Purified immunoglobulins are required for a wide range of applications in biotechnology such as laboratory and clinical reagents, novel therapeutics, and immunoaffinity ligands in chromatography. The present work describes the effective separation of immunoglobulins from mixtures of synthetic immunoglobulin solutions and human serum using immobilized metal affinity chromatography and specified pH and imidazole gradients. Ethylenediamine triacetic acid was used as the chelating agent and Cu(II) as the immobilized ion on an agarose matrix. The modified agarose gel presented Cu(II) and immunoglobulin capacities of 65 µmol/mL and 46 mg/mL, respectively. pH and imidazole gradients were performed in order to find the best conditions for the affinity of immunoglobulins toward the immobilized Cu(II) ions. The chelating systems were able to effectively retain immunoglobulins and showed no measurable affinity towards human serum albumin under all working conditions. In the purification of immunoglobulins from human serum, a pH gradient was able to release immunoglobulins (1.3 mg) with a total purity of 60% (and a purity of 84% for 65% recovery of all adsorbed protein), while an imidazole gradient allowed the recovery of 0.8 mg of immunoglobulins with a total purity of 75% (and a purity of 83% for 70% recovery of all adsorbed protein).


The idea that low-dose aspirin could be recommended for vascular protection on the grounds of age alone, irrespective of the levels of other vascular risk factors, seems to have been first suggested by the editor of the Archives of Internal Medicine, who, in 1991 wrote: "In my opinion, aspirin therapy is indicated in US men aged 50 years or older and in women after the menopause".1 Later, a group of British organisations recommended cardioprotection by daily aspirin for subjects aged over 50 years "whose hypertension, if present, is controlled".2 The US Preventive Services Task Force stated that "men older than 40 years [and] postmenopausal women… may wish to consider aspirin therapy".3 Most recently, a report from Wales,4 based on the individual risk factor data for subjects in a large population cohort, together with data for a cohort of women, gave evidence suggesting that aspirin prophylaxis is reasonable from about 42 years of age on average for men, and for 80% of men from about age 49 years, while in women the average age at which aspirin prophylaxis becomes reasonable was judged to be about 53 years. A report, published as a companion paper to this last, vigorously opposed the idea of aspirin prophylaxis on the grounds of age alone.5

In this issue of the journal Bulugahapitiya et al present evidence based on the levels of vascular risk factor levels of 12 000 patients without diabetes, aged between 30 and 74 years, drawn at random from the practice lists of 304 primary care practices throughout the UK (see page 1429).6 The authors estimate that the age at which vascular risk reaches the level at which aspirin prophylaxis should be considered (10% within 10 years) is 48 years for men, and 57 years …


The main objective in this study was to investigate how the deformation of Docol 600 DL steel plates subject to blast loading can be accurately recreated with different numerical simulations. An initial experiment was undertaken employing a gas gun to simulate the blast loads. The experiments failed to properly emulate a proper blast load, but the experiment served as an initial benchmark for calibration of the numerical models. Focus shifted on to simulating experiments performed at Raufoss in 2010 by Rakvag. Experiments on quadratic 400mm by 400mm, 2mm thick Docol 600 DL steel plates were performed for standoffs at 300mm, 400mm, 450mm and 550mm. Material models for the steel plates were determined from previous work done at SIMLab. Numerical simulations in LS-DYNA and IMPETUS were utilized with a pure Lagrangian approach, an uncoupled Eulerian-Lagrangian approach, a coupled Eulerian-Lagrangian and a discrete particle method. The pure Lagrangian simulations were based on data from the CONWEP standard, thus it failed to properly describe the charge geometry and consequently misrepresented the properties of the blast load. The uncoupled and coupled Eulerian-Lagrangian simulations properly described the charge geometry, but a requirement of a sufficiently fine discretization of the Eulerian mesh rendered full 3D simulations with a high computational demand. A 2D to 3D mapping technique in the Eulerian domain was successfully completed to reduce the computational time. The discrete particle approach yielded the most accurate results while being the easiest to define numerically. Employing the different numerical techniques revealed that the main source of error in recreating expected deformation lies in the capability of properly describing the blast load conditions.


Habitat alteration is one of the major drivers of species loss. Springs may be among the least affected aquatic habitats and are considered to be refugial habitats. Diatom assemblages were sampled from 74 Swiss springs comprising seven spring types over a wide altitudinal and ecological range as well as a wide range of anthropogenic modifications (alterations). Each spring was assigned to a five-point alteration scale, from natural to heavily altered. In total, 504 diatom species were recorded (not including 36 taxa that could not be identified to species level) from five microhabitats, and coded according to rarity and Red List status. The results of this extensive spring-habitat diatom survey were compared statistically with a large stream diatom dataset (DI-CH). The spring diatom microflora was more species rich and included more rare and/or threatened species than the stream microflora. The proportion of Red List species and rare species was highest in the DI-CH dataset, but the proportion of species with no Red List status and rare species was the highest in springs. Species richness, Red List status, and rarity were significantly related to the degree of spring alteration. This is consistent with the hypothesis that unaltered springs function as refuges for the Swiss fresh water microflora, and that they can be regarded as "least-impaired habitats". These may be critically important for the conservation of the European freshwater diatom microflora.


'l'he adsorption of aromatic compounds on synthetic resins from aqueous solution was studied in order to develop a methodology by which adsorption equilibria. in a single' solute system. can be predicted from the physical-chemical properties of a compound of interest. and the adsorption isotherm of a reference compound. To develop this methodology. physical properties of 13 substituted phenols were described by linear free energy relationships (LFER) (Ham ett polar constant and molar attractive constant) and were correlated with parameters in the .·reundlich adsorption isotherm. The methodology was tested using data extracted from the literature and was found to be able to predict adsorption equilibria within a median percent deviation between the experimental and predicted data of 35.73%.


In southern California the natural environmental system involves the continual relocation of sedimentary materials. Particles are eroded from inland areas where there is sufficient relief and, precipitation. Then, with reductions in hydraulic gradient along the stream course and at the shoreline, the velocity of surface runoff is reduced and there is deposition. Generally, coarse sand, gravel and larger particles are deposited near the base of the eroding surfaces (mountains and hills) and the finer sediments are deposited on floodplains, in bays or lagoons, and at the shoreline as delta deposits. Very fine silt and clay particles, which make up a significant part of the eroded material, are carried offshore where they eventually deposit in deeper areas. Sand deposited at the shoreline is gradually moved along the coast by waves and currents, and provides nourishment for local beaches. However, eventually much of this littoral material is also lost to offshore areas. Human developments in the coastal region have substantially altered the natural sedimentary processes, through changes in land use, the harvesting of natural resources (logging, grazing, and sand and gravel mining); the construction and operation of water conservation facilities and flood control structures; and coastal developments. In almost all cases these developments have grown out of recognized needs and have well served their primary purpose. At the time possible deleterious effects on the local or regional sediment balance were generally unforeseen or were felt to be of secondary importance. In 1975 a large-scale study of inland and coastal sedimentation processes in southern California was initiated by the Environmental Quality Laboratory at the California Institute of Technology and the Center for Coastal Studies at Scripps Institution of Oceanography. This volume is one of a series of reports from this study. Using existing data bases, this series attempts to define quantitatively inland and coastal sedimentation processes and identify the effects man has had on these processes. To resolve some issues related to long-term sediment management, additional research and data will be needed. In the series there are four Caltech reports that provide supporting studies for the summary report (EQL Report No. 17). These reports include: EQL Report 17-A Regional Geological History EQL Report 17-B Inland Sediment Movements by Natural Processes EQL Report 17-C Coastal Sediment Delivery by Major Rivers in Southern California EQL Report 17-D -- Special Inland Studies Additional supporting reports on coastal studies (shoreline sedimentation processes, control structures, dredging, etc.) are being published by the Center for Coastal Studies at Scripps Institution of Oceanography, La Jolla, California.


Bayesian decision theory is known to provide an effective framework for the practical solution of discrete and nonconvex optimization problems. This book is the first to demonstrate that this framework is also well suited for the exploitation of heuristic methods in the solution of such problems, especially those of large scale for which exact optimization approaches can be prohibitively costly. The book covers all aspects ranging from the formal presentation of the Bayesian Approach, to its extension to the Bayesian Heuristic Strategy, and its utilization within the informal, interactive Dynamic Visualization strategy. The developed framework is applied in forecasting, in neural network optimization, and in a large number of discrete and continuous optimization problems. Specific application areas which are discussed include scheduling and visualization problems in chemical engineering, manufacturing process control, and epidemiology. Computational results and comparisons with a broad range of test examples are presented. The software required for implementation of the Bayesian Heuristic Approach is included. Although some knowledge of mathematical statistics is necessary in order to fathom the theoretical aspects of the development, no specialized mathematical knowledge is required to understand the application of the approach or to utilize the software which is provided. Audience: The book is of interest to both researchers in operations research, systems engineering, and optimization methods, as well as applications specialists concerned with the solution of large scale discrete and/or nonconvex optimization problems in a broad range of engineering and technological fields. It may be used as supplementary material for graduate level courses.


