield followed by those at Nsukka and Jos in that order. The annual pod and seed production capacities of the plants differed significantly (p < 0.05) in the different locations. The overall annual pod and seed production per location, including yield characteristics, did not differ significantly throughout the years of study. Moringa oleifera was therefore found to be a suitable crop adaptable to various environmental and climatic changes in Nigeria.


BACKGROUND & AIMS
Gut hormones represent attractive therapeutic targets for the treatment of obesity and type 2 diabetes. However, controversy surrounds the effects that adiposity, dietary manipulations, and bariatric surgery have on their circulating concentrations. We sought to determine whether these discrepancies are due to methodologic differences.

METHODS
Ten normal-weight males participated in a 4-way crossover study investigating whether fasting appetite scores, plasma acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), and peptide YY3-36 (PYY3-36) levels are altered by study-induced stress, prior food consumption, and sample processing.

RESULTS
Study visit order affected anxiety, plasma cortisol, and temporal profiles of appetite and plasma PYY3-36, with increased anxiety and cortisol concentrations on the first study day. Plasma cortisol area under the curve (AUC) correlated positively with plasma PYY3-36 AUC. Despite a 14-hour fast, baseline hunger, PYY3-36 concentrations, temporal appetite profiles, PYY3-36 AUC, and active GLP-1 were affected by the previous evening's meal. Sample processing studies revealed that sample acidification and esterase inhibition are required when measuring acyl-ghrelin and dipeptidyl-peptidase IV inhibitor addition for active GLP-1. However, plasma PYY3-36 concentrations were unaffected by addition of dipeptidyl-peptidase IV.

CONCLUSIONS
Accurate assessment of appetite, feeding behavior, and gut hormone concentrations requires standardization of prior food consumption and subject acclimatization to the study protocol. Moreover, because of the labile nature of acyl-ghrelin and active GLP-1, specialized sample processing needs to be undertaken.


Changbai larch (Larix olgensis Henry) is one of the main plantation species in the northern part of China, but so far its utilization has been limited to solid wood, pulping, and paper products. As part of a national initiative, the objective of this work was to develop a good understanding concerning how stand management practices affect larch wood and veneer properties. To cope with the variation of initial and final stand density, the term "relative thinning intensity (RTI)" was introduced to describe the effect of stand thinning on the resulting wood and veneer properties. Nine representative sample trees each from four stands were harvested, then trimmed and bucked. Six 1.25 m long bolts along the entire tree stem were systematically cut to peel 2.6 mm thick veneers. Clear wood specimens were also sawn from matched bolts for mechanical testing for the purpose of comparison and validation. The correlation between the main tree variables and properties of clear wood and veneer was analyzed, and the influence of RTI on key wood and veneer properties was examined and compared. A good correlation was found in density and modulus of elasticity (MOE) between larch clear wood and veneer, giving an R2 of 0.75 and 0.71, respectively. This indicates that veneering can be potentially used to characterize this larch species. The stand with the lowest RTI had the shortest rotation but yielded the best properties of both clear wood and veneer, which highlights the importance of stand management in terms of thinning.


Discrete time spatial time series data arise routinely in meteorological and environmental studies. Inference and prediction associated with them are mostly carried out using any of the several variants of the linear state space model that are collectively called linear dynamic spatio-temporal models (LDSTMs). However, real world environmental processes are highly complex and are seldom representable by models with such simple linear structure. Hence, nonlinear dynamic spatio-temporal models (NLDSTMs) based on the idea of nonlinear observational and evolutionary equation have been proposed as an alternative. However, in that case, the caveat lies in selecting the specific form of nonlinearity from a large class of potentially appropriate nonlinear functions. Moreover, modeling by NLDSTMs requires precise knowledge about the dynamics underlying the data. In this article, we address this problem by introducing the Gaussian random functional dynamic spatio-temporal model (GRFDSTM). Unlike the LDSTMs or NLDSTMs, in GRFDSTM both the functions governing the observational and evolutionary equations are composed of Gaussian random functions. We exhibit many interesting theoretical properties of the GRFDSTM and demonstrate how model fitting and prediction can be carried out coherently in a Bayesian framework. We also conduct an extensive simulation study and apply our model to a real, SO2 pollution data over Europe. The results are highly encouraging.


