Summary: The breast implant capsule is a dynamic structure that forms following the implantation of a device. Although normally benign, increased awareness of breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) highlights that disease may arise from the capsule. BIA-ALCL presents as a late seroma or mass but explains few of the late seromas found in breast implant patients. To date, many of these seromas lack a clear cause and are often described as "idiopathic." Several benign and malignant breast implant capsular diseases can cause a late seroma or mass, including breast implant–associated squamous cell carcinoma. Similar to early reports of BIA-ALCL, these conditions are rare and largely limited to case reports or series. The purpose of this special topic is to present a narrative review highlighting capsular abnormalities that contribute to the formation of late seroma or mass in an attempt to broaden the differential diagnosis and help plastic surgeons identify the cause. Specifically, we review the presentation and management of BIA-ALCL, synovial metaplasia, capsular epithelialization, late hematoma, double capsule, breast cancer, squamous cell carcinoma, mesenchymal tumor, and B-cell lymphoma. Although rare, plastic surgeons should consider these capsular conditions as causes of late seromas and masses. Usually, these conditions may be diagnosed by following the National Comprehensive Cancer Network screening guidelines for BIA-ALCL. Thorough evaluation and workup of late seromas and masses may lead to improved characterization of these rare breast implant capsular conditions and improve our understanding of their pathophysiology and management.


The geometric interpretation of (pseudo)spin 1/2 systems on the Bloch sphere has been appreciated across different areas ranging from condensed matter to quantum information and high energy physics. Although similar notions for larger Hilbert spaces are established in mathematics, they have been so far less explored beyond the two-level case for practical usage in condensed matter settings, or have involved restrictions to sub manifolds within the full Hilbert space. We here employ a coherence vector description to theoretically characterize a general N-level system on the higher dimensional generalized Bloch (hyper)sphere by respecting the structure of the underlying SU(N) algebra and construct physically intuitive geometric pictures for topological concepts. Focusing on two spatial dimensions, we reveal a geometric interpretation for the Chern number in larger Hilbert spaces in terms of a nested structure comprising N-1 two-spheres. We demonstrate that for the N-level case, there is an exterior two-sphere that provides a useful characterization of the system, notably by playing a primary role in determining the Chern number. The external sphere can be directly measured in ultracold atoms via well-established band mapping techniques, thereby imparting knowledge of the topological nature of state. We also investigate how the time evolution of the coherence vector defined on the generalized Bloch hypersphere can be utilized to extract the full state vector in experiments, allowing us to develop a tomography scheme involving quenches for three-level systems. Our geometric description opens up a new avenue for the interpretation of the topological classification and the dynamical illustration of multi-level systems, which in turn is anticipated to help in the design of new experimental probes.


A surface protein antigen (PAC) of Streptococcus mutans, in particular, A-region of the molecule, has been considered as a possible target for the development of an effective anticaries vaccine. This region might be implicated in the induction of dental caries via interaction with salivary components. We have recently specified a unique peptide, TYEAALKQYEADL, as one of the minimum peptides that completely corresponds to the amino acid sequence of a part of the A-region. The unique peptide contains both T and B cell epitopes for the induction of cross-reacting antibodies to the PAC. In this study, we synthesized valine or glycine-substituted peptide analogs of this peptide and examined core B cell epitopes of this unique peptide by using ELISA inhibition assay. As a result, the core amino acid residues of -Y------Y---- for B cell recognition were found to likely be not only important amino acids stabilizing the structure, but also might be essential for induction of the cross-inhibiting antibodies against PAC. These results will hopefully provide us with useful information for the design of an effective anticaries peptide vaccine.


The analysis of categorical data often leads to the analysis of a contingency table. For large samples, asymptotic approximations are sufficient when calculating p-values, but for small samples the tests can be unreliable. In these situations an exact test should be considered. This bases the test on the exact distribution of the test statistic. Sampling techniques can be used to estimate the distribution. Alternatively, the distribution can be found by complete enumeration. A new algorithm is developed that enables a model to be defined by a model matrix, and all tables that satisfy the model are found. This provides a more efficient enumeration mechanism for complex models and extends the range of models that can be tested. The technique can lead to large calculations and a distributed version of the algorithm is developed that enables a number of machines to work efficiently on the same problem.


The degree of labeling, i.e., dye/protein ratio (D/P) is important for characterizing properties of dye labeling with proteins. A method for the determination of this ratio between a fluorescent cyanine dye and bovine serum albumin (BSA), based on the separation of the labeling mixture using micellar electrokinetic chromatography with diode laser‐induced fluorescence detection, is described. Two methods for the determination of D/P were examined in this study. In these methods, a hydrolysis product and impurities, which are usually unfavorable compounds that are best excluded for protein analysis, were utilized to determine the amounts of dye bound to BSA. One is a direct method in which a ratio of the peak area of BSA to the total peak area of all the products produced in the labeling reaction was used for determining the average number of dye molecules bound to a single BSA molecule. The other is an indirect determination, which is based on diminution of all peak areas related to the products except for the labeled BSA. These methods were directly compared by means of a spectrophotometric method. The experimental results show that the indirect method is both reliable and sensitive. Therefore, D/P values can be determined at trace levels using the indirect method.


