Background: The level of high-density lipoprotein cholesterol (HDL-C) is an important risk indicator and used in risk factor counting and quantitative risk assessment; however, the effect of HDL-C in young male patients with acute myocardial infarction (AMI) is unclear. The aim of this study was to investigate the effect of HDL-C in young male patients. Methods: We recruited 267 consecutive young male patients (⩽44 years) diagnosed with AMI. Other 247 participants free from coronary heart disease were enrolled as controls. HDL-C levels of AMI patients and controls were evaluated to analyze the predictive value on AMI. According to the cutoff point of 1.04 mmol/L HDL-C, patients of AMI were divided into two subgroups (normal HDL-C group and low HDL-C group) and were followed up for 2 years. Clinical end points included all major adverse coronary events (MACEs): the main cause of death, nonfatal myocardial infarction, readmissions for acute coronary syndrome, arrhythmias, or revascularization. The prognostic value of HDL-C was evaluated using Cox regression according to MACE. Results: Patients of AMI had decreased proportion in normal HDL-C group compared to controls (47.2% vs. 57.9%; P = 0.017). Logistic regression analysis showed that there was an inverse relationship between HDL-C and AMI in young males. In the low HDL-C subgroup of AMI patients (n = 141), 34 (24.1%) patients experienced a MACE during the 2-year follow-up, compared with 15 (11.9%) patients in normal HDL-C subgroup (n = 126). The Cox regression analysis showed that HDL-C was an independent predictor of a MACE during the follow-up period (hazard ratio = 0.354, P = 0.006). Conclusion: HDL-C was an important parameter for predicting the risk and the clinical outcomes of AMI in young male patients.


A senior capstone transmission expansion planning project is presented for a large-scale synthetic grid. Parameters such as generation, load, and contingencies are incorporated in the case to create summer peak load cases over a period of seven years. The methodologies to create the load case, containing the seven year load growth projection, and the solution case, containing the proposed upgrades for each year, are presented.


This paper is concerned with the initial-boundary value problems of scalar transport equations with uncertain transport velocities. It was demonstrated in our earlier works that regularity of the exact solutions in the random spaces (or the parametric spaces) can be determined by the given data. In turn, these regularity results are crucial to convergence analysis for high order numerical methods. In this work, we will prove the spectral convergence of the stochastic Galerkin and collocation methods under some regularity results or assumptions. As our primary goal is to investigate the errors introduced by discretizations in the random space, the errors for solving the corresponding deterministic problems will be neglected.


This paper discusses the implementation of a casemix accounting system within a large New Zealand public hospital. In the context of health care, casemix accounting systems are involved in attempts to increase the cost-consciousness of clinicians through the rationalisation and codification of clinical activity. The paper considers the power effects of casemix accounting using a perspective that views such information and control systems as disciplinary technologies. The complex and contradictory setting of the hospital characterised by a negotiated order meant that while the casemix accounting system did appear to provide some controlling influence, it also produced forms of resistance on the part of the clinicians. Our experience suggests that such systems are best thought of as making possible a new discursive space within which all organisational participants, in this case both management and clinicians, can act.


A crossover design is considered for the bioequivalence of two test formulations with a control. It could be considered as a better choice over crossover design because of the cost and experimental duration. Oh et al.(1998) derived crossover design and discussed its benefits over the typical crossover designs. We consider here the statistical models for crossover design and show its statistical properties. The statistical procedures for the bioequivalence in crossover design are shown through an example and the results are summarized by satisfying the 3 standards that proposed by the Korea Food and Drug Administration Guidelines for Bioequivalence.


Coffee can exert in vitro and ex vivo antimicrobial activity against several bacteria and fungi which are relevant for food safety and human health, including oral diseases. Coffee's antimicrobial activity can be attributed to several individual compounds, among them naturally occurring coffee compounds and those resulting from the roasting process. However, it is more likely that the antimicrobial activity results from the simultaneous action of various compounds. Some probable mechanisms for the antimicrobial activity are presented in this chapter but the exact mechanism remains to be elucidated. Roasted, but not green, coffee shows antimicrobial activity. The degree of roasting and coffee concentration affect the intensity and spectrum of antimicrobial activity; whereas the influence of other variables needs elucidation. Antimicrobial activity has also been found in coffee by-products with potential use in different applications and will be explored.


Amavata is a chronic, progressive and crippling disorder caused due to generation of ama and its association with vitiated vata dosha and deposition in shleshma sthana (joints). Clinically resembling with Rheumatoid Arthirtis, it poses a challenge for the physician owing to its chronicity, morbidity and complications. The treasure of Ayurveda therapeutics has laid out detailed treatment line for amavata. A 13years old male patient reported to this hospital with pain and stiffness of metacarpophalangeal joints of right hand followed by pain in corresponding joints of other hand 1 year back. This was succeeded by pain and mild swelling on bilateral wrist, ankle and elbow joints. Based on clinical examination and blood investigations, diagnosis of amavata was made and Ayurvedic treatment protocol was advised with baluka sweda (sudation) as external application, rasnasaptak kashayam and dashmoolharitaki avaleha for oral intake for 30 days. The patient was asked for follow up every 15 days up to total of 45 days. Assessment was done subjectively based on clinical symptoms and blood investigations as objective parameters. There was substantially significant improvement and the patient felt relieved of the pain and inflammation of the joints after the treatment. This case study reveals the potential of Ayurvedic treatment protocol in management of amavata and may form a basis for further detailed study of the subject.


Metal complexes with diffuse solvated electrons (solvated electron precursors) are proposed as alternative catalysts for the simultaneous CO2 capture and utilization. Quantum chemical calculations were used to study the reaction of CO2 with H2 and C2H4 to produce formic acid, methyldiol and δ-lactone. Mechanisms of a complete reaction pathway are found and activation barriers are reasonably low. The metal ligand complex readily reduces CO2 and significantly stabilizes CO2˙-. Ligand identity minimally influences the reaction. Additional reactions and future strategies are proposed with the goal of inducing experimental interest.


Thymocytes are known to possess receptors for glucocorticoids (GC) as well as for alpha, 25-dihydroxyvitamin D3 [1,25-(OH)2D3]. We have now investigated the distribution of the receptors for GC and 1,25-(OH)2D3 in rat thymocytes and compared the effects of the two steroid hormones on short term primary cultures of these cells. We report that in thymic cells, as in other tissues, 1,25-(OH)2D3 and GC bind specifically to distinct receptor molecules which exhibit sedimentation coefficients of 3.3S and 3.7S, respectively. Furthermore, the thymocytes that express the 1,25-(OH)2D3 receptor belong to a different and distinct subpopulation than the cells that express the glucocorticoid receptor. Specifically, by separating the thymocytes into two subsets by means of agglutination with the lectin peanut agglutinin (PNA), we have determined that the 1,25-(OH)2D3 receptor-positive cells belong to the PNA-negative medullary mature subset, whereas the GC receptor-positive cells belong to the PNA-positive cortical immature subset of thymocytes. Finally, we have compared the effects of the two steroid hormones on primary cultures of each of the two subsets as well as on unseparated thymocytes and found that GC act on PNA-positive cells to induce cell lysis; this leads to an enrichment in 1,25-(OH)2D3 receptor-positive thymocytes, as indicated by an apparent increase (6-fold) in the 1,25-(OH)2D3 binding in the cells surviving at the end of the culture. In contrast, we found that 1,25-(OH)2D3 acts on the PNA-negative cells to decrease the rate of cell lysis. These data indicates that the target cells for GC and 1,25-(OH)2D3 in the thymus are distinct and that these two hormones exert a different regulatory influence on the gland.


The goal of the research was to analyze the awareness of the moods in two basketball teams, taking into account the type of motor task and the result. The research was conducted on players belonging to the Spanish Amateur Basketball League and on players in the female children's selection during the 2010-2011 season. Three registers were carried out, each one consisting of four sessions, one for each type of motor task. Mood states were recorded before warming up, in the middle of the session and at the end. In order to evaluate them, a reduced version of the Profile of Mood States questionnaire was chosen. A generalized estimates equation model was used, obtaining the following results: a) the different types of motor tasks activate differing mood states; b) a defeat's role as a detonator for negative emotional states is emphasized; c) duels between players, when combined with a loss, generate negative mood states both in boys as well as in girls; d) non-opposition motor tasks (psychomotor and cooperative tasks) activate positive mood states, and can thus be used as affectivity regulators.


Abstract An analytical formulation of the turbulent potential energy spectrum in a stably stratified medium, valid in the inertia buoyancy subrange, is deduced in the framework of classical assumptions (no source, no sink, spectra locality and proportionality of the buoyancy flux to the mean potential temperature gradient) using recently published results of J. Weinstock. This formulation predicts a gap between two spectral ranges where temperature fluctuations mainly result from either turbulent advection or vertical displacements of fluid particles. In the former, the spectrum reduces to the well-known Obbukov-Corrsin-5/3 power law while in the latter, it becomes proportional to the kinetic energy spectrum, with a −3 spectral slope and a reverse potential energy flux. Experimental evidence obtained in the stratosphere supports this theoretical description.


This article shows the role and significance of duodenogastric bile reflux in patients with gastroesophageal reflux disease. Intraesophageal and intragastric pHmetric investigations, as well as biochemical studies of gastric contents were carried out. Antacid dysfunction of the stomach as a result of hypergastrinemia is conditioned by biochemical characteristics of duodenogastric bile refluctant which contains high concentrations of toxic bile acids, trypsin, lysolecithin, as well as by high phospholipase activity of refluctant, and by the reduction of such factors of cytoprotection as sIgA and phospholipids. Duodenogastric reflux in gastroesophageal reflux disease often develops because of the presence of associated biliary and pancreatic pathologies with bacterial overgrowth syndrome.