The goal of the Partial Metrics Project is the automatic acquisition of planning knowledge from target code modules in a program library . In the current prototype the system is given a target code module written in Ada as input, and the result is a sequence of generalized transformations that can be used to design a class of related modules. This is accomplished by embedding techniques from Artificial Intelligence into the traditional structure of a compiler. The compiler performs compilation in reverse, starting with detailed code and producing an abstract description of it. The principal task facing the compiler is to find a decomposition of the target code into a collection of syntactic components that are nearly decomposable. Here, nearly decomposable corresponds to the need for each code segment to be nearly independent syntactically from the others. The most independent segments are then the target of the code generalization process. This process can be described as a form of chunking and is implemented here in terms of explanation-bas|d learning. Chunking has been shown to be an important vehicle for learning in other application domains as well . The problem of producing nearly decomposable code components becomes difficult when target code module is not well structured. The task facing users of the system is to be able to identify well-structured code modules from a library of modules that are suitable for input to the system. In this paper we describe the use of inductive learning techniques, namely variations on Quinlan's ID3 system that are capable of producing a decision tree that can be used to conceptually distinguish between well and poorly structured code. In order to accomplish that task a set of high-level concepts used by software engineers to characterize structurally understandable code were identified. Next, each of these concepts was operationalized in terms of code complexity metrics than can be easily calculated during the compilation process. These metrics are related to various aspects of the program structure including its coupling, cohesion, data structure, control structure, and documentation. Each candidate module was then described in terms of a collection of such metrics. Using a training set of positive and negative examples of well-structured modules, each described in terms of the appointed metrics, a decision tree was produce that was used to recognize other well-structured modules in terms of their metric properties. This approach was applied to modules from existing software libraries in a variety of domains such as vision and numerical methods. The results achieved by the system were then benchmarked against the performance of experienced programmers in terms of recognizing well structured code. In a test case involving 82 modules, the system was able to discriminate between poor and well-structured code 99% of the time as compared to an 80% average for the 25 programmers sampled. The results suggest that such an inductive system can serve as a practical mechanism for effectively identifying reusable code modules in terms of their structural properties


PURPOSE
To evaluate the corneal cross-linking (CXL) effect on symptomatic bullous keratopathy, and its impact on the visual acuity, corneal thickness and pain symptomatology.

METHODS
Twelve patients with symptomatic bullous keratophaty were included. A clinical examination with a specific questionnaire (pain scale-visual numeric analog scale), visual acuity, and corneal thickness measures was performed before corneal cross-linking and 7, 30 and 60 days after the procedure. In all patients, the treatment with the UVA-crosslinking was done after corneal abrasion on the slit-lamp and instillation of 0.1% riboflavin in saline for every five minutes, lasting 30 minutes. Subsequently, the patient underwent the UVA light exposure, using riboflavin and topical anesthesia, every five minutes lasting 30 minutes. The patient received 0.3% ofloxacine drops, and artificial tears until complete reepithelization. The Friedman test was used to compare the means of frequencies of visual acuity, pain symptoms and corneal thickness. A 'p' value<0.05 was considered for rejecting the null hypothesis.

RESULTS
Twelve eyes from 12 patients with recurrent epithelium erosions were treated. The mean follow-up was two months. Significant pain reduction was observed (p<0.001). Corneal thickness and visual acuity measurements presented with no significant difference.

CONCLUSION
The potential use of cross-linking in the treatment of bullous keratopathy pain was proved to be likely. A longer follow-up to confirm whether these results can be reproduced in the long term is necessary.


Prenatal care, one of the most frequently used forms of healthcare in the United States, involves a series of encounters during the gestational period, educates women about pregnancy, monitors existing medical conditions, tests for gestational health conditions, and refers expectant mothers to services such as support groups and social services. However, an increasingly methodologically rigorous literature suggests that the effects of prenatal care timing and quantity on birth outcomes, particularly low birthweight, are modest at the population level. A review and synthesis of the literature suggests that the questions typically being asked may be too narrow and that more attention should be paid to the characterization of infant health, characterization of the content and quality of prenatal care, potential heterogeneous effects, potential indirect effects on health behaviors that may benefit offspring, potential long-term effects, potential spillover effects (i.e., on mothers and their subsequent children), effects of preconceptional and lifetime care, and intergenerational effects.


In the paper, we selected high manganese steel as the binder and titanium carbide as the hard phase, which could attain single austenite bonded titanium carbide after water toughening in order to combine excellent toughness of matrix with good wear resistance of TiC organically for some components that required excellent toughness and wearability. By dint of SEM, XRD etc. detection means, effects of ingredient proportion, preparation technics and heat treatment parameters on hardness, microstructure, and mechanical property were investigated; so the composition and preparation process of TiC cemented were confirmed, which was applied to grinding with large impact force.


Author(s): Sims, John Revel | Advisor(s): Leavitt, Jacqueline | Abstract: Little is understood about displacement in urban contexts. Some of the difficulties that have impeded previous research are methodological as the data necessary for displacement research tends to be speculative, prohibitively expensive, or difficult to obtain. The greater problem I argue is conceptual. Outside of Neil Smith's rent gap hypothesis or the philosophy of property rights, there is little theoretical ground that explains urban displacement or facilitates analysis. Within the literature on urban change, where displacement would seem to have a strong theoretical foundation, displacement tends to exist uncomfortably between a range of theories from the neoclassicist's preference for atomized rational choice, the Chicago School's tenacious equilibrium mechanisms, and most recently, a version of demographic invasion based in economic restructuring. This research on evictions in Los Angeles seeks to challenge these conceptual and empirical shortcomings. Through a spatial pattern analysis of over 70,000 geographically referenced evictions, four distinct geographies of displacement are shown to have existed between 1994 and 1999 in Los Angeles including Downtown, Hollywood, Koreatown, and South Los Angeles. Logged transformations of eviction rates in the 381 census tracts comprising the area of study are furthermore regressed to three factors for each of the six years of the study. Results provide evidence that two of these factors are statistically correlated with eviction rates. The first factor is negatively correlated with eviction rates and describes deterrence to eviction based on relative affluence, educational attainment, and racial segregation in the form of high proportions of whites relative to other racial groups. The second expresses investment in desirable locations through average property sales and nonfamily households and is positively correlated with eviction rates. Taken together, the spatial pattern and spatial regression analyses confirm that evictions are socio-spatial phenomena forming three types of displacement in Los Angeles: (1) poverty- and race-related; (2) investment-related; and (3) a combination of poverty-, race-, and investment-related displacement. The four geographies of displacement are furthermore investigated using exploratory data analysis and archival methods to uncover the specific role that property owners played in each. The results of this research demonstrate that gentrification only partially explains one of the four displacement geographies while the other three are non- or pre-gentrifying contexts more appropriately described through growth machine strategies, uneven development, negative spillover effects, and financial restructuring. The dissertation ends with a call for a number of policy recommendations including a right to counsel in eviction cases and increased tenant organization.


Bone mass and its mineral content are under genetic control. The vitamin D receptor (VDR) gene has been shown to be a major locus for genetic effects on bone mineral density (BMD), and polymorphisms in this gene accounted for a large proportion of genetic variance in BMD in an Australian population. In this study, we investigated whether similar associations are present in a North American population. We studied 139 normal healthy women (age 53.2 ± 14.5, mean ± SD) and 43 severely osteoporotic postmenopausal women (age 65.8 ± 5.9). In the 127 of them with complete genetic studies, the distribution of genotypes, determined by polymerase chain reaction on leukocyte DNA samples, agreed closely with that in the Australian population. BMD was strongly related to age and weight, and, thus was adjusted for these parameters prior to genetic analysis. We found that age modulated the effect of VDR genotypes on femoral neck BMD (FN‐BMD) (TaqI, p = 0.036;BsmI, p = 0.118; ApaI, p = 0.041) such that the effect of genotype was greatest among younger (premenopausal) women and declined with age so that there was no discernible difference by age 70. Among the younger women, a high FN‐BMD was associated with the TT (or aa or bb) genotype while low FN‐BMD was associated with the tt (or AA or BB) genotype. In osteoporotic women, although the difference in FN‐BMD between alternate TaqI homozygotes (TT vs. tt) was 0.13 g/cm2 (or about 18%), the overall difference among the genotype groups was not significant (TaqI, p = 0.13; BsmI, p = 0.21; ApaI, p = 0.09), possibly due to the small sample of osteoporotic women. There was no relationship of VDR genotype to lumbar spine BMD. We conclude that the VDR gene modulates differences in BMD in premenopausal women. Subsequent interaction of the gene and environmental factors and the role of VDR genotypes in predisposing to osteoporosis needs further study.


Abstract The paper discusses the application of a new cell management system implemented in a UK company. The system was originally based upon the Nissan 'green area' (GA) concept but it was extended at the company into a complete business management structure covering the entire business. This new structure involved a GA system in the operational activities of the business, for example shop-floor and commercial activities, a 'business excellence' GA system primarily aimed at business improvement and development projects and a business strategic GA system. The GA system was used throughout the business and integrated the activities of cells in the commercial, engineering and shop-floor domains. It was more than the quality circle concept in that it also provided a mechanism for performance assessment, business control, improvement, training and communication.


This chapter presents an overview of dictionary learning-based speech enhancement methods. Specifically, we review the existing algorithms that employ sparse representation (SR), nonnegative matrix factorization (NMF), and their variations applying for speech enhancement. We emphasize that there are two stages in a speech enhancement system, namely learning dictionary and enhancement. The two scenarios of learning dictionary process, offline and online, are discussed carefully as well. We finally present some evaluation methods and the future lines work.


Phylloquinone (vitamin K(1) = VK(1)) and the menaquinones (MK-n, or vitamin K(2) = VK(2)) are naturally occurring forms of VK. Most of the menaquinone series are synthesized by microorganisms, but we have reported that MK-4 is usual in being synthesized by the conversion of orally ingested VK(1) or MK-n in the major tissues of germfree rats and mice which lack their intestinal microflora. This result led us to deny 1960's Martius' hypothesis that described the participation of bacterial enzyme of the intestinal flora to this conversion. VK acts as a cofactor in the posttranslational synthesis of gamma-carboxyglutamic acid (Gla) from glutamic acid (Glu) residues in the nascent Gla-protein molecule. Therefore, VK is essential for blood coagulation (various clotting factors) and bone structure (as osteocalcin [OC = BGP] and matrix Gla-protein [MGP] in mammals. In addition to the liver, VK is found in the bone, brain, heart, testis, kidney, pancreas and salivary glands mainly as MK-4, and it has been reported that MK-4 itself has specific biological activities in these tissues beside Gla-protein formation. However, the physiological role of MK-4 in these organs has not been fully understood yet. Recently MK-4 has been attracted the attention of researchers due to its activities such as apoptotic activity on the osteoclast cells and leukemia cells, SXR/PXR ligand, and so on. We further review the potent important physiological role of MK-4 in the bone as well as other major tissues.