A 405 nm diode laser-based on-line bioaerosol detector, BioScout, was tested and compared with the Ultraviolet Aerodynamic Particle Sizer (UVAPS). Both instruments are based on laser-induced fluorescence of particles. Only a fraction of microbial particles produce enough fluorescence light to be detected by the instruments. This fluorescent particle fraction (FPF) is aerosol and instrument specific. The FPF values for common bacterial and fungal spores and biochemical particles were experimentally determined for both instruments. The BioScout exhibited higher FPF values for all the test aerosols except coenzyme NADH. The difference was higher for smaller particles. The FPF values of fungal spores and bacteria varied between 0.34 to 0.77 and 0.13 to 0.54 for the BioScout and the UVAPS, respectively. The results indicate that the 405 nm diode laser is a useful excitation source for fluorescence-based real-time detection of microbial aerosols. The FPF results of this study can be utilized to estimate the actual concentrations of bacterial and fungal spores in fluorescence-based ambient measurements. Copyright 2014 American Association for Aerosol Research


In a previous article, "The Gettier Problem and Legal Proof," I argued that epistemic conditions that undermine knowledge in Gettier-type cases also potentially undermine legal verdicts. For this reason, I argued, there is a deeper connection between knowledge and legal proof than is typically presupposed or argued for in the scholarly legal literature. Thus, I concluded, legal proof includes something like a knowledge requirement – in the sense that legal verdicts aim not only at truth and sufficient evidential support but also, as with knowledge, an appropriate connection between their truth and justifying evidential support.This conclusion is compatible with different ways of articulating further epistemological details, and the argument that supports it does not depend on any novel or particularly controversial conceptions of the epistemic concepts or analysis of the Gettier problem. In a thoughtful reply to my article, Mark McBride focuses on the epistemic concept of safety as it applies to legal proof. McBride argues that my analysis depends on an account of knowledge in which safety is a necessary condition, and he argues that this dependence challenges my central claim. In this response, I explain why neither McBride's specific examples nor general analysis undermine my central claim. They do, however, further clarify and illuminate epistemological issues underlying my central claim in ways that are useful and instructive.


The purpose of this research is to discover the factors that shape the relationship between C.V. CS as buyer and the suppliers in order to determine the most appropriate strategy to manage the relationship. This research uses quantitative method and exploratory factor analysis approach. The population of this research consists of 30 suppliers of C.V. CS. Saturated sampling is used as sampling technique in this study. Additionally, the entire population is used as respondents. Research results suggest a new factor which can be considered as a simplified version of the six research variables of communication, trust, capacity and capability, relationship continuity, dependence and commitment. This factor is called strategic partnership. Strategic partnership is considered as the most suitable strategy for C.V. CS to establish a relationship with their suppliers. The findings of this research also indicate that strategic partnership can act as relationship builder between buyers and suppliers. In order to create a perfect strategic partnership, the five forming elements must be fulfilled.


Accurate characterization of genetic diversity is essential for understanding population demography, predicting future trends and implementing efficient conservation policies. For that purpose, molecular markers are routinely developed for nonmodel species, but key questions regarding sampling design, such as calculation of minimum sample sizes or the effect of relatives in the sample, are often neglected. We used accumulation curves and sibship analyses to explore how these 2 factors affect marker performance in the characterization of genetic diversity. We illustrate this approach with the analysis of an empirical dataset including newly optimized microsatellite sets for 3 Iberian amphibian species: Hyla molleri, Epidalea calamita, and Pelophylax perezi. We studied 17-21 populations per species (total n = 547, 652, and 516 individuals, respectively), including a reference locality in which the effect of sample size was explored using larger samples (77-96 individuals). As expected, FIS and tests for Hardy-Weinberg equilibrium and linkage disequilibrium were affected by the presence of full sibs, and most initially inferred disequilibria were no longer statistically significant when full siblings were removed from the sample. We estimated that to obtain reliable estimates, the minimum sample size (potentially including full sibs) was close to 20 for expected heterozygosity, and between 50 and 80 for allelic richness. Our pilot study based on a reference population provided a rigorous assessment of marker properties and the effects of sample size and presence of full sibs in the sample. These examples illustrate the advantages of this approach to produce robust and reliable results for downstream analyses.


RATIONALE
Pulmonologists frequently encounter indeterminate pulmonary nodules in practice, but it is unclear what clinical factors they rely on to guide the diagnostic evaluation.

OBJECTIVES
To assess the current approach to the management of indeterminate pulmonary nodules and to determine the extent to which the addition of a hypothetical diagnostic blood test will influence clinical decision making.

METHODS
Selected pulmonologists practicing in the United States were invited to participate in a conjoint exercise based on 20 randomly generated cases of varying age, smoking history, and nodule size. Some cases included the result of a hypothetical blood test. Each respondent chose from among three diagnostic options for a patient: noninvasive monitoring (i.e., serial CT or positron emission tomography scan), a minor procedure (i.e., biopsy or bronchoscopy), or a major procedure (i.e., video-assisted thorascopic surgery or thoracotomy). Multivariate logistic regression was used to assess the impact of the three risk factors and the diagnostic blood test on decision making.

MEASUREMENTS AND MAIN RESULTS
Four hundred nineteen physicians participated (response rate, 10%). One hundred fifty-three physician surveys met predetermined criteria and were analyzed (4% of all invitees). A diagnostic procedure was recommended for 23% of 6-mm nodules, versus 54, 66, 77, and 84% of nodules 10, 14, 18, and 22 mm, respectively (P < 0.001). Older age limited recommendations for invasive testing: 54% of 80-year-olds versus 61, 64, 63, and 61% of patients 71, 62, 53, and 44 years of age, respectively (P < 0.001). In multivariate analyses, nodule size, smoking history, age, and the blood test each influenced decision making (P < 0.001).

CONCLUSIONS
The pulmonologists who participated in this survey were more likely to proceed with invasive testing, instead of observation or additional imaging, as the size of the nodule increased. The use of a hypothetical blood test resulted in significant alterations in the decision to pursue invasive testing.


This booklet gives an overview of moisture and cloud formations as they relate to aviation. According to the scope notes on the title page, it includes information about "Cloud formation, international classification, abbreviations, and symbols" as well as "General flight conditions associated with stratiform and cumuliform clouds." The text also has self-evaluation questions printed throughout, with the answers printed on the last page.


Abstract More common than severe behaviors, distracting and instructionally disruptive behaviors frequently result in disciplinary decisions being made for the student who is exhibiting them. These behaviors are troublesome not because they threaten the physical or psychological safety of the student or those around him/her, but because they usually occur at a high frequency and make instruction difficult. This article describes a four-phase procedure that can be used to functionally assess distracting and disruptive behaviors occurring in the school setting. A variety of procedures under each of the first three phases will be discussed, as well as the utility of each procedure for the school setting. Procedures for linking information gained in the first three phases of the model to treatment implementation and treatment monitoring will also be discussed. Finally, a case example will be presented to highlight described procedures.