Indonesia is a country in southern Asia consisting of many islands and is the 4th largest populated country in the world. The country has one of the best economies in the world since it has been participating in international trade for many years. However, it has had drawbacks that have made it unable to reach the levels of the developed countries in the world. Therefore, it is necessary to study the facts behind the success and the failure of some business ventures. Additionally, the study of strategies by companies to have a competitive advantage in business is fundamental to understanding the situation in the country. The new research will seek to use the available analyses about the same topic to bring about a new understanding. Theories such as McClelland's locus of control theory can apply in the study to understand the relationship between entrepreneurship and the psychology of people. The paper uses secondary sources review to get information about the topic to propose a solution to the challenges that the companies in the country have been facing towards achieving a competitive returns.


In order to improve the thermal fatigue strength of EDMed molding dies, thermal fatigue tests of the treated surfaces by large-area electron beam (EB) under various conditions and gas nitriding were conducted. The thermal fatigue characteristics of the treated surface were evaluated by surface roughness measurement, microscopic observation, and X-ray residual stress measurement. These results indicate that the EB treatment has more dominant influence on the residual stress than pre-processing, such as EDM and milling, and the residual stress of EB treated surface is released in the early stage of the thermal fatigue test. Moreover, the gas nitriding treatment can inhibit the heat crack generation and its propagation on the surface in the thermal fatigue test.


In this study, the authors investigate compact half-wavelength slotline resonators and its applications to compact ultra-wideband (UWB) bandpass filter designs. The circuit models have been developed for the proposed UWB bandpass filters. By introducing additional slotlines and properly rearranging the filter geometry, the passband frequency response and upper stopband performance are improved. The basic filter and modified UWB filter have been designed, fabricated and validated to demonstrate the proposed design methodology. Their calculated, simulated and measured results show good agreement. The modified UWB filter has extremely compact size of 8.5 mm×7 mm. Both simulated and measured results show that the fabricated modified UWB filter has an UWB passband with a fractional bandwidth of 117.8%.


Introduction Soil microbial communities, including biological soil crust microbiomes, play key roles in water, carbon and nitrogen cycling, biological weathering, and other nutrient releasing processes of desert ecosystems. However, our knowledge of microbial distribution patterns and ecological drivers is still poor, especially so for the Chihuahuan Desert. Methods This project investigated the effects of trampling disturbance on surface soil microbiomes, explored community composition and structure, and related patterns to abiotic and biotic landscape characteristics within the Chihuahuan Desert biome. Composite soil samples were collected in disturbed and undisturbed areas of 15 long-term ecological research plots in the Jornada Basin, New Mexico. Microbial diversity of cross-domain microbial groups (total Bacteria, Cyanobacteria, Archaea, and Fungi) was obtained via DNA amplicon metabarcode sequencing. Sequence data were related to landscape characteristics including vegetation type, landforms, ecological site and state as well as soil properties including gravel content, soil texture, pH, and electrical conductivity. Results Filamentous Cyanobacteria dominated the photoautotrophic community while Proteobacteria and Actinobacteria dominated among the heterotrophic bacteria. Thaumarchaeota were the most abundant Archaea and drought adapted taxa in Dothideomycetes and Agaricomycetes were most abundant fungi in the soil surface microbiomes. Apart from richness within Archaea (p = 0.0124), disturbed samples did not differ from undisturbed samples with respect to alpha diversity and community composition (p ≥ 0.05), possibly due to a lack of frequent or impactful disturbance. Vegetation type and landform showed differences in richness of Bacteria, Archaea, and Cyanobacteria but not in Fungi. Richness lacked strong relationships with soil variables. Landscape features including parent material, vegetation type, landform type, and ecological sites and states, exhibited stronger influence on relative abundances and microbial community composition than on alpha diversity, especially for Cyanobacteria and Fungi. Soil texture, moisture, pH, electrical conductivity, lichen cover, and perennial plant biomass correlated strongly with microbial community gradients detected in NMDS ordinations. Discussion Our study provides first comprehensive insights into the relationships between landscape characteristics, associated soil properties, and cross-domain soil microbiomes in the Chihuahuan Desert. Our findings will inform land management and restoration efforts and aid in the understanding of processes such as desertification and state transitioning, which represent urgent ecological and economical challenges in drylands around the world.


Decision support and knowledge discovery systems often compute aggregate values of interesting attributes by processing a huge amount of data in very large databases and/or warehouses. In particular, iceberg query is a special type of aggregation query that computes aggregate values above a user-provided threshold. Usually, only a small number of results will satisfy the threshold constraint. Yet, the results often carry very important and valuable business insights. Because of the small result set, iceberg queries offer many opportunities for deep query optimization. However, most existing iceberg query processing algorithms do not take advantage of the small-result-set property and rely heavily on the tuple-scan-based approach. This incurs intensive disk accesses and computation, resulting in long processing time especially when data size is large. Bitmap index, which builds one bitmap vector for each attribute value, is gaining popularity in both column-oriented and row-oriented databases in recent years. It occupies less space than the raw data and gives opportunities for more efficient query processing. In this paper, we exploited the property of bitmap index and developed a very effective bitmap pruning strategy for processing iceberg queries. Our index-pruning-based approach eliminates the need of scanning and processing the entire data set (table) and thus speeds up the iceberg query processing significantly. Experiments show that our approach is much more efficient than existing algorithms commonly used in row-oriented and column-oriented databases.


Aim at the foreign randomicity and the color difference between the regular materiel and the foreign in high speed real-time foreign recognition, an approach to real-time foreign recognition based on hypersphere one-class support vector machines is presented. In this method, regular materiel are considered as training samples, and OC-SVM is used to obtain the color distributing of the regular materiel, that is to find out the foreign whose color are not in the range of the regular materiel. To train and simplify OC-SVM, centrifugal coefficient π is presented, and Zoutendijk fastest decline method is adopted to search for working set. The result of experiment shows, this method has good performance in foreign recognition, especially for some foreign whose color is similar to that of regular materiel. Contrast to Gaussian distribution fitting method, the general accuracy of recognition is 8~10% higher.


Design educators in mechanical engineering departments have witnessed an evolution in the types of design problems that students prefer to address in their courses. Anecdotal evidence from discussions with colleagues indicate that over the last 30 years, projects have evolved from the design of purely mechanical systems to projects that require knowledge outside of the traditional engineering paradigm, including social sciences. These evolving interests have added complexity to the role of design educators and have revealed the limits of available design tools used in these courses; these tools are often not sufficient to support decision-making when subjective aspects of the design process are involved, such as customer preferences. Though a number of design tools exist to assist engineers with understanding customer preferences, they do not provide the specificity needed for sensitive design contexts and require direct access to the end-user. We define sensitive design contexts as those that are perceived largely as invasive/ personal, resulting in a high degree of emotional engagement by the user, such as patients in medical environments or victims in disaster areas. The variety and complexity of design considerations to be considered are high. In the following, we will focus on "compassionate design thinking", i.e., on the role and impact of compassion during the design process. This paper presents a baseline approach for establishing a framework for compassionate design. The ultimate goal is to provide context-specific guidelines that can be used without having direct access to the end-user.


In multi-center randomized clinical trials imaging data can be diverse due to acquisition technology or scanning protocols. Models predicting future outcome of patients are impaired by this data heterogeneity. Here, we propose a prediction method that can cope with a high number of different scanning sites and a low number of samples per site. We cluster sites into pseudo-domains based on visual appearance of scans, and train pseudo-domain specific models. Results show that they improve the prediction accuracy for steatosis after 48 weeks from imaging data acquired at an initial visit and 12-weeks follow-up in liver disease


Patch antennas, being limited in bandwidth, are often modified to either be tunable or to yield extended instantaneous bandwidth. Presented is a fragmented patch antenna (FPA) that offers an easily manufactured solution. The FPA is a rectangular patch antenna divided into three sections with varactor diodes placed across the gaps between the sections. The three sections are designed to produce two tunable resonance frequencies that overlap, thereby creating a wide (63.4%) continuously tunable bandwidth.


Abstract The comparison of wet digestion and microwave digestion of Cd, Co, Cr, Cu, Mn, Pb, Zn, Fe, and Ni contents of the river bottom and sea floor sediments from the various locations of Turkey was performed in the present work. After digestions, the heavy metal concentrations were determined by flame atomic absorption spectrometry (FAAS). The heating programs for microwave digestion, different combinations, and volumes of acid mixtures were evaluated for microwave digestion efficiency. The studies in the present work show that the microwave‐assisted digestions in closed system are easier and faster than the wet digestion. Also the results found by the microwave and the wet digestions were reliable and accurate. The procedures were also checked with two‐stream sediment reference material (GBW 07309 and GBW 07310). Results for standard reference material (SRM) were in good agreement with certified values. The relative standard deviations for all metal concentrations were found to be lower than 10%.


The main objective of this study was to develop a spatial model for land suitability assessment for rice (Oryza sativa L.) cultivation using geographic information system (GIS) techniques. The land mapping units, resulting from the overlay of the selected theme layers, have unique land quality information, on which land suitability is based. Results showed that 55.5% of the study area is highly or moderately suitable for rice cultivation, whereas 34% of that area is unsuitable for rice cultivation due to soil and topographic conditions. The model was also validated with field studies. According to the statistical analysis, there was a significant, positive relationship between land suitability classes and grain yields. Grain yield was significantly affected by land suitability class at the level of P < 0.001. The highest grain yield was obtained from rice plots in the S1 class (7287 kg ha-1), followed by S2 (6872 kg ha-1) and S3 (3928 kg ha-1) classes.