A thesis Submitted to the Department of Marketing and Corporate Strategy, Kwame Nkrumah University of Science and Technology (KNUST), in partial fulfillment of the requirement for the degree of Masters of Business Administration (Strategic Management and Consulting Option), 2015


We describe the results of a series of psychophysical experiments that investigated the relationships among defect visibility, content importance, and perceived impairment in digital video. Various types of controlled defects were inserted into normal video and shown to our test subjects. The defects varied in their strength, location, appearance, size, and duration. We measured three specific subjective quantities: the defect detection probability, the perceived impairment, and the content importance. Impairment was found to be tightly related to defect visibility but only weakly related to content importance.


In this book, teachers from a variety of backgrounds reflect on their journeys into teaching and discuss the impact of these diverse experiences on the way they teach. The authors adopt an autoethnographic approach to telling stories of transition and profound transformation, and discuss how these have shaped their professional identities and teaching methods. Stories of change can illustrate the experiences and practices of teaching in a range of educational contexts. By capturing these personal stories, this book will inform and support readers who are studying to become teachers and those already working in education by developing their understanding and empathy with the role. By engaging with the autobiographies of the authors, we suggest that readers will be able to reflect on their own progression and that this has the potential to increase confidence with their personal and professional identities - which are inextricably linked. Autoethnography can develop self-knowledge and understanding in the reader and writer of such texts, offering unique insights and individual ways of being that will benefit students and staff in a range of educational settings. This book values the telling and sharing of stories as a strategy for enabling teachers to learn from one another and help them to feel more supported - you are not alone.


In submitting this contribution for your consideration, its brevity may be urged as a virtue. A great deal has been written concerning the etiology of ectopic gestation, some of which has approached demonstration, more has been speculative, but certainly much has been done toward the solution of many of the attending phenomena. The function of the ciliated epithelium of the oviducts has been made much of as the chief, if not the sole, motive force in the transportation of the ovum into the uterine cavity. Building on this assumption Tait and others have attempted to show that in the destruction of the cilia by the inflammatory diseases of the oviducts, the function of the tubes is destroyed and the resulting inertia is to be regarded as the prime factor in the production of tubal pregnancy. According to Lilienthal, Williams and others, the most frequent site of the chorionic attachment


: The essential information about materno-foetal immunologic interactions is reviewed. After a brief description of placental tissue (decidual cells from uterine mucosa, trophoblast), evidence that immunisation can be achieved by introduction of antigen into normal uterus is presented, although grafts performed in uterus of pregnant females are prolonged. Throphoblast cells bear specific antigens but histocompatibility antigens are usually not detectable at their surface. Proteins and cells from the foetus enter the maternal circulation and vice-versa, resulting in the production of antibodies against cell-associated foetal antigens by the mother. Some regulatory process of the maternal immune response have been investigated including blocking antibodies, maternal and foetal suppressor T cells. The biological roles of trophoblast and that of sustained microchimerism are underlined. Immunologic damage to the foetus can be produced only by inducing a cytotoxic cellular response before pregnancy. Possible analogies between immune responses to foetal allografts and tumors are discussed.


We discuss ghost free models of the recently suggested mimetic dark matter theory. This theory is shown to be a conformal extension of Einstein general relativity. Dark matter originates from gauging out its local Weyl invariance as an extra degree of freedom which describes a potential flow of the pressureless perfect fluid. For a positive energy density of this fluid the theory is free of ghost instabilities, which gives strong preference to stable configurations with a positive scalar curvature and trace of the matter stress tensor. Instabilities caused by caustics of the geodesic flow, inherent in this model, serve as a motivation for an alternative conformal extension of Einstein theory, based on the generalized Proca vector field. A potential part of this field modifies the inflationary stage in cosmology, whereas its rotational part at the post inflationary epoch might simulate rotating flows of dark matter.


The increase of population has an impact on the physical development sector. Thus, various initiatives are implemented so that the physical development of land resources are used optimally and efficiently. One of the development initiatives undertaken is the introduction of the multi-storey building, also known as strata development. Strata development is seen as one of the efficient methods of construction, especially in urban areas. However, there have been issues and challenges related to the strata development resulting in the abandoned development. This will cause a negative impact in the long term, for example in terms of safety, health and sustainability aspects in development. Due to the continuation of this problem, there are initiatives that have been introduced and practiced in some countries, namely En Bloc Sale for strata building. The idea behind this concept is to encourage urban renewal in countries or cities with land scarcity issues. Matters discussed in this research include the concept of En Bloc Sale, process and legal framework used based on experience in Singapore. Accordingly, this research will be conducted in a qualitative method in which it will rely on the analysis of the relevant statutes, rules, regulations, books, journals, articles, theses, seminar papers, electronic materials and various newspaper reports. This research is expected to review En Bloc Sale mechanism as a method of urban renewal and strata scheme termination.


We categorize the three types of renal dysfunction associated with the use of nonsteroidal anti-inflammatory drugs (NSAID): acute renal failure, acute interstitial nephritis, and hyperkalemia. The paper provides clinical examples of each type, discusses pathophysiology, and describes response to therapy, in addition to outlining the usefulness of labeled leukocyte nuclear studies and kidney biopsy. We conclude that these drugs are relatively common causes of renal dysfunction, particularly in selected subpopulations.


The work is devoted to solving the axisymmetric problem of the theory of pressing porous bodies with practical application in the form of force calculation of metallurgical processes of briquetting small fractional bulk materials: powder, chip, granulated and other metalworking wastes. For such materials, the shape of the particles (structural elements) is not geometrically correct or generally definable. This was the basis for the decision to be based on the continual model of a porous body. As a result of bringing this model to a two-dimensional spatial model, a closed analytical solution was obtained by the method of jointly solving differential equilibrium equations and the Guber-Mises energy condition of plasticity. The following assumptions were adopted as working hypotheses: the radial shear stress is equal to the tangential one, the lateral pressure coefficient is equal to the relative density of the compact. Due to the fact that the problem is solved in a general form and in a general formulation, the solution itself should be considered as methodological for any axisymmetric loading scheme. The transcendental equations of the deformation compaction of a porous body are obtained both for an ideal pressing process and taking into account contact friction forces. As a result of the development of a method for solving these equations, the formulas for calculating the local characteristics of the stressed state of the pressing, as well as the integral parameters of the pressing process are derived: pressure, stress, and deformation work.


Abstract The Roma and the Jews make up less than half a per cent of the population of Bosnia and Herzegovina. And yet their leaders could sue their country, successfully, at the European Court of Human Rights, by claiming that the system of reserved seats in the state Presidency and the second chamber of Parliament is monopolised by and for the three 'constituent peoples' (Bosniaks, Croats, and Serbs) and, thus, discriminatory towards minorities and other citizens. The 2009 ruling of the Court in Strasbourg (Sejdić and Finci v. Bosnia and Herzegovina) has shaken the very cornerstones of this unique European consociational ethnocracy and has obliged their leaders to undertake deep constitutional reforms. The three articles that compose this Special Section explore the role played by the 'national minorities' (such as Roma and Jews) in Bosnian politics, in particular in relation to the introduction and implementation of reserved seats for national minorities introduced in local assemblies for the 2008 municipal elections. The articles analyse the use of the system of reserved seats by national minorities, the reactions and the strategies of the ethnic parties representing the three constituent peoples and the patterns of descriptive versus substantive representation of minority interests. Addressing the questions of 'what', 'why' and 'how' of political representation of national minorities in a consociational context, the articles in this Special Section show that Bosnian tripartite ethnocracy hardly supports the intrusion of 'non-constitutive' elements in its framework and that national minorities still face significant obstacles when it comes to representation of their interests in a political system mainly concerned with the group rights of constituent peoples.


The Purcell effect of quantum dot (QD) spontaneous emission with Ag-SiO2 multilayer metamaterial nanostructures has been demonstrated in experiment and simulation. A broadband enhanced spontaneous emission rate of QDs is observed due to large local density of states in the epsilon-near-zero and hyperbolic regions of multilayer structures. Multilayer gratings are utilized to further enhance the QD spontaneous emission as the QDs located inside the grating grooves strongly interact with high-k coupled surface plasmon polariton modes. Photoluminescence decay measurements are in good agreement with both analytical treatment with a nonlocal effect and three-dimensional finite-element simulation. Detailed studies of QD position and polarization effects on emission rate enhancement for multilayer and multilayer grating nanostructures provide important insight for understanding the coupling mechanisms of emitter–multilayer interaction and the engineering of local density of states in metamaterial nanostructures. ...


For recognition of human actions in surveillance videos, action recognition methods in literature are analyzed and coherent feature extraction methods that are promising for success in such videos are identified. Based on local methods, most popular two feature extraction methods (Dollar's "cuboid" feature definition and Raptis and Soatto's "tracklet" feature definition) are tested and compared. Both methods were classified by different methods in their original applications. In order to obtain a more fair comparison both methods are classified by using the same classification method. In addition, as it is more realistic for recognition of real videos, two most popular datasets KTH and Weizmann are classified by splitting method. According to the test results, convenience of tracklet features over other methods for action recognition in real surveillance videos is proven to be successful.


International concern about illegal forestry activities has grown markedly. Asian, African, and European governments have held high-level regional conferences on Forest Law Enforcement and Governance (FLEG). Indonesia has signed path-breaking Memoranda of Understanding on illegal logging with the United Kingdom, China, and Norway. The Convention on Biological Diversity, the United Nations Forum on Forests, the International Tropical Timber Organisation, and the G8 have all issued forceful statements, and incorporated the issue in their work plans. The European Commission has committed itself to formulating a European FLEG Action Plan. Japan and Indonesia have initiated an Asian Forest Partnership, with a major focus on illegal logging. Global Witness, the Environmental Investigation Agency, Transparency International, Greenpeace, Global Forest Watch, and Friends of the Earth have raised public awareness about the problem.