Introduction Non-urethral N. gonorrhoeae infections have been associated with antimicrobial resistance as well as increased HIV transmission and acquisition, however, incidence data from low and middle-income countries are lacking. Methods We collected anal and pharyngeal specimens from MSM and transgender women seeking sexually transmitted disease clinical services quarterly for 2 years. Incident infection was defined as having a positive nucleic acid test among those with no prior infection or prior treatment. We used generalised estimating equations to calculate adjusted incident rate ratios (aIRR). We grouped infections by anatomic site. All models included any condomless sex and number of male sex partners in prior 3 months. Results Of 401 participants, 22% identified as transgender and 31% had HIV infection at baseline. Incidence of anal infection was 30 and 40 cases per 100 person-years with N. gonorrhoeae and C. trachomatis, respectively, while incidence of pharyngeal infection was 22 and 12 cases per 100 person-years with N. gonorrhoeae and C. trachomatis, respectively. In the pharyngeal infection model with either organism, transgender identification was positively associated (aIRR=2.1; 95% CI 1.4–3.0) compared with MSM, whereas each decade increase in age was negatively associated (aIRR=0.7; 95% CI 0.6–0.9). In the anal infection model with either organism, HIV infection was positively associated (aIRR=1.6; 95% CI 1.2–2.1), whereas each decade increase in age was negatively associated (aIRR=0.7; 95% CI 0.6–0.9). Anal infection incidence was increased in those reporting receptive (aIRR=2.7; 95% CI 1.5–4.9) and both receptive/insertive (aIRR=2.6; 95% CI 1.5–4.6) sex versus reporting exclusively insertive sex. Conclusion Incident non-urethral N. gonorrhoeae and C. trachomatis infections were common among MSM and transgender women in Lima, Peru, adding to the paucity of data from Latin America, especially among transgender women. Our findings support World Health Organisation recommendations for anal screening and argue for the addition of pharyngeal screening.


A model of early auditory processing is proposed in which each peripheral channel is processed by a delay-and-subtract cancellation filter, tuned independently for each channel with a criterion of minimum power. For a channel dominated by a pure tone or a resolved partial of a complex tone, the optimal delay is its period. For a channel responding to harmonically-related partials, the optimal delay is their common fundamental period. Each peripheral channel is thus split into two subchannels, one that is cancellation-filtered and the other not. Perception can involve either or both, depending on the task. The model is illustrated by applying it to the masking asymmetry between pure tones and narrowband noise: a noise target masked by a tone is more easily detectable than a tone target masked by noise. The model is one of a wider class of models, monaural or binaural, that cancel irrelevant stimulus dimensions so as to attain invariance to competing sources. Similar to occlusion in the visual domain, cancellation yields sensory evidence that is incomplete, thus requiring Bayesian inference of an internal model of the world along the lines of Helmholtz's doctrine of unconscious inference.


Lamarckian hereditability of acquired characteristics proposed natural cooperation as opposed to natural selection. The endosymbiotic archaea secrete RNA viroids. The archaeal RNA viroids are converted to DNA viroids by endogenous HERV reverse transcriptase and integrated into the genome by HERV integrase. Archaeal endosymbiosis can occur consequent to global warming, stress, dietary fibre deficiency and exposure to low level EMF which leads to increased colonic archaeal growth and endosymbiosis. The archaea will secrete RNA viroids which can get converted to DNA viroids and get integrated into the genome functioning as jumping genes modulating gene expression. The RNA viroids and their DNA templates getting integrated into the genome consequent to environmental stress leads to genomic flexibility and dynamicity which can be inherited. Exposure to environmental stress can alter the genome changing body function in response to stress and genomic change which is acquired is hereditable. Symbiotic genomics forms the basis of global anarchic culture – the tribe of urban nomadic, anarcho-capitalistic, androgynous pagans.


Hide, Horn, Fish, and Fowl: Texas Hunting and Fishing Lore. Edited by Kenneth L. Untiedt. Publications of the Texas Folklore Society LXVII. (Denton: University of North Texas Press, 201 1 . Pp. x+ 367, preface, contributors vitas, index. $41.95 cloth.)The Texas Folklore Society produces handsomely packaged books in its publication series that are on timely topics in folklore studies, and this volume on hunting and fishing lore is no exception. It still seems odd to me that hunting and fishing lore is a relatively "new" topic in folklore studies in light of its longstanding tradition and rich expressive variation in story, song, and custom. A special issue of this journal on hunting and fishing introduced by Jacqueline Thursby (2004), the book Wild Games edited by Dennis A. Cutchins and Eric Eliason (2009), and my study Killing Tradition (2008) were all published just since 2004, each making note of the slim folkloristic bibliography of hunting and fishing folklife. The Publications of the Texas Folklore Society under the leadership of J. Frank Dobie (1888-1964) and Mody C. Boatright (1897-1970) deserve a footnote for featuring some of the earliest folkloristic essays on the topic, however, and there is an association evident in the pages of the series beginning in 1916 of hunting with the state's heritage (see Miles 1961).A difference in tone with this volume from Texas is an admission by the editor that despite the "inclination to hunt for wild game and fish stream and open waters ... we no longer need to do so for our basic survival" (ix) . The early essays address in one way or another a "passion," "drive," or "appeal" of the hunting and fishing experience to six men and at least one woman, Mary Margaret Dougherty Campbell, who does valuably add to the understudied haul of women's narratives about hunting with her observations on the roots of women's hunting in ranch life. Yet in her essay and the ones by the men the answer to the question of what drives people to hunt in the modern world, or this corner of it, is elusive. Several mention hunting's function of providing bonding with one's father (and in John Wolfs memoir, a quashing of hunting by wives upon entering marriage) , and others give references to communing with nature and coming-of-age as a man. But generally in this section and in others, writers are more interested in relating their stories than in reflecting upon or interpreting hunting practices. Occasionally there is an instinctual argument that hunting is "in the blood." The effect of the animal rights movement does not enter into the conversation and neither do the ecological considerations of the loss of wilderness and the rise of suburbanization. There is an awareness of the power of narrative in relating values and social memory, if not of the comparative analysis of hunting and fishing texts, performances, and contexts.The analytical-sounding title "Pranks in Hunting Camp; Or, the Physiological and Psychological Benefits of Ancient Rites Practices in Bucolic and Fraternal Settings" by Robert Flynn appears out of place among the lively reminiscences indicated by first-person narrative chapter headings. …