Diaphragmatic hernia is a structural defect caused by inadequate fusion of the pleuroperitoneal membrane of the diaphragm, allowing peritoneal viscera to protrude into the pleural cavity. The occurrence of Morgagni hernia in the adult is infrequent and almost asymptomatic. Symptomatic cases are even rarer, with a wide range of respiratory and gastrointestinal manifestations that make it difficult to diagnose. We present the case of a 70-year-old man with unexpected onset abdominal pain and respiratory distress. The chest computed tomography scan showed the right-side diaphragmatic Morgagni hernia. The defect was corrected through open surgical repair without complications. Within five months of the procedure, a follow-up radiograph revealed full recovery. This case should alert physicians to consider this diagnosis when faced with an unexpected manifestation of Morgagni hernia.


Studies of political budget cycles in developing countries have generally sought to inform understanding of short-term fiscal dynamics, but can also offer unique insight into broader political dynamics in developing countries. This article correspondingly employs markedly improved data in order to study the impact of elections on tax collection, and draw broader lessons. It shows that while elections as a group have had no significant effect on tax collection, the subset of competitive elections has had a significant negative impact on pre-election tax collection; while this effect appears to be largest where incumbents are particularly unpopular. This provides powerful evidence that the impact of elections on political incentives in developing countries is conditioned by the existence of an electorally competitive opposition, while offering preliminary evidence that popular resistance to taxation by unpopular governments may be an important means by which taxpayers may generate pressure for improved governance.


Platinum-based chemotherapy offers a modest survival advantage over best supportive care (BSC) in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Based on 2 landmark studies that reported improved survival times and quality of life when comparing docetaxel with ifosfamide, vinorelbine, or BSC alone, docetaxel at 75 mg/m(2) given once every 3 weeks has been the standard of care as second-line chemotherapy since 2000. Docetaxel given at this dose and schedule resulted in significant hematologic toxicity, with many patients at risk for neutropenic fever. Pemetrexed is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. A phase III study in 571 patients comparing pemetrexed with docetaxel demonstrated clinically equivalent therapeutic outcomes in second-line treatment of patients with recurrent NSCLC; however, patients on the pemetrexed arm had a more favorable hematologic toxicity profile, with fewer episodes of neutropenia, neutropenic fever, and infections and less use of granulocyte colony-stimulating factor support. Based on these data, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC.


Cryogenic fluid damper seals operating close to the liquid-vapor region (near the critical point or slightly sub-cooled) are likely to develop a two-phase flow region which affects the seal performance and reliability. An all-liquid, liquid-vapor, and all-vapor, i.e., a continuous vaporization bulk flow model is presented for prediction of the seal dynamic forced response. Continuity, momentum, and energy (enthalpy) transport equations govern the two-phase flow of a homogeneous saturated mixture in thermodynamic equilibrium. Static and dynamic force performance characteristics for the seal are obtained from a perturbation analysis of the governing equations. Theoretical predictions and comparisons to experimental measurements in a liquid and gaseous nitrogen seal are presented in Part II. The effects of two-phase flow regimes on the dynamic force coefficients and stability of an oxygen damper seal are also discussed.


Recent studies have revealed that aberrant epigenetic events contribute to the development and maintenance of a malignant phenotype in urothelial carcinoma (UC) of the bladder, and many other tumor types. Thus, drugs capable of reversing epigenetic alterations have been brought to focus, and in the clinic epigenetic therapies demonstrate efficacy in the treatment of particular hematopoietic tumors. However, despite encouraging results from mouse xenograft studies, the clinical application of these agents to the treatment of solid tumors has been less successful. It is clear that new models are needed for the development of therapeutic strategies that target the solid tumor epigenome. Canine UC that develops commonly and spontaneously in dogs may provide a relevant model to directly inform new clinical protocols, to permit discovery and testing of clinical biomarkers, and, ultimately, to predict the response of human tumors in the clinic. Although human and canine UC share histopathologic characteristics, molecular features, and response to medical therapy, little is known about the canine UC epigenetic status. In human UC, EZH2 is overexpressed and, as a consequence of its enzymatic activity that involves the tri-methylation of histone H3 (H3K27me3), is responsible for silencing a large number of genes, including known tumor suppressors. We have determined that EZH2 is also overexpressed in canine UC. Therefore, we hypothesize that EZH2 provides a therapeutic target for UC. Pharmacological inhibition of EZH2 (DZNep) as well as targeted knockdown inhibits cell growth and induces apoptosis in canine UC cells in vitro in anchorage-dependent (2D) and anchorage-independent (3D) cultures. By conducting these experiments in parallel with human UC cell lines, we showed that sensitivity to inhibitor is comparable between human and canine UC cell lines. Upon DZNep treatment, EZH2 is reduced and its activity is inhibited, as evidenced by both decreased global H3K27me3 and upregulation of a set of genes that are commonly silenced by EZH2. In parallel, we showed that inhibition of EZH2 reduced the sphere forming capacity of canine UC cells, suggesting an inhibitory effect in the growth of the stem cell subpopulation. Taking into account that this population is responsible for dissemination, metastasis and emergence of drug resistance, these results support the idea that EZH2 targeting in UC could be a beneficial addition to the existing therapeutic modalities. According to our data, the molecular underpinnings of spontaneous UC are also shared between dogs and humans. Therefore canine UC provides a means to understand epigenetic dysregulation in the urothelium as well as to investigate its clinical targeting. This provides the opportunity to easily evaluate tumor response in vivo and obtain serial tissue samples during treatment. Thus canine studies can provide data that are not easily obtained in human trials and may inform clinical development. Citation Format: Parthena Foltopoulou, Monica Betancur-Boissel, Laurent Boissel, Manar A. AbdelMageed, Philip N. Tsichlis, Elizabeth A. McNiel. EZH2 inhibition targets a stem cell population in a canine urothelial carcinoma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2046. doi:10.1158/1538-7445.AM2014-2046


The ionotropic glutamate receptors, iGluRs, play diverse but important roles in the central nervous system. Specific iGluRs were found to be implicated in neurological pathways that modulate memory and behaviours in lower species including C. elegans. In this project, a bioinformatics approach involving protein BLAST, multiple sequence alignment and phylogenetic analyses was used to examine the evolutionary relationship between C. elegans and other invertebrate species. While most C. elegans iGluRs shared close lineages with their human counterparts, some, including iGluR subtype 5-8 did not share significant lineages with specific human orthologs. Interestingly, phylogenetic trees constructed using full-length and partial sequences specifically showed that C. elegans iGluR-8 remained on a lineage that is noticeably different than that of NMDA and non-NMDA families. Such evolutionary lineages may elucidate important information regarding neurological development in different species and may facilitate the development of therapeutic agents for the treatment of neurological disorders.


We propose a novel kind of terahertz radiation source utilizing grapheme surface plasmon polaritons (GSPPs) excited by parallel moving electron beam. Theoretical analyses show that terahertz radiation can generate from graphene sheet on a periodic grating structure. The intensity of the radiation are greatly enhanced due to GSPPs and the frequency of the radiation can be widely tuned by both of the electron beam energy and chemical potential of graphene. The experiment based on this mechanism are in progress.


BRCA1-mediated homologous recombination is an important DNA repair mechanism that is the target of FDA-approved PARP inhibitors, yet details of BRCA1-mediated functions remain to be fully elucidated. Similarly, immune checkpoint molecules are targets of FDA-approved cancer immunotherapies, but the biological and mechanistic consequences of their application are incompletely understood. We show here that the immune checkpoint molecule PD-L1 regulates homologous recombination in cancer cells by promoting BRCA1 nuclear foci formation and DNA end resection. Genetic depletion of tumor PD-L1 reduced homologous recombination, increased non-homologous end joining, and elicited synthetic lethality to PARP inhibitors olaparib and talazoparib in vitro in some, but not all, BRCA1 wild-type tumor cells. In vivo, genetic depletion of tumor PD-L1 rendered olaparib-resistant tumors senstive to olaparib. By contrast, anti-PD-L1 immune checkpoint blockade neither enhanced olaparib synthetic lethality nor improved its efficacy in vitro or in wild-type mice. Tumor PD-L1 did not alter expression of BRCA1 or its co-factor BARD1 but instead co-immunoprecipitated with BARD1 and increased BRCA1 nuclear accumulation. Tumor PD-L1 depletion enhanced tumor CCL5 expression and TBK1 activation in vitro, similar to known immune-potentiating effects of PARP inhibitors. Collectively, these data define immune-dependent and -independent effects of PARP inhibitor treatment and genetic tumor PD-L1 depletion. Moreover, they implicate a tumor cell-intrinsic, immune checkpoint-independent function of PD-L1 in cancer cell BRCA1-mediated DNA damage repair with translational potential, including as a treatment response biomarker.


Background. Stroke-related sensorimotor impairment potentially contributes to impaired balance. Balance measures that reveal underlying limb-specific control problems, such as a measure of the synchronization of both lower limbs to maintain standing balance, may be uniquely informative about poststroke balance control. Objective. This study aimed to determine the relationships between clinical measures of sensorimotor control, functional balance, and fall risk and between-limb synchronization of balance control. Methods. The authors conducted a retrospective chart review of 100 individuals with stroke admitted to inpatient rehabilitation. Force plate–based measures were obtained while standing on 2 force plates, including postural sway (root mean square of anteroposterior and mediolateral center of pressure [COP]), stance load asymmetry (percentage of body weight borne on the less-loaded limb), and between-limb synchronization (cross-correlation of the COP recordings under each foot). Clinical measures obtained were motor impairment (Chedoke-McMaster Stroke Assessment), plantar cutaneous sensation, functional balance (Berg Balance Scale), and falls experienced in rehabilitation. Results. Synchronization was significantly related to motor impairment and prospective falls, even when controlling for other force plate–based measures of standing balance control (ie, postural sway and stance load symmetry). Conclusions. Between-limb COP synchronization for standing balance appears to be a uniquely important index of balance control, independent of postural sway and load symmetry during stance.