Background Uncertainty underlies the effectiveness of somatostatin analogues for slowing the progression of polycystic kidney or liver disease. Methods Eligible studies included randomized controlled trials (RCTs) evaluating somatostatin analog as therapy for patients with polycystic kidney disease (PKD) or polycystic liver disease (PLD) compared to placebo or standard therapy. Two reviewers independently screened studies identified from databases (MEDLINE, EMBASE, Cochrane Database), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Outcome measurements were changes in total liver volume (TLV), total kidney volume (TKV), and estimated glomerular filtration rate (eGFR). Results Of 264 nonduplicate studies screened, 10 RCTs met the inclusion criteria. The body of evidence provided estimates warranting moderate confidence. Meta-analysis of 7 RCTs including a total of 652 patients showed that somatostatin analogs are associated with a lower %TLV growth rate compared to control (mean difference, -6.37%; 95% CI -7.90 to -4.84, p<0.00001), and with a lower %TKV growth rate compared to control (mean difference, -3.66%; 95% CI -5.35 to -1.97, p<0.0001). However, it was not associated with a difference in eGFR decline (mean difference, -0.96 mL/min./1.73m2; 95% CI -2.38 to 0.46, p = 0.19). Conclusions Current body of evidence suggests that somatostatin analogs therapy slows the increase rate of TLV and TKV in patients with PKD or PLD compared to control within a 3-year follow-up period. It does not seem to have an effect on the change in eGFR. Somatostatin analogs therapy can be a promising treatment for ADPKD or ADPLD, and we need to continue to research its effectiveness for ADPKD or ADPLD.


Analyses of temporal and geographic distributions of the minerals of beryllium, boron, copper, mercury, and molybdenum reveal episodic deposition and diversification. We observe statistically significant increases in the number of reported mineral localities and/or the appearance of new mineral species at ~2800 to 2500, ~1900 to 1700, ~1200 to 1000, ~600 to 500, and ~430 to 250 Ma. These intervals roughly correlate with presumed episodes of supercontinent assembly and associated collisional orogenies of Kenorland (which included Superia), Nuna (a part of Columbia), Rodinia, Pannotia (which included Gondwana), and Pangea, respectively. In constrast, fewer deposits or new mineral species containing these elements have been reported from the intervals at ~2500 to 1900, ~1700 to 1200, 1000 to 600, and 500 to 430 Ma. Metallogenesis is thus relatively sparse during periods of presumed supercontinent stability, breakup, and maximum dispersion. Variations in the details of these trends, such as comparatively limited Hg metallogenesis during the assumed period of Rodinia assembly; Proterozoic Be and B mineralization associated with extensional environments; Proterozoic Cu, Zn, and U deposits at ~1600 and 830 Ma; and Cenozoic peaks in B, Cu, and Hg mineral diversity, reveal complexities in the relationship between episodes of mineral deposition and diversification on the one hand, and supercontinent assembly and preservational biases on the other. Temporal patterns of metallogenesis also reflect changing near-surface environments, including differing degrees of production and preservation of continental crust; the shallowing geotherm; changing ocean chemistry; and biological influences, especially those associated with atmospheric oxygenation, biomineralization, and the rise of the terrestrial biosphere. A significant unresolved question is the extent to which these peaks in metallogenesis reflect true episodicity, as opposed to preservational bias.


Graphics processing units (GPUs) are playing more important roles in parallel computing. Using their multi-threaded execution model, GPUs can accelerate many parallel programmes and save energy. In contrast to their strong computing power, GPUs have limited on-chip memory space which is easy to be inadequate. The throughput-oriented execution model in GPU introduces thousands of hardware threads, which may access the small cache simultaneously. This will cause cache thrashing and contention problems and limit GPU performance. Motivated by these issues, the authors put forward a locality-protected method based on instruction programme counter (LPC) to make use of data locality in L1 data cache with very low hardware overhead. First, they use a simple Program Counter (PC)-based locality detector to collect reuse information of each cache line. Then, a hardware-efficient prioritised cache allocation unit is proposed to coordinate data reuse information with time-stamp information to predict the reuse possibility of each cache line, and to evict the line with the least reuse possibility. Their experiment on the simulator shows that LPC provides an up to 17.8% speedup and an average of 5.0% improvement over the baseline method with very low overhead.


Finding the power allocations that maximize the sum-rate of a K-user N-tone Digital Subscriber Line (DSL) system is known to be NP-hard. In this paper we devise a polynomial-time algorithm to approximate the maximum sum rate of the system. The development of this algorithm is guided by the fact that, to approach the sumrate maximum, the users should operate in an FDMA-mode over frequency tones where the crosstalk coefficients exceed a certain threshold, and should share the tones for which the crosstalk coefficients are sufficiently small. Drawing on this insight, the algorithm partitions the N tones into three sections and imposes an appropriate signalling structure on each section. The first section contains those tones for which the crosstalk coefficients are small and uses an iterative water-filling technique to determine the power allocations. The second section contains the tones with intermediate crosstalk coefficients and uses a primal-dual algorithm, and the third section contains the tones with large crosstalk coefficients and uses a dual FDMA algorithm. To decouple the overall optimization of power allocation across the three sections, we use tools from Lagrangian duality and sensitivity analysis to devise an iterative scheme that can optimally allocate each user's power budget to the three sections. Our numerical simulations, show that the sum-rate of the proposed algorithm is very close to that of the 'optimal' spectrum balancing algorithm, but requires considerably less computational effort.


A multi-hop energy harvesting wireless sensor network (EH-WSNs) is a key enabler for future communication systems such as the internet-of-things. Optimal power management and routing selection are important for the operation and successful deployment of EH-WSNs. Characterizing the optimal policies increases significantly with the number of nodes in the network. In this paper, optimal control policy is devised based on minimum-delay transmission in a multi-hop EH-WSN using reinforcement learning (RL). The WSN consists of M EH sensor nodes aiming to transmit their data to a sink node with a minimum delay. Each sensor node is equipped with a battery of limited capacity to save the harvested energy and a data buffer of limited size to store both the sensed and relayed data from neighboring nodes. Centralized and distributed RL algorithms are considered for EH-WSNs. In the centralized RL algorithm the control action is taken at a central unit using the state information of all sensor nodes. In the distributed RL algorithm the control action is taken locally at each sensor node using its state of information and the state information of neighboring nodes. The proposed RL algorithms are based on the state-action-reward-state-action (SARSA) algorithm. Simulation results demonstrate the merits of the proposed algorithms.


The aryl hydrocarbon receptor (AhR) pathway is now considered an important pharmacological target for many human diseases. This study examined the effects of grape seed extract (GSE) obtained from the Koshu grape variety on AhR activity. The Koshu-derived GSE inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated AhR activation in vivo and in vitro. These results suggest that Koshu GSE has an antagonistic effect on TCDD-induced AhR activation. Furthermore, gavage administration of TCDD resulted in the elevation of liver function, but administration of Koshu GSE together with TCDD did not elevate serum aspartate aminotransaminase (AST) and alanine transaminase (ALT) levels. These results suggest that Koshu GSE may have the potential to prevent liver disorders.


The dissipation in a silicon rectifier depends on the characteristics of the rectifier (threshold voltage and ohmic resistance) and the circuit constants (inductive, resistive, or capacitive load). Dissipations under these different conditions are calculated. The maximum permissible dissipation is limited by maximum junction temperature and thermal stability. The stability criterion depends on the thermal resistance, the reverse characteristic and its change with respect to temperature, the reverse voltage, and the circuit configuration. Derating curves are obtained, based on known variations of the reverse characteristics of silicon rectifiers with temperature and voltage. The maximum permissible transient dissipation depends on the total surge energy. The energy dissipated in the rectifier is high when the load capacitance is high and the external series resistance is low. A design embodying all the foregoing considerations is illustrated.


Wireless spectrum is a precious resource and must be allocated and used efficiently. Conventional spectrum allocations let a government agency (e.g., FCC) sell a portion of spectrum to one provider. This is not only restrictive, but also limits spectrum reuse and may lead to significant under-utilization of spectrum. In this paper, we develop a novel truthful double-auction scheme to let any resource owner (e.g., a cellular provider), who has spare spectrum at a given time period, sell to one or more providers that need additional spectrum at that time. Spectrum auctions are fundamentally different from conventional auction problems since spectrum can be reused and competition among buyers is complex due to wireless interference. Our proposal is the first double-auction design for spectrum allocation that explicitly decouples the buyer-side and seller-side auction design while achieving: 1) truthfulness; 2) individual rationality; and 3) budget-balance. To accurately capture wireless interference and support spectrum reuse, we partition the conflict graph so that buyers with strong direct and indirect interference are put into the same subgraph, and buyers with no interference or weak interference are put into separate subgraphs. Then, we compute pricing independently within each subgraph. We then develop a scheme to combine spectrum allocation results from different subgraphs and resolve potential conflicts. We further extend our approach to support local sellers whose spectrum can only be sold to buyers within certain regions, instead of all buyers. Using conflict graphs generated from real cell tower locations, we extensively evaluate our approach and demonstrate that it achieves high efficiency, revenue, and utilization.