LOCALIZATION in urban environments is a key prerequisite for making a robot truly autonomous, as well as an important issue in collective and cooperative robotics. It is not easily achievable when moving objects are involved or environment changes. Ego-motion estimation is the problem of determining the pose of a robot relative to its previous location without an absolute frame of reference. Mobile robot localization is the problem of determining the pose of a robot relative to a given map of the environment. The performance of ego-motion estimation completely depends on the consistency between sensor information at successive time steps, whereas the performance of global localization highly depends on the consistency between the sensor information and the a priori environment knowledge. The inconsistencies make a robot unable to robustly localize itself in real environments. Explicitly taking into account the inconsistencies serves as the basis for mobile robot localization. In this thesis, we explore the problem of mobile robot localization in highly dynamic environments. We proposed a multiple-model approach to solve the problems of egomotion estimation and moving object detection jointly in a random sample consensus (RANSAC) paradigm. We show that accurate identification of static environments can help classification of moving objects, whereas discrimination of moving objects also yields better ego-motion estimation, particularly in environments containing a significant percentage of moving objects. It is believed that a solution to the moving object detection problem can provide a bridge between the simultaneous localization and mapping (SLAM) and the detection and tracking of moving objects (DATMO) problems. Based on the ego-motion estimation framework, to provide reliable moving object detection, data association can still be problematic due to merge and split of objects and temporal occlusion. We propose the use of discriminative models to reason about the joint association between measurements. Scaling such a system to solve the global localization problem will increase the reliability for mobile robots to perform autonomous tasks in crowded urban scenes. We propose to use a multiple-model approach based on the probabilistic mobile robot localization framework and formulate an extension to the global localization problem. Besides, detecting objects of small sizes at low speeds, such as pedestrians, is difficult, but of particular interest in mobile robotics. We propose the use of prior knowledge from the mobile robot localization framework to deal with the problem of pedestrian detection, and formalize the localization-by-detection and detection-by-localization framework. The proposed approach will be demonstrated using experimental testing with real data.


Cleft lip and palate syndromes are among the most common congenital malformations in humans. Mammalian palatogenesis is a complex process involving highly regulated interactions between epithelial and mesenchymal cells of the palate to permit correct positioning of the palatal shelves, the remodeling of the extracellular matrix (ECM), and subsequent fusion of the palatal shelves. Here we show that several matrix metalloproteinases (MMPs), including a cell membrane-associated MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were highly expressed by the medial edge epithelium (MEE). MMP-13 was expressed both in MEE and in adjacent mesenchyme, whereas gelatinase A (MMP-2) was expressed by mesenchymal cells neighboring the MEE. Transforming growth factor (TGF)-beta3-deficient mice, which suffer from clefting of the secondary palate, showed complete absence of TIMP-2 in the midline and expressed significantly lower levels of MMP-13 and slightly reduced levels of MMP-2. In concordance with these findings, MMP-13 expression was strongly induced by TGF-beta3 in palatal fibroblasts. Finally, palatal shelves from prefusion wild-type mouse embryos cultured in the presence of a synthetic inhibitor of MMPs or excess of TIMP-2 failed to fuse and MEE cells did not transdifferentiate, phenocopying the defect of the TGF-beta3-deficient mice. Our observations indicate for the first time that the proteolytic degradation of the ECM by MMPs is a necessary step for palatal fusion.


In this first book-length study of synchronic umlaut, a comprehensive comparative analysis of the phonology and morphology of the umlaut alternation in present-day German and the Austronesian language Chamorro is presented in the framework of Optimality Theory. A fresh perspective of the phonology-morphology interface and the interaction between segmental and metrical structure with wider cross-linguistic implications is developed, including a new conception of morphological conditioning based on morphological faithfulness and Representation as Pure Markedness. The Chamorro data collected for this study contribute significantly to the documentation of this endangered language.


Depending on who you talk to and what you read, there are two, very different, attitudes towards family based treatment (FBT): the only treatment for which empirical support is strong, an approach too mechanical to trust. Each camp views the conclusion of the other as not only wrong, but backward. The debates have been contentious; they have also ignored issues which, if properly considered, would be grounds for a thoughtful perspective, one that better serves the public health. Achieving the middle ground is imperative. In a discipline as young as ours weighing evidence cautiously can have a civilising influence, not only on how we are perceived by patients and families but also on how we will be judged by other disciplines and by purchasers of care. This article offers a carefully measured, detailed argument for consensus. It reviews the evidence-base for FBT and shows why broad claims of its benefit are greatly overstated, but also why it should not be discounted. Understanding the circumstances when use of FBT is inappropriate and when failure to consider it might be equally so addresses an important question on which our field is presently divided.


textabstractWithin the realm of globalization of R&D, offshoring is a relatively recent and still emerging phenomenon. Rooted in the notion of comparative advantage, offshoring of R&D involves disaggregation and global distribution of the firm's R&D value chain activities to leverage innovation capacity of low-cost countries. Characteristically different from market- and technology-seeking globalization of R&D, offshoring is motivated by the intertwining competitive needs to gain efficiency and access knowledge resources. This study represents a systematic, grounds-up attempt to explore the terrain of the phenomenon of offshoring of R&D and its influence on the competitive advantage of firms. Specifically, going beyond structural cost savings, the research examines the link between offshoring of R&D and the firm's innovative capability and organizational flexibility—the two most important organizational capabilities of high technology firms. Employing an interpretive approach, the research includes multiple case studies of intra-firm and inter-firm offshoring of software R&D across a range of industries. The study demonstrates that by strategically organizing and managing offshoring of R&D, firms can significantly enhance their innovative capability and organizational flexibility. The findings suggest that offshoring of R&D is a new global organizational form that not only serves as an adaptive device but also allows firms to achieve ambidexterity.