EDM is an efficient machining process for forming a high aspect ratio hole in higher hardness materials with various advantages resulting from its characteristics of non-contact and thermal process. A series of blind holes of 10 mm diameter with depth of 3 mm were produced on D0403 alloy and D0376 alloy by EDM process using a copper electrode for different combination of process parameters. Material removal rate (MRR) and tool wear rate (TWR) are reported as performance factors of the machining process. The experiments were conducted based on varying the process parameters such as pulse on time, pulse off time and current which can affect the machining process to obtain the required quality characteristics. The surface roughness values for hole are reported here for quality performance factor. The obtained results are compared with SG iron with same machining parameters. The results show that material removal rate is a non linear function of pulse on and off time ratio.


In considering health information systems, great hope is attached to the use of child health records as a data source for research and community planning. In order to test the completeness of child health records data and their agreement with other sources, information about living conditions, use of medical services and health problems in preschool children were studied in 707 child health centres' records. The results show a considerable number of deficiencies in the system which could, to a certain extent, be remedied by improved instructions to the staff. Health problems in the area of child care also need to be fully defined.


This database provides construction of Large Urban Regions (LUR) in the world. A Large Urban Region (LUR) can be defined as an aggregation of continuous statistical units around a core that are economically dependent on this core and linked to it by economic and social strong interdependences. The main purpose of this delineation is to make cities comparable on the national and world scales and to make comparative social-economic urban studies. Aggregating different municipal districts around a core city, we construct a single large urban region, which allows to include all the area of economic influence of a core into one statistical unit (see Rozenblat, 2020 or Rogov & Rozenblat, 2020 for Russia). In doing so we use four principal urban concepts (Pumain et al., 1992): local administrative units (Municipality or localities: MUNI), morphological urban area (MUA), functional urban area (FUA) and conurbation that we call Large Urban Region (LUR). The LURs are the spatial extensions of influence of one or several FUAs or MUAs. MUAs and FUAs are defined by various national or international sources. We implemented LURs using criteria such as the population distribution among one or several MUAs or FUAs, road networks, access to an airport, distance from a core, presence of multinational firms. FUAs and MUAs perimeters, if they form a part of a LUR, belong to a unique LUR. In this database we provide the composition of the LURs in terms of local administrative units (MUNI), Morphological Urban Area (MUA), Functional Urban Area (FUA).


As apparel manufacturers have increased their outsourcing garment making to cope with the rapid changing market, the information sharing has been the most important factor for the Korean apparel industry. The purpose of this research was to identify the properties and effects of information sharing system between Korean apparel manufactures and contractors. For this study, two apparel manufactures which actually used the information sharing systems were case-studied for the properties and effects of the information sharing system. The results of this study are shown as follows; 1) The companies ("J" and "S"), studied in this paper used sharing information mostly on order, delivery, and accounts within their contractors based on information sharing system. Company "J" turned out to have strong partnership with their contractors and developed more flexible manufacturing system and QR strategy. They shared not only basic transaction information but also quality inspection information and work-in-process information by using information sharing system. 2) The effects of information sharing system were proved as business transaction time reduced more than 60 percent, compared when staffs had to face to face, or use phone or fax to deliver documents. This study was investigated to provide an example which introduces information sharing system objectively and systematically to the apparel industry.


This study was conducted to investigate the effect of in ovo administration of a mixture of Astragalus polysaccharide (APS) and Newcastle disease vaccine (NDV) on growth performance, intestinal development, and mucosal immunity in newly hatched chicks. Six hundred specific-pathogen-free (SPF) Leghorn fertilised eggs were incubated in a commercial hatchery and divided into four groups: (a) control group injected with 1 ml of 0.9% physiological saline, (b) APS group injected with 1 ml of 1 mg/ml APS solution, and (c) NDV group injected with 1 ml of 104.0 EID50 /dose of NDV solution, and (d) APS + NDV group injected with a mixture of 0.5 ml of 2 mg/ml APS plus 0.5 ml 104.0 EID50 /dose ND vaccine (NDV) on Day 18.5 of incubation. The results showed that in ovo injection of APS or the mixture of APS and NDV increased the body weight at 1 day (IW) and final weight (FW) at 28 days and increased the feed conversion ratio (FCR) at 1-7, 8-14, 15-21, and 1-28 days of age. The villus height (VH) was increased (p < 0.05), and the crypt depth (CD) was decreased (p < 0.05) in the duodenum compared with the control group. The VH/CD ratios were increased (p < 0.05) in the APS + NDV group compared with controls, NDV group, and APS group on d3. The levels of slgA in washings were increased (p < 0.05) on Days 3, 7, 14, 21, and 28, and the number of IgA+ cells in the duodenum was increased on Days 7, 14, 21, and 28. In addition, the IgA+ cells were promoted from the villus root to the apex in the APS + NDV group. It can be concluded that in ovo administration of NDV conjugated with APS compared with NDV alone may be more effective in promoting growth performance and intestinal mucosal immunity.


During pellet injection and supersonic molecular beam injection, we have observed the increase of electron density and the enhancement of hard x-ray radiation, but the runaway electrons normally decrease without additional fuelling when the density of plasma increases. This phenomenon may come from the synergetic effects of Dreicer and avalanche runaway electrons. The experimental results are consistent with the calculation based on the theory of avalanche runaway in the HL-1M tokamak.


Larval bot fly burdens and the presence of immunoglobulin G (IgG) antibodies to larval antigens of Alouattamyia baeri (Shannon & Greene) were determined in howler monkeys, Alouatta palliata authority, from Barro Colorado Island, Panama, during July and August of 1991 and 1992. Monkeys produced antibodies (IgG) to both 1st- and 3rd-instar proteins of the monkey bot as measured by an enzyme immunoassay. The response to 1st-instar antigen was correlated with number of bots for the 1991 data and for pooled data from 1991 and 1992. No correlation was observed for the response to 3rd instar antigen. First-instar extracts were composed of 9 major proteins as visualized by SDS-PAGE. Bands at 17, 25, and 32 kDa were positive in Western blots. Third-instar extracts contained at least 13 major bands, with those at 120 and 130 kDa reactive in immunoblots. The immune response to A. baeri may be involved in limiting larval bot numbers.


Background Rohingya refugees in Bangladesh are vulnerable to infectious diseases such as COVID-19 due to the crowded living conditions with fragile shelters, and limited water, sanitation and hygiene facilities and practices. While risk communication and community engagement (RCCE) is the cornerstone of outbreak control, there is limited evidence available on the effectiveness of the RCCE strategies in this setting. Objectives The goal of this study is to evaluate the effectiveness of RCCE strategies and to explore the challenges and community recommendations in relation to COVID-19 preventive measures in the context of Rohingya refugee camps in Bangladesh. Materials and methods It was a qualitative study. Methods used were (a) observation of RCCE intervention by 3 clinical supervisors accompanying 25 Community Health Workers (CHWs) and (b) 5 focus group discussions engaging 60 community representatives. Data were analyzed using a thematic analysis approach, separately for observation and focus group discussions. Results The study identified a number of good practices of RCCE, including selecting CHWs from the local community, engaging female CHWs, using local dialect, and collaborating with community/religious leaders. Certain good practices need scaling up, such as utilization of multiple communication methods and interpersonal communication skills. Some areas need improvement, such as CHWs being overburdened with multiple tasks, less effort to active listening, repeated delivery of same messages, inadequate linkage to culture, context, and resources, and less effort to empower the community. Engaging the community, five critical themes were identified in relation to poor COVID-19 preventive practices: culture, religion, and language; local context and resources; community trust and interaction with aid workers; communication methods; and gender and social inclusion. Religious misinterpretation, cultural barriers, physical barriers, lack of resources, breach of trust between the community and aid workers, inconsistent/complex messages, lack of gender and social inclusion, and stigmatization are among some key factors. Some key actions were recommended to improve COVID-19 RCCE strategy. Conclusion We urge the RCCE partners to make use of the findings and recommendations to develop a robust RCCE strategy relevant to local culture and context, responsive to people's concerns and needs, and inclusive of gender, age and social vulnerabilities.


Magnetic resonance spectroscopic imaging (MRSI) based studies investigating brain metabolite alterations due to HIV infection generally acquired MR spectra from single or multi-voxels covering regions related to HIV. In this study, we acquire whole-brain MRSI data to map regional metabolite variations in the entire brain, determine regions mostly affected by HIV clade-C infection, and identify the mechanism by which HIV damages the brain. Results show widespread increases in myo-inositol, glutamate/glutamine, choline, and creatine, and decreases in N-acetylaspartate, indicating neuronal dysfunction and astrogliosis in the white matter, as well as disruptions in synaptic transmission, neurotoxicity and inflammation throughout the brain.


A diagnosis of osteoporosis is facilitated by bone mineral density (BMD) measurement of the lumbar spine and hip using dual energy X-ray absorptiometry (DXA), interpreted in accordance with criteria published by the World Health Organization (WHO). The use of peripheral DXA is growing in primary care and guidance on its use has recently been published by the National Osteoporosis Society (NOS), recommending a triage approach using thresholds specific to each type of peripheral device. However, no data currently exist for the Norland Apollo heel densitometer (Cooper Surgical, Trumbull, USA). 215 women between 50 years and 75 years of age (mean age 64.6 years) referred for hip and spine BMD measurements also had a heel BMD measurement. Device specific upper and lower thresholds were calculated for the Norland Apollo heel densitometer to give a 90% sensitivity and 90% specificity for osteoporosis at the hip or spine. Patients with a heel T-score of above -1.2 are very likely to have normal bone density on axial densitometry, whilst patients with heel T-score of below -2.2 are very likely to have osteoporosis at the hip or spine. Patients whose measurements lie between the thresholds should be referred for axial DXA.