Two significant phenomena emerge from recent internet development: consumers are influenced by social network; and consumers engage in consumption and production of user-generated content. This dissertation studies social influence and social media.
In Chapter 1, we study how summer internship employer choices of MBA students at a major university are influenced by the choices made by their fellow students. We develop a simultaneous model of each individual's choice as a function of other students' choices. Our model of interdependence in decision making is structural and equilibrium-based. Also, the model is general enough to allow both positive and negative effects of average group choices on any individual's decision. The structure of our data enables us to identify endogenous social effects separately from exogenous or correlated effects. Specifically, in our data we see each student making choices about whether or not to apply for each job opening; exogenous and correlated effects do not vary in this sample and therefore endogenous effects are identified. We employ a two-stage procedure to address the endogeneity of choices: we estimate empirical choice probabilities in the first stage, and taste parameters for employer attributes and peer influence in the second stage. Our results show that as expected, students prefer jobs with strong employer attributes (e.g. high salary, large firm size). In addition, students are influenced by their peers' choices. However, in contrast to previous studies, we find negative (rather than positive) social effects. That is, strong attributes also make an internship employer less attractive, leading to a lower choice probability relative to cases of zero or positive social effects. This negative social effect is consistent with congestion, i.e. students are aware that a good internship will attract the interest of more students, thus lowering the odds of getting it. We find that these negative social effects are stronger for students with more work experience and stronger GMAT scores. While positive social effect leads to concentration of choices, negative social effect helps prevent concentration.
In chapter 2, we analyze how large content-sharing websites operate for companies like Google and Yahoo. A content website provider needs to understand content users to achieve different objectives. Consumers searching content take sampling probability as given in deciding consumption, and producers are motivated by endorsement. Sampling probability is a key policy instrument. Endorsement may explain why a small number of producers generate most content. Individual behaviors alone cannot explain genesis and persistence of sampling probability and endorsement. Two distinguishing features of content—being free and non-rival preclude application of celebrated market equilibrium theory. We develop a content equilibrium from first principles. Consumer and producer can be compatible, and their interaction gives rise to endogenous sampling probability and endorsement. Inequality arises: higher quality producers always earn more endorsement and produce more content; and higher quality content is easier to find. Content system is optimal for consumer welfare despite inequality. Content system possesses a self-organization property to find equilibrium from other less desired states. We use this framework to show policy conflict may arise due to content firm's multiple identities.


Author(s): Martens, Lauren Herl | Advisor(s): Farese, Jr., Robert V | Abstract: Loss-of-function mutations in progranulin (GRN) that result in haploinsufficiency of the progranulin protein (PGRN) have been causally linked to frontotemporal dementia (FTD). PGRN levels are tightly regulated, as high levels cause cancer and low levels cause FTD. PGRN is a secreted glycoprotein implicated in cell survival, proliferation, and inflammation. In the central nervous system (CNS), PGRN is expressed by neurons and microglia, but its cellular functions remain unclear. We generated a murine model of PGRN-deficiency in order to begin to elucidate the CNS function of PGRN, and to model aspects of human FTD. We explored the cell type contributions of PGRN deficiency to CNS injury using the acute toxin model of 1-methyl-4-(2'methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), which is known to cause both neuroinflammation and neuron death. We determined that PGRN deficiency leads to uncontrolled neuroinflammation that is detrimental to neuron survival. Therefore, microglial PGRN is critical for regulating neuroinflammation following acute brain injury. The PGRN deficient mice were aged in order to determine whether they model FTD behaviorally and/or pathologically. The homozygous PGRN deficient mice developed behavioral changes that may be linked to their age-dependent CNS inflammatory phenotype. These data suggest the importance of microglial PGRN in normal aging. Interestingly, the heterozygous and homozygous PGRN deficient mice have similar early behavioral changes, but the heterozygous mice lack any gross neuroinflammatory pathology. These early behavioral phenotypes in PGRN-deficient animals are linked to alterations in neuronal activity, suggesting that PGRN is important for neuronal function. It is likely that PGRN deficiency causes early neuron dysfunction that triggers gliosis. The gliosis then proceeds uncontrolled due to the lack of microglial PGRN that exacerbates the neuronal phenotype, thereby causing a vicious positive feedback loop that is detrimental to neuronal function and survival. Our data suggests that PGRN is important for both neuronal and microglial function in normal aging. Further characterization of these aging phenotypes in cell-type specific models of PGRN deficiency are critical for exploring this hypothesis. Overall, the development of therapeutic strategies to regulate PGRN levels in both neurons and microglia has implications for both neurodegeneration and CNS injury.


The game of football has transformed from just being a game into a huge economic market attracting investors from all over the world. As clubs spend more and more money on player acquisitions, player registrations (considered intangible assets) now represent a significant part of the total assets of major European football clubs. Due to this, treatment of player registrations has become a significant accounting issue.The purpose is to analyze and compare from the perspective of an investor, how a sample of European football clubs account and disclose values of player registrations. The purpose aim to answer the questions how and what kind of information each club discloses on their financial statements. Also, are current accounting procedures and disclosure harmonized, and do they present a true and fair view of top European clubs financial status.A descriptive case study was the most appropriate as it aims to answer the questions "how" and "why". A sample selection filter was set in the beginning of the process together with the research questions. The final sample was set to be: Arsenal FC, Manchester United, Borussia Dortmund, Juventus FC and FC Porto. The purpose of the selection filter was to get a study both fair on economical as well as competitive sports level. Primary data consist of information from annual financial reports, and in order to enhance validity, interviews with professionals have been conducted and used. Findings show similarities as well as differences in disclosure and treatment of football player registrations. All clubs meet the minimum requirements from IAS 38 and UEFA. However, how and what kind of information each clubs disclose differ substantially and due to lack of valuation models and the possibility to capitalize home-grown players and free agents, the value of player registrations is not presented in a true and fair view.