The effect of manganese doping on the magnetic and structural properties of strontiumtitanate (SrTiO3) was studied. Neutron powder diffraction, x-ray diffraction, magneticmeasurements, scanning electron microscopy and energy dispersive spectroscopy of x-rays wereutilized. Air-sintered Sr(MnxTi1-x)O3 (SMT) with x = 0:02 and x = 0:05 were homogeneoussingle phase orthorhombic (space group Pbnm) perovskite samples. The symmetry was orthorhombicalready at room temperature, and no symmetry change was observed down to 11K. An anomaly in the magnetic susceptibility was observed in x = 0:02 sample at 75 K. Incontrast to earlier reports, no ferromagnetism was observed.


This edited reflects the current state of knowledge about the role of microRNAs in the formation and progression of solid tumours. The main focus lies on computational methods and applications, together with cutting edge experimental techniques that are used to approach all aspects of microRNA regulation in cancer. We are sure that the emergence of high-throughput quantitative techniques will make this integrative approach absolutely necessary in the near future. This book will be a resource for researchers starting out with cancer microRNA research, but is also intended for the experienced researcher who wants to incorporate concepts and tools from systems biology and bioinformatics into his work. Bioinformaticians and modellers are provided with a general perspective on microRNA biology in cancer, and the state-of-the-art in computational microRNA biology.


This paper compares computational evolution using local and global evaluation functions in the context of solving two classical combinatorial problems on graphs: the k-coloring and minimum coloring problems. It is shown that the essential difference between traditional algorithms using local search (such as simulated annealing) and distributed algorithms (such as the Alife&AER model) lies in the evaluation function. Simulated annealing uses global information to evaluate the whole system state, which is called the global evaluation function (GEF) method. The Alife&AER model uses local information to evaluate the state of a single agent, which is called the local evaluation function (LEF) method. Computer experiment results show that the LEF methods are comparable to GEF methods (simulated annealing and greedy), and in some problem instances the LEF beats GEF methods. We present the consistency theorem which shows that a Nash equilibrium of an LEF is identical to a local optimum of a GEF when they are "consistent." This theorem explains why some LEFs can lead the system to a global goal. Some rules for constructing a consistent LEF are proposed.


By varying the dopant-to-pyrrole ratio in a wide range from 0 to 60% a series of 5-sulfosalicylic acid sodium doped polypyrrole was synthesized in situ in aqueous solution with ferric chloride as the oxidant. The resulting polypyrroles were characterized with the four-probe, laser light scattering and thermo-gravimetry analysis, differential thermal analysis, respectively. Our results indicate that the particle size plays a determinative role to tune the conductivity in the studied range of dopant concentration; and this series of polypyrrole with size-tuned-conductivity exhibits little less thermal-stability although its size and conductivity changes simultaneously and acutely with the dopant concentration. The association of the conductivity with particle size was interpreted in terms of a theoretical model proposed by Baughman and Shacklelette.


Chemicals capable of lightening the skin – variously known as skin-bleaching, skin-lightening, depigmenting, skin-evening and skin-brightening agents – are among the most commonly used skin preparations in the world. Globally, Africa reportedly exhibits a high prevalence of skin lightener use. In this review, we provide both clinical and social perspectives on skin lightener use in Africa, with particular emphasis on South Africa. We narratively explore the timeline associated with skin lightener use in South Africa and attempt to interweave the social rhetoric of this specific paradigm. Despite the risks associated with exposing the skin to known constituents of these formulations, such as hydroquinone and mercury, chronic use continues. In spite of legislation banning hydroquinone and mercury in cosmetics in South Africa, these ingredients are present in widely available products. We recommend better implementation of policies and greater ethical responsibility of multinational cosmetic companies in addition to the initiation of a system of random product testing and penalties that could improve industry compliance.


Enterprises are increasingly organising their activities and IT support around key business processes. These processes and their interrelationships may be identified in a process architecture. Ould (2005) claims that the Riva method identifies the process architecture that an organisation should have, and asserts that organisations in the same business have the same process architecture. This assertion is not self-evidently true, and it has not been corroborated by the literature. But it is an important claim: if true, then process architectures could be reused either for new process development, or for appraising an organisation's existing architecture. We assessed the assertion by comparing the process architectures produced by applying Riva to two higher education institutions. The results partially support the view that an essential process architecture underpins higher education institutions, and also that for regulated business domains the optimal process architecture may be one based upon designed as well as essential business entities. The conclusion is that process architecture reuse, with its attendant potential savings of time and money, is worth investigating further, even though the extent to which the invariant assertion is testable may not be clear yet.


By summarizing the research and development status in recent years, this thesis especially introduces the preparation method and enhancement mechanism of the functionally gradient material of Mo-MoSi2. Results of experiments show that: alloying and compounding can significantly improve the room-temperature brittleness and high temperature strength;and the application of Chemical Vapor Deposition (CVD) method in the preparation of Mo-MoSi2 multiphase anti-oxidation coating, has obvious advantages in that it reduces cracking and improves the coating quality. Finally, the developing trend of Mo-MoSi2 and its prospected difficulties and hot issues are also pointed out.


The Wilson disease copper-transporting ATPase plays a critical role in the intracellular trafficking of copper. Mutations in this protein lead to the accumulation of a toxic level of copper in the liver, kidney, and brain followed by extensive tissue damage and death. The ATPase has a novel amino-terminal domain ( approximately 70 kDa) which contains six repeats of the copper binding motif GMTCXXC. We have expressed and characterized this domain with respect to the copper binding sites and the conformational consequences of copper binding. A detailed analysis of this domain by X-ray absorption spectroscopy (XAS) has revealed that each binding site ligates copper in the +1 oxidation state using two cysteine side chains with distorted linear geometry. Analysis of copper-induced conformational changes in the amino-terminal domain indicates that both secondary and tertiary structure changes take place upon copper binding. These copper-induced conformational changes could play an important role in the function and regulation of the ATPase in vivo. In addition to providing important insights on copper binding to the protein, these results suggest a possible mechanism of copper trafficking by the Wilson disease ATPase.