This book presents a detailed and practical explanation of the law of Civil Procedure in Kenya. It discusses the principles of Civil procedure Law in a practical setting. The intricate points of law have been illustrated by examples, and in the introduction the subject has been dealt with by topics rather than in the strict order of sections in the Act and Rules. This has been done to avoid cross-referencing to enable users to adequately grasp the doctrinal aspects of the subject.


A method for analysing numerically the commutating characteristics in small universal motors is given. This analysis method can be applied to evaluate the commutating characteristics at the machine design stage and make it possible to perform relative comparisons of these characteristics before and after a modification of design specifications. The method consists of an iterative separate calculation of the circuit parameters by the finite element method on one hand and a solution of the commutation equation on the other hand until the value of the commutating coil current converges. This method is characterised by the various quantities related to commutation that can be easily calculated and examined. In a commutation equation, combined static and dynamic characteristics of brush contact voltage are adopted. The quality of commutation can be evaluated by the contact voltage at the trailing edge of the brush. An example of the commutation analysis is given for a motor of the type used in vacuum cleaners and the results obtained are in good correspondence with those found in experiments.


Reviewing archaeological research in the Willandra Lakes area over the past forty years shows a number of methodological and conceptual problems. One of these is the use of ethnographic models of Aboriginal behaviour to organise the archaeological data. Such models privilege spatial over temporal relationships and minimise the extent of archaeological changes over time. Of research to date, it is Bowler's correlations of archaeological and hydrographic changes since the Late Pleistocene which best match the limited archaeological data available. A comparison of the Pleistocene archaeology from the Willandra Lakes and Tasmania reveals time-averaged records that are amenable to the analysis of patterns of mobility and material use, but not of functionally defined sites nor of typologically defined artefact assemblages. The periodicity and intensity of human occupation of the Willandra Lakes can be studied using large samples of stone artefacts drawn from wide areas, allied with a strategy of dating of land units based on multiple C14 and Optical dates. Such a strategy requires the reconsideration of the relationships between behaviour, function, space and time and a reformulation of much of our existing knowledge of the archaeology of Pleistocene Australia.


Among the identifiable cells in the abdominal ganglion of Aplysia californica are five that generate bursting rhythms endogenous to the cells. In the four bursting cells of the left upper quadrant the rhythm is modulated by a unitary inhibitory postsynaptic potential; in the bursting cell of the right lower quadrant the rhythm is modulated by a unitary excitatory postsynaptic potential. Both the excitatory and inhibitory postsynaptic potentials are mediated by separate branches of a single interneuron. The pharmacological properties of the double action interneuron as well as those of the follower cells suggest that a single transmitter (acetylcholine) is involved in both the excitatory and the in-hibitory action of the interneuron.


Ranula is a soft cystic tumor in the floor of the mouth, unilateral at first, but later, as the cyst enlarges, perhaps passing beyond the median line. The name "ranula" is only descriptive of appearance, having no significance otherwise. Formerly ranula was, and is at present by some, supposed to be a cyst containing pent-up salivary gland secretions from stenosis of Wharton's or Rivini's ducts, as a result of inflammation in some part of the duct or its meatus; or from occlusion of the duct by an accumulation of salivary calculus. Bland Sutton says: "There is at the present time a strong tendency to restrict the name 'ranula' to cysts arising in connection with ducts of the three sets of salivary glands opening into the mouth, and to designate them as submaxillary, sublingual and parotid ranuhe according to the gland affected." Continuing, he says: "In the majority of cases ranulae


This paper presents a tracked robot composed of the proposed crawler mechanism, in which a planetary gear reducer is employed as the transmission device and provides two outputs in different forms with only one actuator. When the crawler moves in a rough environment, collision between mechanism and environment inevitably occurs. This under-actuated crawler can absorb the impact energy that should be transmitted to the actuator. A modular concept for the crawler is proposed for enlarging its use in robot systems and mechanical design of a modular crawler is conducted. Using this crawler module, a four-crawler-driven robot is realized by easily assembling. Experiments are conducted to verify the proposed concept and mechanical design. A single crawler module can well perform the proposed three locomotion modes. The four-crawler-driven robot has good adaptability to the environment which can get over obstacles both passively and actively.


Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC

The DEK oncogene is overexpressed in a wide range of cancers, including acute myeloid leukemia (AML). While DEK was initially described as a protein binding to certain topological chromatin structures, recent studies implicate DEK in the epigenetic and transcriptional regulation of specific genes. To assess the global gene binding of DEK, we performed chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). We demonstrate that DEK does not bind evenly throughout the genome, but rather accumulates around transcription start sites, with binding to promoters and initial parts of the coding sequences. Furthermore, gene set enrichment analysis revealed that DEK preferentially binds genes associated with epigenetic regulation of gene expression. Our results represent the first genome-wide characterization of DEK binding, and further establish DEK as a transcriptional regulator with a specific set of target genes.

Citation Format: Carl Sanden, Linnea Jarvstrat, Tove Ullmark, Bjorn Nilsson, Urban Gullberg. Genome-wide mapping of binding sites for the DEK oncoprotein by ChIP-seq. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 762. doi:10.1158/1538-7445.AM2013-762


Virtual ground modeling is one of key topic for real-time vehicle dynamic simulation. This paper discusses about the virtual 3D road modeling process using parametric surface concept. General road data is a type of lumped position vector so interpolation process is required to compute contact of internal surface. The parametric surface has continuity and linearity within boundaries and functions are very simple to find out contact point. In this paper, the parametric surface formula is adopted to road modeling to calculate road hight. Position indexing method is proposed to reduce memory size and resource possession, and a simple mathematical method for contact patch searching is also proposed. The developed road process program is tested in dynamic driving simulation on off-road. Conclusively, the new virtual road program shows high performance of road hight computation in vast field of off-road simulation.


Human Computer/Robot Interaction has concerned about developing agents and tools for an effective performance in a user interaction scenario. In particular, the study on the usage of social media tools by older adults has been of a core theme to investigate. In this study, the interaction with a social network site tool, Facebook photo albums, supported by an agent embedded in an assistant robot is analyzed. Therefore, we present a study that explores the relationship between the type of interaction with the social network tool, and the level of perceived usefulness, ease of use, ease of learning and satisfaction by the elderly as users. The study found that the type of interface interaction with the social media tool affect the perception of the older adults in usefulness, ease of use, ease of learning and satisfaction: the older adults perceived the Facebook photo albums tool more useful, easy to use, easy to learn and felt more satisfied during the interaction with the robotic interface supported by the agent. Based on the results of this work, we can approach toward the integration of social network sites technologies for older adults and robots, not only for interaction design considerations, but also to help the seniors to overcome technological and social isolation.


Many inflammatory diseases, as well as infections, are accompanied by elevation in cellular levels of Reactive Oxygen Species (ROS). Here we report that MPYS, a.k.a. STING, which was recently shown to mediate activation of IFNβ expression during infection, is a ROS sensor. ROS induce intermolecular disulfide bonds formation in MPYS homodimer and inhibit MPYS IFNβ stimulatory activity. Cys-64, -148, -292, -309 and the potential C88xxC91 redox motif in MPYS are indispensable for IFNβ stimulation and IRF3 activation. Thus, our results identify a novel mechanism for ROS regulation of IFNβ stimulation.


This article is a research in two parts about common views between Maria Zambrano and the Italian poet Cristina Campo. At first, it's an analyse of Zambrano's translation to the Campo's text, untitled "Atencion y poesia". It is detected there a very particular Zambrano's interpretation. Moreover, the reader is introduced into the Roman period of Zambrano and the new philosophical conceptions that she started to experience in it, as a new perception of time. This research concludes with a comparative about both texts Campo/Zambrano, illustrating the thinking resemblances
and/or divergences among them.


Mapping of groundwater potential over space, built by synergizing environmental variables and machine learning models, was of great significance for regional water resources management. Taking the Chihe River basin in Anhui province as an example, thirteen influence factors were used to predict the spatial distribution of groundwater, including elevation, slope, aspect, plan curvature, profile curvature, topographic wetness index (TWI), drainage density, distance to rivers, distance to faults, lithology, soil type, land use, and normalized difference vegetation index (NDVI). The potential of groundwater resource in this region was predicted using GIS-based machine learning models, including logistic regression (LR), deep neural networks (DNN), and random forest (RF) model. Then, the accuracy of prediction results was evaluated by calculating the RMSE, MAE and R evaluation index. The results show that there is no collinearity among the 13 environmental impact factors, which can provide corresponding environmental variables for the evaluation of regional groundwater potential. Machine learning models show that groundwater potential is concentrated in moderate to high potential areas. Among them, the moderate to the high potential of this area accounted for 81.14% in the LR model, 90.36% and 87.55% in the DNN model and the RF model, respectively. According to the result of these evaluation indexes, the three models all have high prediction accuracy, among which the LR model performs more prominently. The good prediction capabilities of these machine learning technologies can provide a reliable scientific basis for spatial prediction of groundwater potential and management of water resources.


This paper describes the first steps in our work towards using an airborne imaging spectrometer (AISA) as a source of information in an operational, large area forest in- ventory system. The necessary properties of algorithms for this kind of task are discussed, including handling of the atmo- spheric effects. An algorithm for automatic selection of spectral channels for estimation of forest parameters is presented and it is applied to AISA data from Southern Finland.