Abstract The purpose of this study was to examine the differences in the ground reaction force (GRF) patterns between elite and novice players during two types of handball shots, as well as the relationships between throwing performance and the GRF variables. Ball velocity and throwing accuracy were measured during jump shots and 3-step shots performed by 15 elite and 15 novice players. The GRF pattern was recorded for the vertical and the anterior-posterior GRF components (Kistler forceplate type-9281, 750Hz). One-way ANOVA was used for the group differences and the Pearson coefficient for the correlation between throwing performance and GRF variables (SPSS 21.0, p ≤ 0.05). The elite players performed better in both types of shot. Both groups developed consistent and similar GRF patterns, except for the novices' inconsistent Fz pattern in the 3-step shot. The GRF variables differed significantly between groups in the 3-step shot (p ≤ 0.05). Significant correlations were found only for ball velocity and predominantly for the novice players during the 3-step shot (p ≤ 0.05). The results possibly highlight a shortage in the novice ability to effectively reduce their forward momentum so as to provide a stable base of support for the momentum transfer up the kinetic chain, a situation that may predispose athletes to injury.


Bhutan is a small yet water-abundant country. The country suffers from frequent flooding and is lately experiencing a growing risk of localized droughts due to inappropriate water resource management and climate change. Such a situation calls for much more efficient use and management of water in Bhutan. This paper undertakes an extensive analysis of the country's water resources for better planning and management of the available water resources. Bhutan can be divided into three zones, the Southern Foothills, the Central Inner Himalayas, and the Higher Himalayas. The top four leading industries of Bhutan are related to water, either directly or indirectly. The country at present is at a very early stage of development. The government has prioritized water resources management over recent years. Water for hydropower in Bhutan has been in focus as compared to that allocated for irrigation, industries, and environmental demand. The demand for water in Bhutan has also increased in the last decade due to population increase, changes in lifestyle, and economic advancements through tourism and hydropower projects. Climate variation, deteriorating water quality, frequent floods, and increasing urbanization threaten the sustainability of water resources. Water accessibility issues for settlements due to the country's harsh geographical landscape is leading towards localized water scarcity. Serious attention to rainwater harvesting and groundwater recharge is required to address localized water scarcity issues.


This paper describes how government policy thinking about the well-being of children and young people developed between the Children Act 1989 and the Children Act 2004. These two Acts are milestone statements about how services to children in England and Wales should be delivered. It is an account informed by the author's own experience as a government adviser on children's social care over much of this period and supporting documentation. It traces the strands of government policy thinking about how to deliver services for children from children in need to the articulation of the five Every Child Matters outcomes. It argues that attempts to achieve coordinated service planning for children and young people played a significant role in the formulation of shared objectives and the articulation of child outcomes. However, it argues that looking at real outcomes exposes how children in the UK do relatively badly compared with other rich nations. It questions whether we can realistically expect our services to deliver significantly improved outcomes given the impact of enduring inequality in our society.

This paper is dedicated to the memory of David Lambert CBE, former Assistant Chief Inspector of the Social Services Inspectorate in London, who died suddenly on 7 October 2010. He lent me articles to assist me in writing this paper.


The periodical publication of individual poems from the Lyrical Ballads, 1798, are an index to their popularity. So far, over ninety-three have been identified. In 1954, Robert Mayo compiled a list of fifty-one periodical reprints of poems from Lyrical Ballads., twenty-four of which appeared between 1798 and 1800. (1) In 1902, Robert Woof assembled a checklist of over forty published in the Caroller and Morning Post between December, 1797, and December, 1830 seven from the 1798 edition. David Erdman later added a reprint of Coleridge's "The Dungeon" in his edition of Coleridge's Essays on His Times (3:285-99). In 1970, Oliver Warner discovered a review of Lyrical Ballads in the Naval Chronicle, 1799, that included a lengthy excerpt of "The Rime of the Ancyent Marinere." I now add seven previously undocumented reprints. An analysis of all reprints highlights their value as publicity, their possible impact. on the reputation And sale of the first edition, and proof of Wordsworth's public significance. The new reprints were discovered by electronic searches in the Gale Cengage Learning data base of British Newspapers, 1600-1900, (2) starting with September. 1798, when Mark Reed notes some copies were first printed and distributed. through the end of 1800 (247). (3) The current additions are all from newspapers, and include one reprint each of "Goody Blake and Harry Gill," "The Convict." and "The Dungeon," as well as four separate reprints of "We Are Seven." (4) For the complete list, see Appendix A. These seven new reprints affirm the belief that the poetry of the first edition was widely known and read by a diversity of readers. The complete list shows that the poetry appeared in at least twenty-three different periodicals. Review journals included lengthy excerpts or entire poems alongside critiques of the volume. Monthly literary miscellanies like the Edinburgh Magazine and Lady's Magazine published individual poems. Thrice-weekly papers stall as Lloyd's Evening Post, the Whitehall Evening Post, and the General Evening Post (published by Stephen Jones, who was also responsible for the Whitehall Evening Post) each reprinted one of the poems. Even daily newspapers like the Star, the Albion and Evening Advertiser, and the Morning Chronicle (which was edited by James Perry. an acquaintance of Wordsworth) all reprinted poems from Lyrical Ballads--in spite of limited space and commitments to news and advertisements. Outside of London, the Derby Mercury reprinted "We are Seven" on April 24, 1800. As in many provincial newspapers, however, the Derby Mercury published a great deal from London newspapers. Indeed, on April 7 a reprint of "We are Seven" had appeared in the Courier, followed by a reprint in the Whitehall Evening Post on April 22. Along will location, the periodicals represent a variety of political ideologies. The Star, a pro-government newspaper, and the Morning Chronicle, a Whig publication, each published "We are Seven," proving that at least the less political poems of Lyrical Ballads crossed party lines. If not for their social and political commentary, what made them so appealing to newspapers? Why did editors choose to publish the poetry of Lyrical Ballads? The table in Appendix B shows the number of times each of the poems of the first edition of Lyrical Ballads was reprinted in newspapers, literary magazines, and review journals. The more popular poems were reprinted often. Newspaper editors, for example, favored shorter poems, probably because space for poetry was limited. Of fifteen total reprints in newspapers, only two were of more than one hundred lines, although eight of the twenty-three poems of the first edition were longer. As Coleridge explained in a letter to Daniel Stuart, publisher of the Courier and the Morning Post, in newspapers "every short poem, that has any merit at all, must be suitable in is turn, whatever kind it may [be] of " (Letters, 2:413). Length may account for two poems most frequently: the sixty-nine-line "We are Seven" appeared in live newspapers, while Coleridge's thirty-line "The Dungeon" appeared in two. …


Atherosclerosis is a chronic inflammat ion condition as a response to the lipoproteins deposition in the artery wall.Oxidized low density lipoprotein (OxLDL) the major of atherosclerosis development . Lectin- like oxidized lo density lipoprotein 1 (LOX-1) is primary  receptor for OxLDL in endothelial cells. Recent studies have shown that LOX-1 might b e potential for the atherosclerosis drugs development. This study was designed to investigate the response of LOX-1 vaccination with alum as adjuvant for atherogenesis to prevent increas ing of NF-kB , CRP, and decrease of eN OS . This study was experimental laboratory with post t est only control group design for 56 days using 28 male Wistar rats. Rats were divided into 7 groups which were negative control with normal diet AIN 93 M, positive control with atherogenic diet AIN 93 M, atherogenic diet AIN 93 M and LOX-1 protein treatment with dosage 1 ng + alum (P1) , 10 ng + alum (P2), 100 ng + alum (P3), 1μg + alum (P4) and alum only (P5). On the 57th day, the rats were sacrificed and taken its serum spesimen to measure CRP leve l with enzyme immunoassay method and aorta tissues to measure NF-kB activation and expression eNOS with immunohistochemical method . Statistical analysis showed that the administration of LOX-1 protein in the treatment groups is significant to prevent NF-kB activation (p=0,00) and prevent decreased expression of eNOS (p=0,00), but not significant to prevent increased CRP level (p=0,83). The conclusion of this study is that the LOX-1 protein vaccination  have poten cy to prevent atherosclerosis with decreas ing NF-kB activation and prevent decreasing eNOS expression . Keywords: Atherosclerosis vaccine, LOX-1, NF-kB, eNOS, CRP


Hepatitis B virus (HBV) seroprevalence and serology profiles were retrospectively determined for 957 individuals in the Development of Antiretroviral Therapy for Africa (DART), human immunodeficiency virus (HIV) infected population. Baseline HBV serology markers were tested for and samples identified for viral load test in the HBV sub study investigating development of HBV Tenofovir (TDF)/lamivudine (3TC) resistance in HIV-1 positive treatment naA¯ve individuals initiating TDF/3TC combination therapy as part of HAART. The patients received TDF/3TC combination therapy as part of HAART and samples were taken at baseline and at 4, 12, 24 and 48 weeks and every 48 weeks thereafter until last visit, up to 6 years. All samples were tested for anti-HBc and HBsAg with further testing for anti-HBs and HBe markers in anti-HBc+/HBsAg- and anti-HBc+/HBsAg+samples respectively using enzyme immune assays. In this population 164 patients were HBsAg positive giving a 17.1 % HBsAg seroprevalence (males 18.3 %, females 15.8 %). Five hundred and thirty (530) samples or 55.4 % were positive for the anti-HBc marker. One hundred and thirty five patients had isolated anti-HBc and will be tested for occult HBV, 103 were anti-HBc+/HBsAg+/HBe marker + and were identified for viral load tests on baseline and follow up samples to investigate HBV TDF/3TC resistance evidenced by viral rebound. The results infer a high prevalence of HBV co-infection in HIV infected individuals in Zimbabwe. HIV positive individuals are at risk of co-infection with HBV because of the shared routes of infection of HIV and HBV. This is supported by the high level of exposure to HBV evidenced by 55.4 % anti-HBc seroprevalence in the DART cohort. There was evidence of active hepatitis, 103 individuals with positive HBe markers, and HBV DNA tests can be done on these baseline and follow up samples to monitor the efficacy of TDF/3TC combination therapy in suppressing viral rebound. Viral load tests can also be done on 135 samples with isolated anti-HBc to determine the prevalence of occult HBV in this cohort.
KEY WORDS: HBV seroprevalence, HIV co-infection, HBV tenofovir/lamivudine resistance
iii
ACKNOWLEDGEMENTS
This thesis was made possible through the support of the Development of Antiretroviral therapy for Africa (DART) study group who provided the samples. I am grateful to Dr Chirara, Prof Robertson and other members of the DART study for allowing me to contribute to the DART HBV sub study through this project. Dr Chirara and Prof Robertson provided me with invaluable support, guidance and mentorship throughout the project.
The University of Zimbabwe department of medical microbiology virology laboratory members provided me with the necessary training to do this work and opened the doors of their laboratory for me to work in, for that I am most grateful. Thank you Ms Berejena and Mr T. Mamvura.
I also thank my classmates in the MSc medical microbiology program for the shared experiences throughout this program.