Strong evidence shows that renin-angiotensin system (RAS) is affected by adverse maternal nutrition during pregnancy. Early treatment of offspring with RAS inhibitors is able to prevent the development of prenatally programmed hypertension. The aim of this study was to evaluate renal RAS activity and inflammatory mechanisms and the effects of RAS inhibition in prenatally programmed hypertension. Sprague-Dawley rats were fed with standard diet (control group) or low protein (LP) diet during the period of pregnancy. After birth, dams were switched back to standard rat chow. After weaning, LP pups were randomized to either no treatment or to treatment with losartan. LP offspring presented lower birth weight when compared to CT group (5.3 ± 0.1 vs 6.4 ± 0.2 g, respectively, p<0.05). At 20 weeks of life, blood pressure levels were higher in the untreated LP group when compared to CT group (128.5 ± 0.9 vs 109.2 ± 1.9 mmHg, respectively, p<0.05). We also observed adverse histological features in the kidney of untreated LP animals when compared to CT group, including augmentation of relative interstitial area (9.27 ± 0.32 vs 3.86 ± 0.27 %, respectively, p<0.05), collagen concentration (3.53 ± 0.87 vs 0.68 ± 0.19%, respectively, p<0.05) and number of PCNA positive cells (7.36 ± 1.82 vs 1.95 ± 0.15 cells/0.274 mm2, respectively, p<0.05). Untreated LP group also had higher number of CD3 and CD68 positive cells in the kidney compared to CT group [CD3: 9.3 ± 0.5 vs 5.1 ± 0.3 cells/0.274 mm2 and CD68: 13.5 ± 1.0 vs 8.2 ± 0.9 cells/0.274 mm2, respectively, p<0.05), and higher levels of reactive oxygen species (3.6 ± 0.4 vs 1.7 ± 0.2 mmol/mg, respectively, p<0.05). In addition, renal levels of angiotensin II (Ang II) were higher in the untreated LP offspring compared to CT group (p<0.05), and inhibition of RAS was able to prevent renal injury and abolished infiltration of inflammatory cells, besides its hemodynamics benefits. The finding of high renal levels of Ang II associated with increased inflammatory infiltration and deleterious histological outcomes and the effectiveness of RAS inhibition in prevent them indicate that RAS, via Ang II/AT1 receptor, is responsible for initiating and perpetuating the inflammatory and fibrotic processes in the prenatally programmed kidney.


High density (HD) pressboard is an essential element in power transformers combining good electrical insulation properties with effective mechanical characteristics that well suit design requirements of power transformers. In order to ensure a correctly functioning transformer, it is therefore very important to characterize and to understand the mechanical properties of pressboard under different operating conditions. Pressboard is composed of natural polymeric chains, whose mechanical properties are affected by moisture and temperature. Moreover, temperature and moisture conditions in power transformers vary throughout manufacturing process and service/operation life-time. An accurate definition of the mechanical properties is, therefore, necessary. The present article focuses on the effect of different combinations of temperature/moisture and mechanical load on the deformation behavior of HD pressboard samples. A mechanical constitutive model is developed for finite element (FEM) simulation based on a viscoelastic- viscoplastic material description. Special attention is given on the complex through-thickness deformation behavior of HD pressboard. Thorough analyses are performed based on the comparisons between the results of experimental characterization and FEM modeling and simulations. The good agreement between experimental and modeling results shows a great potential for application in mechanical design of transformer insulation.


In this study, an in-house program to predict steady state operation of micro gas turbines is constructed using MATLAB. The program consists of two parts: design and off-design simulations. The program is fully modular in its structure, and performance of each component (compressor, combustor, turbine, recuperative heat exchanger and pipe elements) is calculated in a separate calculation module using mass and energy balances as well as models for off-design characteristics. The off-design modules of compressor and turbine use performance maps, which are program inputs. The off-design operation of a micro gas turbine under development was predicted by the program. The prediction results were compared with those by commercial software, and the validity of the in-house program was confirmed.


We present an up-to-date compilation of the principal observed parameters of 558 pulsars, including positions, timing parameters, pulse widths, flux densities, proper motions, distances, and dispersion, rotation, and scattering measures. We also list the orbital elements of binary pulsars and some commonly used parameters derived from the basic measurements. Uncertainties are quoted for most quantities, and references to the original literature are given. Figures are used to illustrate the sample distributions of some of the more important parameters. Machine-readable versions of the tabulated information are available, together with software designed to make the data base useful to others working in the field


Formation of residual stresses and crystallographic textures during rolling have been studied using elasto-plastic deformation for polycrystalline material (Leffers-Wierzbanowski model). The rotation of grain crystal lattices is the basic mechanism of texture formation and anisotropic behavior of metals during plastic deformation. The classical definition of crystal lattice rotation leads in some cases to different texture predictions than the definition based on the orientation preservation of selected sample planes and/or directions (preservation condition). Also predicted residual stresses can be influenced by a choice of rotation definition. In the used deformation model of polycrystalline material, the intensity of grain-matrix interaction is described by the parameter L= aG, where G is shear modulus and a is elasto-plastic accommodation parameter. Model calculations have been done for different values of this parameter and for two definitions of lattice rotation. The predicted second order residual stresses and crystallographic textures for cold rolled ferrite steel are compared with experimental ones.