Background/Aims Depression and allergic diseases, including asthma, are frequently reported as comorbid conditions. However, their associations have been rarely examined in community-based elderly populations. Methods The analyses were performed using the baseline data set of the Korean Longitudinal Study of Health and Aging, which consists of 1,000 elderly participants (aged > 65 years) randomly recruited from an urban community. Depression was assessed using the Geriatric Depression Scale, Center for Epidemiologic Studies Depression Scale, and Hamilton Rating Scale for Depression. Major and minor depressive disorders were diagnosed by psychiatrists. Allergic conditions were assessed using structured questionnaires, lung function, and skin prick test. Quality of life and comorbidities were assessed using structured questionnaires. Results Prevalence of asthma and major depressive disorder were 5.4% and 5.3%, respectively. The rate of depression was not significantly different between the non-asthmatic and asthmatic groups. No correlation was observed between the scores obtained using the depression scales and self-reported asthma. However, chronic, frequent, and nocturnal cough were significantly associated with depression and scores obtained using the depression scales, which remained significant in multivariate logistic regression analyses (chronic cough: odds ratio [OR], 3.23; 95% confidence interval [CI], 2.57 to 12.74; p = 0.04). Rhinitis was independently associated with high Mini-Mental State Examination scores (OR, 1.11; 95% CI, 1.05 to 1.17; p < 0.001) and low 36-item short-form (OR, 0.96; 95% CI, 0.80 to 0.98; p = 0.002). Conclusions Depression may not be significantly associated with asthma and allergic diseases in elderly populations, but cough is a significant factor affecting depression.


We introduce H(θ))-open sets H(r)-open sets defined by a given hereditary class, and investigate some properties and characterizations by using H(r)-open sets. We also introduce and investigate the notions of H-preserving mappings, strong H(θ)-continuous mappings and H(θ)-continuous mappings. AMS Subject Classification: 54A05


It is shown that the rate of development of spatial instability caused by small-scale self-focusing strongly depends on the mutual arrangement of nonlinear media and spatial filters in a setup. The expressions are obtained for the arrangement of elements providing the minimal growth rate of intensity fluctuations. The results of two-dimensional calculations confirm the efficiency of this method of suppressing small-scale self-focusing.


The outline of history, state of preservation  and damages causes of mural paintings by Waclaw Taranczewski  in the church of St. Anna in Poznan The aim of this article is to present the history of mural paintings by Waclaw Taranczewski in the church of St. Anna in Poznan, particularly in relation to unprofessional restoration interventions which were applied in the past and chich have contributed to the present polychromy's state of preservation. Analysis of this state allowed to identify causes that have direct and indirect impact on it. A number of examinations was applied, including studies of microbiological and climatic conditions, and then used to determine destructive factors present in the structure of these paintings and in their environment. A detailed diagnosis of these factors was then presented and the proper methodology to stop progressive destructive processes was briefl outlined.


Objective To investigate the effect of dopamine (DA) on the glutamate (Glu)-uptake ability of astrocytes, and the role of trace amine-associated receptor 1-excitatory amino acid transporter 2 (TAAR1-EAAT2) signaling pathway in Glu uptake by astrocytes. Methods In the primary cultured astrocytes pretreated with DA, extracellular Glu levels were measured by the Amplex Red glutamic acid assay kit. The levels of TAAR1 and EAAT2 transcriptions were detected by reverse transcription PCR and their protein levels were analyzed by Western blotting. After TAAR1 plasmid and TAAR1 siRNA were separately transfected into the primary astrocytes pretreated by DA, Western blotting was performed to determine the level of EAAT2 and Amplex Red glutamic acid assay kit was used to analyze Glu uptake in primary cultured astrocyte supernatants. Results The expression of EAAT2 in the primary cultured astrocytes significantly decreased in response to DA, and the level of TAAR1 increased. DA significantly enhanced the Glu uptake in primary cultured astrocyte supernatants. After TAAR1 siRNA transfection, EAAT2 expression was upregulated by DA treatment and Glu content in the supernatants was downregulated. On the contrary, after TAAR1 plasmid transfection, EAAT2 expression descended and Glu level ascended in the supernatants. Conclusion DA reduces the Glu-uptake ability of astrocytes through TAAR1-EAAT2 signaling pathway, causes extracellular Glu accumulation, and ultimately destroys the function of astrocytes.


The paper based on the results researches carried out during 1976-2010 in the research field for soil water balance study from Agricultural Research and Development Station Oradea. On the watering depth (0-75 cm) the soil water reserve was maintained between easily available water content and field capacity and the average of the irrigation rate used were of 2655 m 3 /ha. The irrigation determined the improve of the microclimate conditions (water/temperature+light report; wet I in comparison with median wet) the increase of the daily water consumption and finally of the total water consumption with 49.7 %. The irrigation determined the yield gains very significant every year; the relative differences in comparison with unirrigated variant were of 60.5%, variation interval 9227%; the yield stabilities were improved, standard deviation decreased with 25.1%. The irrigation determined the increase of the yield quantity obtained for 1 m 3 of water used with 7%. The results


Baptism in the Corinthian church was an expression of allegiance to honour not only Christ but also the 'patron' apostle in whose testimony the convert had believed (1 Cor 1.12–17). Some apostles known to the Corinthians had died (cf. 15.6), yet their testimony lived on and bore fruit in Corinth, resulting in baptism for the honouring of the dead apostles. In the context of 15.20–34 Paul uses this practice to expose the hypocrisy of those who deny the resurrection and yet seek to honour apostles who depend on the resurrection for receiving honour, as do Christ and God the Father.


Synopsis The mountain areas of Rhum, developed in Tertiary volcanic rocks, exhibit various landforms and deposits of periglacial origin, the most important of which were formed by cold climate geomorphological processes during the later stages of the Late-glacial period. Blockfields were developed in the west, in well jointed granophyre; in the east there are frost shattered tors, an altiplanation terrace, and huge screes were initiated below all the steeper higher peaks. Contemporary processes continue to produce screes and induce solifluction and the development of small scale patterned ground.


A regional gravity survey of the Cuyuna Iron Range, Minnesota, was conducted during the summer of 1955 by the U. S. Geological Survey. It was believed that gravity data would aid in the understanding of the major structures of the range. It was found that synclinal and steeply dipping structures produced positive gravity anomalies while anticlinal structures produced negative anomalies. This principle was noted in areas of well known geology and then applied to outlying areas of the district. The outstanding gravity feature is a narrow positive anomaly extending from south of Brainerd eastward through Aitkin, the axis of the anomaly being somewhat south of the South Range. This gives support to the theory that the Biwabik formation passes under the stratigraphically higher South Range member as a synclinal structure. However, this anomaly is also explained using one main iron formation and assuming an anticlinal structure between the North and South Ranges and a syncline between the South Range and Bay Lake. A large magnitude negative gravity anomaly north of Mille Lacs is postulated to result from an intrusive mass extending to the erosion surface. Aero-magnetics are used to strengthen the gravity interpretation. The need is realized for additional regional gravity coverage to the east of the area included in this survey and a detailed gravity study of the area between the North and South Ranges.


Deviations of the position of the ey in the roll plance, ocular trosion (OT), and the subjective visual vertical (SVV) wre systematically studied in 111 patients with acure vascular brainstem lesions. Of the 111 partents, 104 (94%) showed a direction‐specific pathological tilt of the static SVV in our series, Sevenry‐one (83%) of 86 partients exhibited pathological static OT of one (47%) or both (36%) eyes. OT and SVV tilts are therefore sensitive signs in acture unilateral brainstem disorders. Measurements of SVV and OT may prove to be useful components of the neuroophthalmological evaluation. With respect to the directions of pathological tilt, SVV an OT are generally in the same direction. Based on neuroimaging, we conclude that all unilateral brainstem lesion caudal to the upper pons cause ipsiversive Ot of one or both eyes, with concurrent ipsiversive tilts of SVV adjustments; all lesions rostral to this pontine level cause Contraversive tills of OT and SVV. Evidence is presented that pathological tilts of OT and SVV are secondary to a dysfunction of the tonic bilateral vestibular imputs that stabilize the eyes and head in normal upright position in the roll plance and dominate our perception of verticality.


A study of a good many children who have been brought finally to serious account for misdeeds, and especially children who were referred to me from the juvenile court, has shown in almost every case a slate of the nervous system in which the symptoms, although often resulting in criminal acts, were none the less expressions of a condition having its beginning long before, in the bad handling of nervous habits, a stimulation of them, or a neglect of them altogether. It was not punishment that seemed to be needed in a single case, and it is a matter of interest that in the juvenile court alone is crime considered a symptom, as it should be, for which the doctor-judge seeks a remedy, and, if possible, a specific one. A hundred years ago the medical profession emerged from the conception of disease as heaven-sent and from the almost dark ages


This study presents an analytical method for winding factor calculation and back electromotive force (EMF) prediction in air-core permanent magnet linear synchronous motors. In the proposed method, the voltage on each coil of a phase winding is calculated by adding the voltage induced in individual conductors considering a phase shift proportional to the conductor diameter. The proposed method can be used to find back EMF waveform of air-core linear motors with any winding configuration in terms of dimensional specifications of magnet track and winding assembly. Once the back EMF equation is obtained, it can be used to predict the thrust of the motor.The results of the proposed analytical model are compared with finite element analysis results for three different motors to verify the validity of the proposed modelling method. In order to investigate the effect of simplifying assumptions in model derivation, experimental back EMF result on a three-phase eight-pole motor is presented and compared with the proposed analytical model.


The diagnostic phase of cancer care is an anxious time for patients. Patient navigation is a way of assisting and supporting individuals during this time. The aim of this review is to explore patient navigation and its role in the diagnostic phase of cancer care. We reviewed the literature for definitions and models of navigation, preparation for the role and impact on patient outcomes, specifically addressing the role of the nurse in patient navigation. Interviews and focus groups with healthcare providers and managers provided further insight from these stakeholder groups. Common to most definitions of navigation is the navigator's multifaceted role in facilitating processes of care, assisting patients to overcome barriers and providing information and support. Navigation may be provided by laypersons, clerical staff and/or healthcare professionals. In the diagnostic phase it has the potential to affect efficiency of diagnostic testing, patients' experience during this time and preparation for decision-making around treatment options. Patient care during the diagnostic phase requires various levels of navigation, according to individual informational, physical and psychosocial needs. Identifying those individuals who require more support--whether physical or psychosocial--during the diagnostic phase is of critical importance.