Retroviral insertion mutagenesis is considered a powerful tool to identify cancer genes in mice, but its significance for human cancer has remained elusive. Moreover, it has recently been debated whether common virus integrations are always a hallmark of tumor cells and contribute to the oncogenic process. Acute myeloid leukemia (AML) is a heterogeneous disease with a variable response to treatment. Recurrent cytogenetic defects and acquired mutations in regulatory genes are associated with AML subtypes and prognosis. Recently, gene expression profiling (GEP) has been applied to further risk stratify AML. Here, we show that mouse leukemia genes identified by retroviral insertion mutagenesis are more frequently differentially expressed in distinct subclasses of adult and pediatric AML than randomly selected genes or genes located more distantly from a virus integration site. The candidate proto-oncogenes showing discriminative expression in primary AML could be placed in regulatory networks mainly involved in signal transduction and transcriptional control. Our data support the validity of retroviral insertion mutagenesis in mice for human disease and indicate that combining these murine screens for potential protooncogenes with GEP in human AML may help to identify critical disease genes and novel pathogenetic networks in leukemia. (Cancer Res 2006; 66(2): 622-6)


Transcription of the ribosomal genes accounts for the majority of transcription in the cell due to the constant high demand for ribosomes. The number of proteins synthesized correlates with an effective ribosomal biogenesis, which is regulated by cell growth and proliferation. In the work presented in this thesis, we have investigated the ribosomal RNA genes 45S and 5S rRNA, which are transcribed by RNA Pol I and RNA Pol III, respectively.The focus of this work is the chromatin remodelling complex B-WICH, which is composed of WSTF, the ATPase SNF2h and NM1. We have studied in particular its role in ribosomal gene transcription. We showed in Study I that B-WICH is required to set the stage at rRNA gene promoters by remodelling the chromatin into an open, transcriptionally active configuration. This results in the binding of histone acetyl transferases to the genes and subsequent histone acetylation, which is needed for ribosomal gene activation. Study II investigated the role of B-WICH in transcription mediated by RNA polymerase III. We showed that B-WICH is essential to create an accessible chromatin atmosphere at 5S rRNA genes, which is compatible with the results obtained in Study 1. In this case, however, B-WICH operates as a licensing factor for c-Myc and the Myc/Max/Mxd network. Study III confirmed the importance and the function of the B-WICH complex as an activator of ribosomal genes. We demonstrated that B-WICH is important for the remodelling of the rDNA chromatin into an active, competent state in response to extracellular stimuli, and that the association of the B-WICH complex to the rRNA gene promoter is regulated by proliferative and metabolic changes in cells.The work presented in this thesis has confirmed that the B-WICH complex is an important regulator and activator of Pol I and Pol III transcription. We conclude that B-WICH is essential for remodelling the rDNA chromatin into a transcriptionally active state, as required for efficient ribosomal gene transcription.


N-(Adamant-2-yl)hexamethyleneimine hydrochloride (hemantane) is a new potential antiparkinsonian drug with a complex mechanism of action. The drug exhibits the properties of a low-affinity blocker of the ion channels of NMDA receptors, increases the dopamine content in striatum, and inhibits monoamine oxidases (MAO-B). This combination of properties suggests that hemantane can also possess neuroprotector properties. In this context, the ability of hemantane to prevent from the development of MPTP neurotoxin action on the locomotor activity in mice and the EEG activity in rats has been studied. Preliminary single (and the more so, repeated over a period of 5 days) peroral administration of hemantane in a dose of 10 mg/kg significantly reduced the manifestations of MPTP-induced oligokinesia in C57BL/6 mice. Acute of subchronic (7-day) pretreatment with hemantane prevented the development of EEG changes typical of parkinsonism. The results of statistical EEG data processing showed that a systemic introduction of MPTP (30 mg/kg) on the background of hemantane pretreatment produced no reliable changes against control characteristics. Thus, hemantane is capable of protecting experimental animals from MPTP neurotoxicity.


Community based forestry has the potential to contribute much more to achieving sustainable development and poverty reduction than is the case today. This paper describes and analyzes these potentials and demonstrates their feasibility with real world cases of community forest businesses and innovative policies and business partnerships. This preliminary assessment is offered as a first step in a longer-term effort to understand existing forest product and service markets, and to identify the most promising market opportunities for local community producers, focusing particularly on developing countries. Part I presents the broader context of forestry's changing relation to rural development and poverty reduction. Part II develops a framework for considering which market niches have potential for poor producers. Part III proposes strategies and targeted actions to realize that potential.


Authorship Maturity a Bibliometric study on the International Journal of Library Science is made from the volumes published in IJLS during (2010-2013). Studies reveal that the team research is more favorable than the solo research. This study brings out the authorship trend and its growth. The analysis, degree of collaboration in IJLS ranked 0.64 during the period of study. The analysis of this study includes Year Wise and Volume Wise Distribution of article Citations, Authorship Patterns of cited articles, prolific authors etc;


An artificial opal is a compact arrangement of transparent spheres, and is an archetype of a three-dimensional photonic crystal. Here, we describe the optics of an opal using a flexible model based upon a stratified medium whose (effective) index is governed by the opal density in a small planar slice of the opal. We take into account the effect of the substrate and assume a well- controlled number of layers, as it occurs for an opal fabricated by Langmuir-Blodgett deposition. The calculations are performed with transfer matrices, and an absorptive component in the effective index is introduced to account for the light scattering. This one-dimensional formalism allows quantitative predictions for reflection and transmission, notably as a function of the ratio between the irradiation wavelength and the sphere diameter, or as a function of the incidence angle or of the polarization. It can be used for an irradiation from the substrate side or from the vacuum side and can account for defect layers. The interface region between the opal and the substrate (or vacuum) is shown to have a strong influence, regardless of the exact opal structure. This break in the periodicity at the interface is a general, but often ignored feature, of any external coupling to a photonic crystal. Our calculations provide also the main features of the Bragg peak for reflection, including its width and strength. Comparisons of this versatile model with experiments show that despite its simplicity, it is powerful enough to explain numerous observations.


Bunda College of the University of Malawi provides all university level agricultural education in Malawi. Currently there are around 240 students, with a planned expansion to about 420. College entrants are largely from rural backgrounds. On qualifying, a wide range of occupations is open to students: after three years of training, diplomates find employment in both public and private sectors; after five years, graduates are employed predominantly in the public sector. There are 40 staff members distributed over a wide range of disciplines constituting the School of Agriculture, which is grouped into four departments: agricultural engineering, crop production, livestock production, and rural development. The latter is multidisciplinary, and during 1976-78 was headed by a professor of agricultural economics. Throughout 1975-78, considerable time was concentrated on restructuring the curricula for the general degree and diploma in agriculture. The present curricula and experience of their development provide bases for discussion and the identification of recurrent themes and guidelines. There is no claim to perfection; curriculum development is a dynamic process. Experience from the microcosm of a single university college can provide insights which pragmatic academic staff may appreciate more readily than generalizations from surveys.


This study aims to develop an unobtrusive assessment method for information literacy in the context of crisis management decision making in a digital serious game. The goal is to only employ in-game indicators to assess the players' skill level on different facets of information literacy. In crisis management decision making it is crucial to combine an intuitive approach to decision making, build up by experience, with an analytical approach to decision making, taking into account contextual information about the crisis situation. Situations like these have to be trained frequently, for example by using serious games. Adaptivity can improve the effectiveness and efficiency of serious games. Unobtrusive assessment can enable game developers to make the game adapt to the players current skill level without breaking the flow of gameplay. Participants played a gameplay scenario in the Dilemma Game. Additionally, participants completed a questionnaire that was used as a validation measure for the in-game information literacy assessment. Using latent profile analyses, unobtrusive assessment models could be identified, most of which correlate significantly to the validation measure scores. Although inconsistencies in correlations between the information literacy standards, which call for broader testing of the identified unobtrusive assessment models, have been observed, the results display a good starting point for an unobtrusive assessment method and a first step in the development of an adaptive serious game for information literacy in crisis management decision making.


Asthma has been defined as a disease of chronic airway inflammation in which many cells and cellular products participate with variable degrees of airflow obstruction and hyperresponsiveness that lead to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Prominent among these cellular elements are two cell types referred to as the invariant natural killer T (iNKT) cells and a subpopulation of T cells expressing the molecule CD161, which are both thought to play a role in the pathogenesis of asthma. Although the presence of iNKT and other CD161(+) cells in murine models has been associated with asthma, relatively few studies have been performed in the adult patient with asthma that have been often conflicting and even fewer studies are available in children. The present study was performed to investigate the peripheral blood frequencies of iNKT and CD161(+) T cells in children with asthma. A total of 35 children, 19 stable asthmatic patients, 6 who had experienced an asthmatic attack within 24 hours and had not received any treatment, and 10 healthy controls, aged 6-12 years, were enrolled in the study. iNKT and CD161(+) T-cell frequencies in blood were measured together with quantitative levels of IL-4 and interferon (IFN) γ using a cytofluorimetric approach. The results show that iNKT cells are increased in pediatric asthmatic patients undergoing exacerbations of asthma. These cells also produced less IFN-γ and more IL-4 than children with stable asthma and in healthy control children. These results suggest that iNKT cells might participate in the development of the asthmatic exacerbations. The increased production of IL-4 in conjunction with the decrease of IFN-γ may be mechanistically responsible, at least partially, for the heightening of the immunologic response leading to the asthmatic attack in children. Knowledge of these interactive mechanisms involving the iNKT cell and our understanding of its role in the exacerbation of asthma hold great promise in the development of better diagnostic predictive markers of disease progression as well as new forms of therapeutic interventions.