Corrosion rates of steel alloys were investigated in gas oil and its mixture with waste cooking oil and animal waste lard over 1, 3, 7 and 21 days under desulfurizing condition. Co-processing conditions were attempted to simulate by batch-reactor experiment at temperatures between 200 and 300 o C and pressures between 20 and 90 bar in the presence of 2 volume% hydrogen sulfide. Integral and differential corrosion rates were defined by weight losses. Intense sulfide corrosion of carbon steels was less impacted by the biomass sources. Thinner scales in gas oil was probably due to frequent cohesive failure, whereas thicker layers in biomass mixtures were allowed to form to afford limited physical protection. The high corrosion rate of low alloy steel with temperature over time is related to inefficient protection by the metal sulfide scales. Greater activation energy and enthalpy balance in the formation of activated complex is expected to reflect in thick cohesive scales. Loose layers and the less unfavorable entropy balance in the transition state did not lead to valuable barrier protection. High sulfide corrosion resistance of stainless steels is in chemical in nature markedly impacted by the biomass fuel sources and contributed especially by the acidic species. Corrosion rates increased with temperature by magnitude similar to those of carbon steels, which probably owes to the less unfavorable entropy and free energy balance between the initial and transition states of the reactants.


Flexibility in power plants with amine based carbon dioxide (CO2) capture is widely recognised as a way of improving power plant revenues. Despite the prior art, its value as a way to improve power plant revenues is still unclear. Most studies are based on simplifying assumptions about the capabilities of power plants to operate at part load and to regenerate additional solvent after interim storage of solvent. This work addresses this gap by examining the operational flexibility of supercritical coal power plants with amine based CO2 capture, using a rigorous fully integrated model. The part-load performance with capture and with additional solvent regeneration, of two coal-fired supercritical power plant configurations designed for base load operation with capture, and with the ability to fully bypass capture, is reported. With advanced integration options configuration, including boiler sliding pressure control, uncontrolled steam extraction with a floating crossover pressure, constant stripper pressure operation and compressor inlet guide vanes, a significant reduction of the electricity output penalty at part load is observed. For instance at 50% fuel input and 90% capture, the electricity output penalty reduces from 458 kWh/tCO2 (with conventional integration options) to 345 kWh/tCO2 (with advanced integration options), compared to a reduction from 361 kWh/tCO2 to 342 kWh/tCO2 at 100% fuel input and 90% capture. However, advanced integration options allow for additional solvent regeneration to a lower magnitude than conventional integration options. The latter can maintain CO2 flow export within 10% of maximum flow across 30–78% of MCR (maximum continuous rating). For this configuration, one hour of interim solvent storage at 100% MCR is evaluated to be optimally regenerated in 4 h at 55% MCR, and 3 h at 30% MCR, providing rigorously validated useful guidelines for the increasing number of technoeconomic studies on power plant flexibility, and CO2 flow profiles for further studies on integrated CO2 networks. Crown Copyright © 2016 Published by Elsevier Ltd. This is an open access article under the CC BY


Kilowatt-class fiber lasers and amplifiers are becoming increasingly important building blocks for power-scaling laser systems in various architectures for directed energy applications. Currently, state-of-the-art Yb-doped fiber lasers operating near 1060 nm operate with optical-to-optical power-conversion efficiency of about 66%. State-of-the-art fiber-coupled pump diodes near 975 nm operate with about 50% electrical-to-fiber-coupled optical power conversion efficiency at 25C heatsink temperature. Therefore, the total system electrical-to-optical power conversion efficiency is about 33%. As a result, a 50-kW fiber laser will generate 75 kW of heat at the pump module and 25 kW at the fiber laser module with a total waste heat of 100 kW. It is evident that three times as much waste heat is generated at the pump module. While improving the efficiency of the diodes primarily reduces the input power requirement, increasing the operating temperature primarily reduces the size and weight for thermal management systems. We will discuss improvement in diode laser design, thermal resistance of the package as well as improvement in fiber-coupled optical-to-optical efficiency to achieve high efficiency at higher operating temperature. These factors have a far-reaching implication in terms of significantly improving the overall SWAP requirements thus enabling DEW-class fiber lasers on airborne and other platforms.


This paper discusses requirements and strategies for the next generation of IMA modules in line with the goals of the European Research project SCARLETT. Even though the SCARLETT project starts from concepts and technology which is already available in modern aircrafts, the project's vision is to push the state of the art far beyond what is available today, with substantial consequences for the aerospace industry. SYSGO is one of the key members of the SCARLETT project and is responsible for the evaluation and specification of the platform software requirements, including multi-core support. With the operating system PikeOS, a field-proven implementation of the concept of SSV (Safe and Secure Virtualization) technology, SYSGO provides the foundation for the realization of various components within these projects, ranging from Core Processing Modules, Remote Data Concentrators and Remote Electronics as well as Simulation Environments. This paper provides a short overview of the project's framework, the key drivers, the goals and the anticipated innovations. It presents the new architecture for electronic device integration proposed by the SCARLETT project together with the resulting requirements for the platform software. In addition to SCARLETT project overview, this paper discusses specific software aspects resulting from the project and how they can be addressed with a safe and secure virtualization technology of a modern operating system.


Li[Ni1/3Co1/3Mn1/3]O2 was synthesized by modified combustion method and effect of calcination temperature on characteristics was investigated. The cycle of Li[Ni1/3Co1/3Mn1/3]O2 was determined by electrochemical measurements, the microscopic structural features were investigated using Fourier transform infrared spectroscope(FTIR), Scanning Electron Microscopy (SEM), X-ray diffraction (XRD). The results show that the compound has layered structure with hexagonal lattice. With the increase of calcination temperature, the size of primary particle rises. The Li[Ni1/3Co1/3Mn1/3]O2 calcined at 900 oC shows excellent electrochemical performances with large reversible specific capacity of 152 mAhg-1 in the voltage range of 2.75-4.20 V.


This paper addresses three basic questions about an under-studied food subsidy program, the Child and Adult Care Food Program (CACFP): (1) Does CACFP reach targeted low-income children? (2) How do eligible families and child care providers who participate differ from those who do not participate? (3) What is the association between attending CACFP-participating child care and children's food intake, weight, and food security? We use the Early Childhood Longitudinal Study, Birth Cohort to examine these questions for a representative sample of young children and their providers. We find that program eligibility rules leave many poor children outside the CACFP program. Yet, among poor preschoolers in center-based care, participation in the program is correlated with positive outcomes such as increased consumption of milk and vegetables, and healthier weight (BMI). We discuss the implications of our findings, especially in relation to other food and child care subsidy programs.