Disputes about the research and development of syndrome traditional Chinese medicine(TCM) new drug in Guidance for syndrome TCM new drug development still exist, including the fact that it is unclear whether the compound TCM preparations just targeting a sort of syndrome is in line with the TCM theory and that it is obscure what are clinical advantages of syndrome new drug as compared with new drug targeting both disease and syndrome. Based on TCM classical theory, dating back to intervention opinions of successive dynasties, theory of three-dimensional N levels was proposed from the aspects of intervention modes, intervention latitudes and formulae to illustrate that the syndrome TCM new drug is in line with TCM theory. As for the first dimension, the intervention modes of TCM could be classified into targeting disease, targeting pathology and targeting symptoms, and the basic elements were extracted as constitution, disease, pathogenesis, pathology, location, symptoms, Western medicine pathology and Western medicine indicators. Among them, the mode targeting TCM constitution and the mode targeting pathology provided the theoretical possibility of TCM syndrome new drug, while the mode targeting disease was suitable for disease syndrome new drug. As for the second dimension, the intervention latitudes were summarized, including Yin-Yang, Qi-blood-body fluid, viscera, meridian, tri-jiao, Wei-Qi-Ying-blood, six channels, and local part. The relatively broad latitudes such as Yin-Yang, Qi-blood-body fluid, and meridian might be suitable for the development of TCM syndrome new drug. As for the third dimension, the TCM formulae could be divided into four types according to the range of indications, including broad indications, viscera pathogenesis indications, disease-targeting indications and symptom-targeting indications. The first two types were suitable for TCM syndrome new drug development, while the disease-targeting indication type fit for disease-syndrome new drug. According to theory of three dimensional N levels, the clinical orientation of syndrome TCM new drugs and their advantages over disease-syndrome new drugs were as follows: syndrome TCM new drugs may be considered for novel disease without clear basic pathogenesis or advance regulation, complicated diseases, complicating diseases, geriatric disease and ba-lancing TCM constitution.


Preface and Acknowledgements. The Author. Foundations at the Crossroads. Foundations as Judges -- The Art of Deciding Who Gets a Grant. Foundations as Editors -- How the Quality of Writing Affects Grant Proposals. Foundations as Citizens -- How Accessible and Accountable are Foundations? Foundations as Acitvists -- How Political Ideology and Influence Affect Grant Decisions. Foundations as Entrepreneurs -- How Program Officers View Risk Taking. Foundations as Partners -- Problems in Building Trust Between Grantmakers and Grantseekers. Conclusion -- Faces of Foundations in the Future.


A third season of excavation by the joint Kuwaiti-British team took place at the Ubaid-related site of H3 in northern Kuwait during the spring of 2001. Permission to excavate was again granted by Dr al Rumayhi, Secretary General of the National Council for Culture, Arts and Letters, to whom we are most grateful. The work was only possible because of the generosity of a number of funding bodies: the NCCAL in Kuwait; the British School of Archaeology in Iraq; the Institute of Archaeology, University College London; the Charlotte Bonham-Carter Charitable Trust; the Central Research fund of London University; the Society for Arabian Studies; and, above all, Kuwait Shell, our industrial sponsor. The success of the season was due to their generosity and to the dedication and skill of all members of the two teams. Objectives this year included the continuation of work in the multi-cellular building in Area A identified in the second season, and the uncovering of the building visible on the surface in the adjacent Area C. The multi-cellular building proved to be structurally complex and had an unexpected depth of deposit in its chambers. These deposits proved to be extremely rich in finds which will greatly enhance our understanding of the site when analyses are completed. In Area C, the new building was defined and excavated to its base although its relationship with the adjacent building(s) in Area A remains to be defined. Limited work was also carried out in the previously excavated military dug-out, or foxhole, Area F, where work was completed. Two teams worked in Area A which was subdivided this season into an east and a west sector, while a third team investigated Area C.


Encarsia costaricensis Evans and Angulo, reared from the greenhouse whitefly, Trialeurodes vaporariorum from Costa Rica, is described and illustrated. New host and distribution records are reported for Encarsia lycopersici De Santis reared from T. vaporariorum on tomato (Lycopersicon esculentum L.) from Brazil.


Cutaneous phototype is considered mainly related to cutaneous pigmentation and to the eumelanin/pheomelanin ratio, which is mostly genetically determined by the melanocortin 1 receptor (MC1R) polymorphisms. However, data in literature indicate that, in addition to stimulation of eumelanin synthesis, the MC1R signalling activates antioxidant, DNA repair and survival pathways. New emerging aspects regarding photoprotection and skin phototypes are going beyond those features connected to the melanin content in the skin. Important new findings link the MC1R to nuclear receptors activation, shedding light on new extra‐melanogenic effects dependent on the α‐melanocyte‐stimulating hormone (α‐MSH) activity and new ways through which such functions are modulated. These evidences indicate that several factors including melanin play a part in defining the basis for individual sun sensitivity, suggesting that the cutaneous phototype represents a 'biochemical fingerprint'.


This study explores the application of multiphase pumps as an alternative to conventional separation using rigorous steady-state simulation models incorporating a newly developed multiphase pumping model. The simulation results show that multiphase pumps are advantageous in not only reducing facilities, but can also increase production rates by lowering the backpressure on wells. Additionally, the complexities associated with multiphase flow through a single pipeline are compared to running dual single-phase pipelines and important considerations observed with the steady-state simulation are highlighted.


Aim: The study was undertaken to assess presence of sub-clinical bluetongue in the state of Assam, one of the un-affected north-eastern state of India. Materials and Methods: Serum samples were collected from apparently healthy as well as suspected sheep, goat and cattle from different districts of Assam encompassing various agro-climatic zones. Anti-BT antibodies were screened in sera using indirect enzyme linked immunosorbent assay (iELISA). Results: Out of total 313 animal serum samples screened (sheep-68, goat-195, cattle-50), 58.82% of sheep, 31.79% of goat and 70.00% of cattle serum samples were found positive. The prevalence of anti-BT antibodies in different agro climatic zones ranged between 31-50%. Conclusion: This study revealed high seroprevalence of bluetongue in cattle, sheep and goats in Assam. Incidence of bluetongue in animals of Assam being not reported so far; the present seroprevalence status of bluetongue in Assam indicates presence of sub-clinical infection in the state for the first time.


In this era of globalization, competition is so high. An organization will be able to survive, compete and even thrive if an organization's performance continues to operate effectively and efficiently. This study aims to examine and analyze whether job satisfaction to OCB with mediation effect on organizational commitment in PT. Pilih Utama. The population of this research were 52 PT. Pilih Utama employees and use all of the population for sampled. Methods of statistical analysis was used "Partial Least Square" (PLS) with the help of SMART PLS software and "Statistical Product and Service Solutions" (SPSS) 17.0. This study was found a significant positive effect on job satisfaction to OCB, a significant positive effect on job satisfaction to organizational commitment, a significant positive effect on commitment organizational to OCB, and proves that organizational commitment mediates the effect of job satisfaction to OCB


Ampicillin administered to rabbits (20 mg/kg per day) over a period of three days subsequently provoked a death rate of 40%. No deaths were observed after treatment with gentamycin (10 mg/kg per day) or with a combination of ampicillin and gentamycin. On the fourth day weight loss in the three treated groups was 12%, 11% and 9%, respectively, compared to controls. At the same time food intake in the treated groups was only 15% to 20% of the amount consumed by controls. In the caecum, ampicillin treatment resulted in dominance of a strain of Enterobacter aerogenes. Gentamycin had no effect on bacterial flora, although in combination with ampicillin, the number of caecal bacteria (aerobic and anaerobic) was reduced. Flora modification might be responsible for accumulation of NH3 and an unbalance of free acids. Caecotrophy was inhibited by administration of ampicillin. When administered intramuscularly, ampicillin produced results comparable with those obtained orally, although gentamycin was ineffective.


Time-dependent and systematic variations in the band gain and central frequencies of instruments used to study the cosmic microwave background (CMB) are important factors in the data-to-map analysis pipeline. If not properly characterized, they could limit the ability of next-generation experiments to remove astrophysical foreground contamination. Uncertainties include the instrument detector band, which could systematically change across the focal plane, as well as the calibration of the instrument used to measure the bands. A potentially major effect is time-dependent bandpass uncertainties caused by atmospheric fluctuations. More specifically, changes in atmospheric conditions lead to frequency-dependent changes in the atmospheric transmission which, in turn, leads to variations in the effective gain and central frequency of the instrument's bandpass. Using atmospheric modeling software and ACTPol bandpasses, we simulate the expected variations in band gain and central frequency for 20, 40, 90, 150, and 240 GHz bands as a function of precipitable water vapor, observing angle, and ground temperature to set limits on the expected uncertainties in band gain and central frequency. We then introduce the uncertainties to parametric maximum-likelihood component separation methods on simulated CMB maps to forecast foreground removal performance and likelihoods on the tensor-to-scalar ratio r. We conclude that to confidently measure a σ(r = 0) ∼ 10−3 with a bias on the recovered r under control, the uncertainty in the relative gain of the bandpass must be less than 2% and the uncertainty in the central frequency must be less than 1%. We also comment on the possibility of self-calibrating bandpass uncertainties.