I have spoken of the first kind of medisense, abstraction, which breaks one idea away from another. There is an opposite influence by which when one idea has its vividness increased it gives an upward impulse to a number of other ideas with which it is connected so that it forms one set with them. The law of this is often called the law of the association of ideas. That is well enough. But it is inaccurate to call this phenomenon association, as Germans especially often do. Association is a different thing. More accurate German writers call the action of which we are now speaking reproduction. But even that is not free from objection. For the idea which receives an upward impulse, making it grow more vivid, was not necessarily ever so near the surface of consciousness before; or if it was, that circumstance has nothing to do with it. It is a great mistake to suppose that ideas only become associated into sets in the upper layer of consciousness, although such action is more lively there. Most English and American psychologists of today use the term Reproduction; but I prefer the older English word Suggestion, to which some of the very best writers still adhere. The only objection to it is that the word is used in another sense in reference to the phenomena of hypnotism.


This paper presents an approach to system-level optimization of error detection implementation in the context of fault-tolerant real-time distributed embedded systems used for safety-critical applications. An application is modeled as a set of processes communicating by messages. Processes are mapped on computation nodes connected to the communication infrastructure. To provide resiliency against transient faults, efficient error detection and recovery techniques have to be employed. Our main focus in this paper is on the efficient implementation of the error detection mechanisms. We have developed techniques to optimize the hardware/software implementation of error detection, in order to minimize the global worst-case schedule length, while meeting the imposed hardware cost constraints and tolerating multiple transient faults. We present two design optimization algorithms which are able to find feasible solutions given a limited amount of resources: the first one assumes that, when implemented in hardware, error detection is deployed on static reconfigurable FPGAs, while the second one considers partial dynamic reconfiguration capabilities of the FPGAs.


INTRODUCTION
Approximately 18% of the U.S. population are uninsured, a proportion that may continue to rise, particularly among Hispanics, as the cost of medical care increases faster than the growth in wages.

METHODS
Health insurance trends were analyzed by race-ethnic category, and among Hispanic workers by occupation type and industrial sector, using data on employed respondents > or =18 years from 1997 to 2007 National Health Interview Survey (NHIS) (mean annual n = 17,392, representing 123 million US workers on average over this 11 year period).

RESULTS
From 1997 to 2007, the relative decline in health insurance coverage for US workers was greatest among Hispanics (7.0%). Hispanic workers in the Construction and Services industries had the greatest overall decline in coverage (24.9% and 14.7%), as well as Hispanic blue collar workers (14.0%).

CONCLUSION
Hispanic workers in general, and those employed in blue collar, construction, and services sectors in particular, are at greater risk for poor access to health care due to a lack of health insurance coverage.


Background: An investigation on copper metabolism usually includes the measurement of serum levels of copper and caeruloplasmin. Using these levels, some laboratories derive levels of non-caeruloplasmin-bound copper (NCC); however, a considerable number of patients may show negative values, which is not physiologically possible. Aim: To derive an equation for adjusted copper in a manner similar to that widely accepted for adjusted calcium. Methods: A linear regression equation for the relationship between caeruloplasmin and copper was used: [copper] (μmol/l) = 0.052×[caeruloplasmin] (mg/l). An equation for copper adjusted for caeruloplasmin was derived using this equation and the reference interval of 10–25 μmol/l for copper. Results: The derived equation was [adjusted copper] (μmol/l) = [total copper] (μmol/l)+0.052×[caeruloplasmin] (mg/l)+17.5 (μmol/l). The adjusted copper concentrations on the 2.5th and 97.5th centiles were 12.7 and 21.5 μmol/l, respectively, with the population having a gaussian distribution. The relationship between NCC and the adjusted copper concentrations is linear and independent of caeruloplasmin concentration. Conclusion: Calculation of copper adjusted for caeruloplasmin uses the same variables as those for NCC. Accordingly, the problems that are caused by the lack of specificity of caeruloplasmin immunoassays are the same as those identified for NCC. This calculation, however, overcomes the negative values that are found in a considerable minority of patients with NCC, as well as age and sex differences in the caeruloplasmin reference interval. As the concept is already familiar to non-laboratory healthcare professionals in the form of calcium adjusted for albumin, this method is potentially less confusing than that for NCC.


The key to bridging your global innovation gap In today's global economy, it would be short-sighted to rely solely on local resources for new-product innovations. Instead, knowledge and activity critical to innovation most likely lie outside your company's home territories--sometimes far outside. And this distance makes it harder than ever to obtain and integrate these resources, eating away at your competitive edge. How to tackle this challenge? In Managing Global Innovation, INSEAD's Yves L. Doz and Keeley Wilson show you how to build and leverage a global innovation network. Drawing on extensive research and real-life company examples, they walk you through a set of practical frameworks for acquiring and integrating innovation-critical knowledge from multiple sources. You'll learn to optimize your innovation footprint, improve communication and receptivity, and enhance collaboration in order to succeed on a global scale. Based on in-depth research within more than three dozen corporations--including Citibank, Essilor, GE, GlaxoSmithKline, HP Labs, HP Singapore, Nokia, Novartis, Shiseido, Siemens, Snecma, Synopsys, and Xerox--this book bridges theory and practice. Managing Global Innovation gives you the tools to harness critical expertise from around the globe--and channel it into your innovation programs.


This thesis studies the effect of fiber reinforcement on crack development in concrete structures. Background for choice of subject, is that cracks due to external restraint are observed on many of today's bridges, and it is assumed that fiber reinforcement may limit this crack development. Hence, a laboratory experiment was performed during the summer of 2015, in connection with the specialization project written by the undersigned. The experiment studied the effect of steel fibers and polymer fibers on the crack development, compared to a concrete without fiber reinforcement. In the fiber mixes, one saw a much denser crack development than for the reference concrete, and the crack widths were much smaller in the fiber mixes. On the initiative of Norwegian Public Roads Administration, it was decided to carry out the same measures to reduce cracks on a real bridge. This full-scale experiment has been conducted in connection with this thesis. The chosen bridge is the pedestrian and bicycle bridge Sandsg̊ard Bridge in Ganddal, close to Sandnes. The bridge is 50 meters long and the edge beams, à 16 meters, were cast with six different concrete mixes, five of them containing fiber reinforcement. First some relevant theoretical background is presented, and three models for calculation crack widths are introduced. Then a brief description of the laboratory experiment is presented, followed by a description of the full-scale experiment on Sandsg̊ard Bridge. Calculations of the crack widths are performed for the two experiments. Simulations of the two experiments are performed in the finite element program, CrackTeStCOIN. This computer program is used for simulation of the temperature and stress development of the experiments. Based on the simulated stresses, and an assumption of an effective elastic modulus of 10 000 MPa and 12 000 MPa for the laboratory and full-scale experiment respectively, the occurring strains are calculated. The simulated strains are compared with the strains obtained from the three investigated calculation models. Lastly, the effect of the different fiber reinforcement are discussed.


As of 2015 hydraulic fracking for unconventional shale gas in Ontario is not currently being used. In this paper, qualitative in person interviews of government officials and a province wide survey of municipal leaders were conducted to determine the level of support for the potential use of unconventional fracking in Ontario. Potential reasons for the current absence of unconventional fracking in Ontario are geology and lack of investment. Although fracking is a topic of discussion in most municipal governments, support is low. The likely future of unconventional fracking in Ontario is slim, but it cannot be completely ruled out. There is a general consensus that municipal support is important if horizontal fracking was to be used in Ontario.


The products of genes recB and recC are responsible for conjugal recombination and for the repair of chromosomal double chain breaks in Escherichia coli. The product of the recD gene, which combines with the RecB and RecC proteins to comprise the RecBCD enzyme, is not required for either recombination or repair. On the contrary, RecBCD enzyme is a potent exonuclease which inhibits recombination by destroying linear DNA. The RecD Ejection model supposes that RecBCD enzyme enters DNA at a double-chain end and travels destructively along the DNA until (typically) it encounters the recombination hotspot sequence chi. Chi then alters the RecBCD enzyme by weakening the affinity of the RecD subunit for the RecBC heterodimer. With the loss of the RecD subunit from the enzyme, the resulting protein, RecBC(D-), becomes deficient for exonuclease activity and proficient as a recombinagenic helicase. Thus, the RecD Ejection model proposes that chi participates in recombination by acting as a toggle to convert RecBCD (a powerful exonuclease) to RecBC(D-) (a recombinase). We review the properties of RecBCD and its cognate site chi, including recent results that support both the RecD Ejection model and the view that chi plays only an indirect role in recombination.


The evolution of United States (US) national and federal drought policies is examined, and the relative effectiveness of the hierarchy of federal, state and local drought management programs and practices is evaluated within the context of changing philosophies of water management. While there is no 'national' drought management policy, there is a strong federal policy that attempts to coordinate the management responses of numerous federal agencies. Drought and flood management comprise the key components of assuring national 'water security'. Early 20th century US water resources management was very effective in providing the essential prerequisites of 'water and economic security' through a rapid expansion of water storage capacity, flood control, hydropower, irrigation and conveyance facilities as the basis for a robust national economic development program. Increasing water supply capacity has proven to be the most effective strategic drought management option. Today, federal drought management policies and programs focus mainly on demand reduction strategies, buttressed by a powerful array of environmental regulatory programs that strive to attain sustainable resource use. Climate uncertainty will again require greater focus on supply-side options that increase water supply robustness and resilience, especially in the growing urban areas of the semi-arid west.