Quartz-bearing mafic granulite from Holubov, in the Blansky Les complex, Bohemian Massif, Czech Republic contains two types of corona structures: pyroxene+plagioclase rim on garnet (Type-1 corona), and garnet rim on anorthite+spinel (An+Spl) mosaics (Type-2 corona). Significantly, Type-2 structures are enclosed by an orthopyroxene-depleted halo which, in places, seems to embay the Type-1 coronal pyroxene, indicating that the Type-2 coronas are a late feature. Type-1 coronas formed during uplift by the resorption of garnet and quartz: 2 Grs+Prp+3 Qtz = 3 Di+3 An and 2 Alm+Grs+3 Qtz = 3 Fs+3 An. Decompression is also supported by patterns of zoning in garnet (rimward decrease in X Ca , compensated by reverse zoning in andesine) and the formation of the An+Spl nucleus of Type-2 coronas at the expense of early kyanite and grossular-rich garnet: 5 Grs+(Prp,Alm)+12 Ky = 15 An+3 (Spl,Hc) Coronal grains of garnet are interpreted to have formed during cooling at substantially lower pressures as the An+Spl mosaics reacted with matrix (and, locally, coronal) orthopyroxene. These contrasting corona structures record near-isothermal ( approximately 900-750 degrees C) decompression of the granulite from approximately 14 kbar to approximately 2-3 kbar, and subsequent near-isobaric cooling. They are indicative of a clockwise P-T-t path.


This Letter reports the use of an inductively coupled plasma technique for fabrication of proton-exchanged (PE) LiNbO3 (LN) waveguides. Planar and stripe waveguides have been formed in Y-cut LN which are difficult to obtain with the conventional molten acid method due to the occurrence of surface damage. Secondary ion mass spectrometry, scanning electron microscopy, and infrared absorption spectrum characterization results revealed that a uniform vertical PE profile with a single low order crystal phase has been directly obtained as a result of this unique process. X-ray photoelectron spectroscopy characterization of the treated surface revealed the existence of NbO as the cause for a sometimes darkened surface and confirms the ability to completely restore the surface to LN by oxygen plasma treatment. Atomic force microscopy measurement confirms that good surface quality has been maintained after regeneration of the surface to LN.


Aim: The aim of this study was to report a novel POU Class 3 Homeobox 4 (POU3F4) variant and to provide further guidance on genetic counseling for incomplete partition (IP) type III families in the Korean population by showing two new contrasting cases in terms of genotypes and inheritance. Materials and Methods: Two consecutively recruited hearing-impaired probands with seemingly nonsyndromic features and their biological mothers were included in this study. Sanger sequencing and quantitative polymerase chain reaction (PCR) assays were performed for POU3F4. Results: A novel frameshift variant of POU3F4, c.852delC (p.Ile285Serfs*3), was identified in one of the patients. This mutation is predicted to truncate the protein within the POU homeodomain, resulting in the complete loss of the last nucleus localization signal. The proband's biological mother was also shown to be a carrier of this c.852delC (p.Ile285Serfs*3) mutant allele. A de novo genomic deletion on chromosome Xq21.2 was confirmed in another subject via quantitative PCR. This subject's biological mother, however, was not a carrier of this deletion. This indicates that the large upstream deletion of POU3F4 in the second proband occurred de novo. This finding is compatible with the previously proposed tendency for a high de novo rate of large genomic deletions involving the X-linked deafness-2 (DFNX2) locus. Conclusion: This study adds a novel, probably pathogenic POU3F4 truncation variant to the literature and provides guidance toward effective genetic counseling for IP III subjects based on more frequent de novo occurrence of POU3F4 deletions than POU3F4 point variants.


Humans have been beleaguered by fl oods since centuries, for there isa description of deluge, which is even immortalized in Bible. Also Silesiahas been affl icted with them for hundreds of years, they repeated periodicin every century. Floods affl icted Silesia in 18th century and tookplace mostly after Prussia had seized the power. The fi rst statutory regulationwas the eff ect of these dangerous natural phenomena, thus it was toprotect from fl oods. Nonetheless it wasn't perfect, as some troubles appearedduring 19th century. However the fl ood from 1854 was the fi rstthat wreaked real havoc: deluge of Wroclaw city came in the aftermath ofthis event. The range of fl ooded areas forced the provincial authorities( Provinziallandtag ) to take action in order to improve the situation. Socalled Provinziallandtag was the most signifi cant element of the self-government,which had been formed in Prussia at the time. Therefore it isworth reminding about most important circumstances of its establishmentin 19th century. Setting state, provincial loan off ice was initiative of 11thprovincial authorities in 1854. It developed a project of statut and theamount of securities, which were to be an object of transaction. It was oneof the best prepared petitions from 1851–1873. Desperate situation ofprovincial economy was the main reason of setting the loan off ice (previousattempts at improving the situation appeared to be fruitless and onlytemporary). Members of parliament thought that it had been necessary tocreate a new credit institution, as the loan off ice had not played its role sofar. The fl oods from 1850s, which ruined the economy were the mainreason of hard economic situation of province. Financing the repair ofinfrastructure required huge amounts of money, which could be gainedfrom credits with profi table interest. These were not guarantied by banksector, thus it was agreed that this task might be undertaken by an institutionof self-government, supported by subsidies. The main part of publicationdeals with system of off ice, its fi nancial politics, its main trappingsof business.There are charts in this work, which stands for fi nancial situation ofoffice. Normal 0 21 false false false PL X-NONE X-NONE /* Style Definitions */
 table.MsoNormalTable
 {mso-style-name:Standardowy;
 mso-tstyle-rowband-size:0;
 mso-tstyle-colband-size:0;
 mso-style-noshow:yes;
 mso-style-priority:99;
 mso-style-parent:"";
 mso-padding-alt:0cm 5.4pt 0cm 5.4pt;
 mso-para-margin:0cm;
 mso-para-margin-bottom:.0001pt;
 mso-pagination:widow-orphan;
 font-size:10.0pt;
 font-family:"Times New Roman","serif";}


1913. Diaghilev's Ballets Russes premieres Stravinsky's 'Rite of Spring' in Paris. The infamous first-night proves to be an electric experience for one member of the audience, the young couturiere Coco Chanel. When she and Stravinsky meet in 1920, both sense a charge, and the exiled composer hesitates over whether to accept the wealthy designer's offer to bring his family to summer at her villa. The Stravinsky entourage - ailing wife Catherine, and four children - arrive, and the composer enjoys a new burst of creative activity. Chanel, meanwhile, is hatching her plan to launch her classic fragrance, No.5. Soon she and her guest embark upon an affair which touches both deeply, but is complicated by their rigid devotion to their work, and Stravinsky's commitment to his family. As Catherine, now confined to her bed, comes to suspect what is happening around her, the two lovers must consider the depth of their feelings, and whether, with the autumn drawing in, theirs is a relationship that can survive.


Coronaviruses (CoVs) stand out for their large RNA genome and complex RNA-synthesizing machinery comprising 16 nonstructural proteins (nsps). The bifunctional nsp14 contains an N-terminal 3'-to-5' exoribonuclease (ExoN) and a C-terminal N7-methyltransferase (N7-MTase) domain. While the latter presumably operates during viral mRNA capping, ExoN is thought to mediate proofreading during genome replication. In line with such a role, ExoN-knockout mutants of mouse hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus (SARS-CoV) were previously found to have a crippled but viable hypermutation phenotype. Remarkably, using an identical reverse genetics approach, an extensive mutagenesis study revealed the corresponding ExoN-knockout mutants of another betacoronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), to be non-viable. This is in agreement with observations previously made for alpha- and gammacoronaviruses. Only a single MERS-CoV ExoN active site mutant could be recovered, likely because the introduced D191E substitution is highly conservative in nature. For 11 other MERS-CoV ExoN active site mutants, not a trace of RNA synthesis could be detected, unless – in some cases – reversion had first occurred. Subsequently, we expressed and purified recombinant MERS-CoV nsp14 and established in vitro assays for both its ExoN and N7-MTase activities. All ExoN knockout mutations that were lethal when tested via reverse genetics were found to severely decrease ExoN activity, while not affecting N7-MTase activity. Our study thus reveals an additional function for MERS-CoV nsp14 ExoN, which apparently is critical for primary viral RNA synthesis, thus differentiating it from the proofreading activity thought to boost long-term replication fidelity in MHV and SARS-CoV. Importance The bifunctional nsp14 subunit of the coronavirus replicase contains 3'-to-5' exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) domains. For the betacoronaviruses MHV and SARS-CoV, the ExoN domain was reported to promote the fidelity of genome replication, presumably by mediating some form of proofreading. For these viruses, ExoN knockout mutants are alive while displaying an increased mutation frequency. Strikingly, we now established that the equivalent knockout mutants of MERS-CoV ExoN are non-viable and completely deficient in RNA synthesis, thus revealing an additional and more critical function of ExoN in coronavirus replication. Both enzymatic activities of (recombinant) MERS-CoV nsp14 were evaluated using newly developed in vitro assays that can be used to characterize these key replicative enzymes in more detail and explore their potential as target for antiviral drug development.


Summary Clotting factor VIII (fVIII)-inhibitory antibodies represent a major problem in the treatment of haemophilia A. To understand the inactivation mechanisms and to pave the way towards modifications of recombinant clotting factors that reduce their immunogenicity, the exact localization of immunodominant epitopes is required. Here, a random peptide phage display library was employed to identify epitopes of polyclonal fVIII antibodies isolated from patient's plasma by affinity chromatography. FVIIIbinding specificity and inhibitory activity of the isolated fVIII antibodies were confirmed by ELISA and Bethesda assays. Phage selection on the individual samples yielded several phages which were displaced from binding to the respective antibody preparation by fVIII. Their homology with amino acid motifs of human fVIII and immunoprecipitation results with radioactively labelled fVIII fragments suggested putative epitopes in the A1, A2 and C1 domains of fVIII for one and in the C2 domain for another patient. Synthetic peptides corresponding to the A2, C1 and C2 domain epitopes blocked antibody binding to fVIII and partially neutralized the inhibitory activity of the respective plasma in Bethesda assays. These results provide the proof of principle that random peptide libraries can be used for the mapping of epitopes in a polyclonal antibody preparation.