Gas source localization (including gas source declaration) is critical for environmental monitoring, pollution control and chemical safety. In this paper we approach the gas source declaration problem by constructing a tetrahedron, each vertex of which consists of a gas sensor and a three-dimensional (3D) anemometer. With this setup, the space sampled around a gas source can be divided into two categories, i.e. inside ("source in") and outside ("source out") the tetrahedron, posing gas source declaration as a classification problem. For the declaration of the "source in" or "source out" cases, we propose to directly take raw gas concentration and wind measurement data as features, and apply a median value filtering based extreme learning machine (M-ELM) method. Our experimental results show the efficacy of the proposed method, yielding accuracies of 93.2% and 100% for gas source declaration in the regular and irregular tetrahedron experiments, respectively. These results are better than that of the ELM-MFC (mass flux criterion) and other variants of ELM algorithms.


BACKGROUND
A new synthetic cyclic adenosine monophosphate phosphodiesterase inhibitor, cilostazol, has been shown to inhibit platelet aggregation and act synergistically with endogenous prostaglandin I2 to enhance smooth-muscle cell vasodilitation. The effect of cilostazol in ischemia/reperfusion injury-induced compartment syndrome was investigated.

METHODS
Sixteen rabbits underwent femoral artery occlusion after ligation of branches from the terminal aorta to the femoral artery. After 7 hours of ischemia, reperfusion was established with heparinized polyethylene shunts. Experimental animals (n = 8) received cilostazol (3.0 mg/kg) and control animals (n = 8) received normal saline as an intravenous infusion 10 minutes before shunt placement. During reperfusion, anterior compartment pressure was continuously monitored in the left lower extremity, and femoral artery blood flow was measured by laser Doppler fluorometry. To quantitate skeletal muscle oxidative metabolism and viability, triphenyltetrazolium chloride (TTC) reduction (micrograms of TTC per milligram of protein) of tibialis anterior muscle from the right lower extremity was measured at femoral artery occlusion, 7 hours of ischemia, and 2 hours of reperfusion. To assess tissue edema, dry/wet weight ratios were also determined at these intervals. Data were expressed as means +/- SE. Comparisons within groups were performed by analysis of variance, and comparisons between groups with two-tailed unpaired t tests.

RESULTS
At 2 hours of reperfusion, the difference between controls and cilostazol-treated animals was extremely significant (p = 0.0008). Preischemia and 2-hour reperfusion TTC and dry/wet weight ratios were not significantly different within or between experimental groups, nor was femoral artery blood flow during reperfusion.

CONCLUSION
Cilostazol inhibits the increase in compartment pressure central to the development of the compartment syndrome. The mechanism appears to be independent of altered tissue permeability or oxidative metabolism.


This article presents a new current peak point tracking third harmonic injected bus clamping pulsewidth modulation (CPPTTHBCPWM) technique for effective active and reactive power control in a transformerless H5 solar photovoltaic inverter. The proposed technique reduces the switching loss compared to that of the traditional switching technique by using a new reference signal and eliminating unwanted gate pulses. The proposed CPPTTHBCPWM technique ensures better utilization of the dc bus voltage, lowers the total harmonic distortion, and lowers the converter loss compared to the conventional modulation techniques. The proposed modulation technique also reduces the thermal stress in the switching devices and increases the power converter lifetime. The proposed modulation technique is simulated in MATLAB/Simulink environment and validated in the laboratory using a reduced-scale prototype test platform.


tetrachloride) indicates acetone-as carbon tetrachloride extracts acetone-2,4-dinitrophenylhydrazone but not 2,4-dinitrophenylhydrazine. If only a pale yellow colour appears a further 2 ml. of 5 N sodium hydroxide may be added and the solution shaken thoroughly once more. If the lower layer still shows a pale yellow colour the reaction is positive, if it is colourless the reaction is negative-with some experience blanks should be unnecessary, except when the reaction is performed in electric light, which lend the blank a yellow tint. Artificial daylight is no advantage. The concentration of the reagents is chosen in such a way that measuring is unnecessary so long as the ratio of the amount of the different fluids is fairly 1: 1 :1. The test can show acetone in a quantity down to 0.008-0.01 mg. in 2 ml. or 0.4-0.5 mg. per 100 ml. The patient's expired air is led to the solution of 2,4-dinitrophenylhydrazine through a glass tube of the kind used at most laboratories for van Slyke and Cullen's urease method. One of the ends of the tube forms a small globe provided with five holes to make the air bubbles small and so increase the absorption of acetone. Rubber tubing with an ordinary glass mouthpiece is fitted to the other end of the tube.


Interatomic potentials for pure Ag and Mg–Ag alloy have been developed in the framework of the second nearest-neighbors modified embedded-atom method (MEAM). The validity and the transferability of the Ag potential were obtained by calculating physical, mechanical, thermal, and dislocation related properties. Since the {1 1 1}-generalized stacking fault energy curves obtained from first-principle calculations was used to develop the Ag potential, the critical resolved shear stress to move screw dislocations in Ag single crystal is in good agreement with the experimental data. By combining the ability of the potential to predict the surface energies with its accuracy in describing dislocation properties, the potential is thought to be a predictive model for analyzing the fracture properties of Ag. In addition, the performance of the potential was tested under dynamics conditions by predicting the melting temperature, where a good agreement with experimental value was found. The Ag-MEAM potential was then coupled to an existing Mg-MEAM potential to describe the properties of the binary system MgAg. While the heat of formation, the elastic constants, and the (1 1 0) γ-surface of the MgAg compound in the B2 phase were used to parameterize the potential, heat of formation for MgAg alloys with different stoichiometry, thermal properties of the B2-MgAg compound, as well as dislocation related properties in B2-MgAg compound were tested to validate the transferability of the potential. The heat of formation of Mg5Ag2, MgAg, and MgAg3, the elastic constants and the thermal properties of B2-MgAg obtained with the proposed potential align with first-principles and experimental data. In addition, the core structure of both 〈0 0 1〉 and 〈1 1 1〉 dislocations in {1 1 0} are in agreement with theoretical predictions, and the magnitudes of the critical resolved shear stress obtained at 0 K for both slip systems partially validate the slip behavior of B2-MgAg. Furthermore, the interaction between silver solute element and dislocations from the basal plane is correctly captured by the potential.


Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

BACKGROUND: Reversible EGFR TKIs, gefitinib and erlotinib, have shown antitumor efficacy in NSCLC patients with activating mutations in EGFR kinase domain. But the clinical efficacy of these agents is limited by the development of acquired drug resistance, which is most commonly caused by T790M resistance mutation in EGFR. This mutation has been detected in approximately 50% to 60% of patients. The 2nd generation irreversible EGFR inhibitors inhibit EGFR with T790M, but their clinical efficacy to NSCLC patients with T790M appears to be limited due to severe adverse effects caused by concomitant WT EGFR inhibition. Therefore, an EGFR TKI which inhibits T790M mutant EGFR selectively with less activity against WT EGFR may be beneficial. Here we report ASP8273, a novel, small molecule EGFR TKI that inhibits the kinase activity of EGFR containing the activating and T790M resistance mutations with less activity against WT EGFR.

METHODS: The inhibitory effect and the selectivity of ASP8273 were evaluated against mutant EGFR (L858R, del ex19, L858R/T790M and del ex19/T790M) and WT EGFR using in vitro enzymatic and cell-based assay. Binding mode of ASP8273 to EGFR was assessed by mass spectrometry. Antitumor activity of ASP8273 was evaluated in xenograft models using PC-9 (del ex19), HCC827 (del ex19), NCI-H1975 (L858R/T790M) and PC-9ER (Erlotinib Resistant)(del ex19/T790M) NSCLC cells.

RESULTS: ASP8273 inhibited mutant EGFR containing del ex19 or L858R activating mutations as well as the T790M resistance mutation with lower IC50 values than WT EGFR. Mass spectrometry analysis revealed that ASP8273 is covalently bound to a mutant EGFR(L858R/T790M) via C797 in the kinase domain of EGFR. In NCI-H1975 cells, ASP8273 induced long-lasting inhibition of EGFR phosphorylation for 24 h after washout of compound.

In assays using endogenously EGFR-dependent cells, ASP8273 inhibited the growth of PC-9(del ex19), HCC827(del ex19), NCI-H1975(del ex19/T790M) and PC-9ER(del ex19/T790M) with IC50 values of 8-33 nM, more potently than that of NCI-H1666(WT) with IC50 value of 230 nM.

In mouse xenograft studies, ASP8273 induced tumor regression in NCI-H1975 (L858R/T790M), HCC827 (del ex19) and PC-9 (del ex19) xenograft models by repeated oral dosing in a dose-dependent manner. Dosing schedules did not affect the efficacy of ASP8273. In an NCI-H1975 xenograft model, complete regression of tumor was achieved after 14-days of ASP8273 treatment. Complete regression was maintained in 50% of mice more than 85 days after cessation of ASP8273 treatment.

CONCLUSIONS: ASP8273 inhibits the growth of NSCLC cells with EGFR activating and T790M resistance mutations with evidence of tumor regression. Therefore, ASP8273 may show therapeutic efficacy in NSCLC patients with EGFR mutations. Clinical trials of ASP8273 in NSCLC patients are planned in the US/EU and Asia.

Citation Format: Hideki Sakagami, Satoshi Konagai, Hiroko Yamamoto, Hiroaki Tanaka, Takahiro Matsuya, Masamichi Mori, Hiroyuki Koshio, Masatoshi Yuri, Masaaki Hirano, Sadao Kuromitsu. ASP8273, a novel mutant-selective irreversible EGFR inhibitor, inhibits growth of non-small cell lung cancer (NSCLC) cells with EGFR activating and T790M resistance mutations. [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 1728. doi:10.1158/1538-7445.AM2014-1728