At first, my thinking was that competition analysis had evidently become too clever for its own good. As items proving the accusation, I could point to economic evidence which is incapable of being understood by people of average intelligence and moderate numeracy, or which is based on plainly wrong hypotheses which would make excellent sense if the facts matched the theory, but which are distractions if they do not match; assuming that the commercial world runs on the lines of block exemptions (a phenomenon which is diminishing but which remains chronic in some quarters); speculative assumptions about how cartels work (assuming malign rationality and intent and corporate cooperative coordination, which are often absent). So my first thought was grumpily to accede to the proposition that the modern law is "too clever by half". But then my thoughts advanced. I reflected that competition analysis sometimes attributes too much weight to traditional dogma from which modern, fresh theory ought to liberate us. The law on rebates by dominant players cannot be described without an apology; the law on parallel trade is unique on earth; the law on compulsory licensing allows it either anywhere or almost nowhere, depending on one's reading of the judicial runes; the Guidance paper about dominance gives imperfect guidance, despite the efforts devoted to the drafting process, as the Commission is reluctant to cede, in the forward-looking, economically-sophisticated 21st century, an inch of territory gained in the economically primitive wars of competition law religion in the late 20th century; the method of calculating fines, which involves collecting huge sums from enterprises which are found guilty of economic crimes, huger than for any other kind of breach of a public norm in any democracy, does not punish the gravest offences more severely than lesser offences. In short, some competition law doctrines are not consistent with common sense. Far from being sophisticated, they are rather primitive and deserve a fresh look. This paper reflects on the fact that at different periods in our legal history, lawyers have confronted the choice between strictness and flexibility. I suggest that we do not need to adopt better principles. We need not more cleverness, but more common sense. Where the results are unsatisfactory or unpersuasive, the explanation may be that the facts were imperfectly analysed. I suggest that we do not need less or more sophisticated analysis; we need more open-minded analysis driven by a willingness to seek truth from facts. My conclusions may be summarised as follows. In Europe, questions of substance and of process have been regularly entwined together. One can compare the deferential approach of the ECJ in performing its appellate function over Commission action with its robust principle-driven approach to ruling on problems referred by national courts. The tension between rigid predictability and flexible but potentially arbitrary unpredictability has been clear for centuries. We should learn that if the supposedly absolute principle is too rigid, lawyers and judges will find a way round it. The law and the procedure must be adapted to fresh needs and insights, since rigid adherence to unrealistic rules of procedure or substance will ultimately lead to injustice, and creativity will be deployed to get round the absurdity. Guidance from the public authority is highly desirable, but it should be realised that the authority is issuing guidance, not insurance. Fact-finding is utterly crucial, as weak facts make decisions more like propaganda than quasi-judicial determinations. If the law contradicts common sense, and is not being cured, then it needs frank and open-minded examination, followed by reform or convincing explanation. There are several candidates for a frank reappraisal in European competition law.


This paper critically examines the intersections of global tourism and fitness in the Marathon des Sables, an annual ultramarathon in the Sahara desert in which over a thousand athletes run the equivalent of five marathons in six days. It demonstrates how the globalization of health and fitness resonates with familiar Western productions of exotic cultures for the purposes of tourist consumption. Of particular interest here is how established colonial asymmetries are recast in a neoliberal context as runners test their resilience, endurance and strength against an 'extreme' Saharan landscape. While the paper calls attention to these asymmetries, it is more concerned with troubling reductive colonial encounters in order to reveal their instability, heterogeneity and ambivalence. Indeed, the central conceit of the Marathon des Sables – that superior Western fitness regimes and technologies will dominate the race – is inverted by the overwhelming success of Moroccan runners and disaggregated by the biopolitical regulation of elite running bodies. These unexpected intersections of global tourism and fitness demand further attention because they reconfigure our received notions of who (and what) is capable of exerting agency in postcolonial encounters.


In the nineteenth century, architects and family reformers launched promotional campaigns portraying houses no longer as simply physical structures in which families lived but as emblems for family cohesiveness and identity. Clark explains why, despite the fear of standardization and homogenization, the middle class has persisted in viewing the single-family home as the main symbol of independence as as the distinguishing sign of having achieved middle-class status.


The paper proposes a methodology to self-evolve an online fuzzy logic controller (FLC). The proposed methodology does not require any initialization at all, it can start with an empty set of fuzzy control rules or with a simple collection of fuzzy control rules obtained from an expert operator. The FLC design is online, using only the input/output data obtained during the normal operation of the system while it is being controlled. The FLC is composed of a simple structure, where each input variable has its own set of fuzzy control rules, and is evaluated individually by the proposed methodology avoiding the high increase in the number of fuzzy control rules. The FLC structure and their antecedent and consequent parameters are both online modified by the proposed methodology. Only simple information about the system and controller is need, specifically the universe of discourse of the input and output variables, an information that is mandatory to control any process. The performance of the proposed methodology is tested on a simulated continuous-stirred tank reactor (CSTR) system where the results show that the proposed methodology has the capability of designing the FLC in order to successfully controlling the CSTR system by evolving/modifying the FLC structure when unknown regions of operation are reached (unknown for the controller).


Set expansion is the task of finding elements of a set given example members. We are interested in the design of algorithms and techniques for a set expansion tool that expands a set by searching, finding and extracting candidates from the World Wide Web. Existing approaches mostly consider sets of atomic data. We extend this idea to the expansion of sets of t-uples, that is relation instances or tables. We propose an approach for extracting relation instances from the World Wide Web given a handful set of t-uple seeds. For instance, when the user proposes the set of seeds , ,  the system returns a relation containing currency codes with their corresponding country and capital city. We show how a random walk in a heterogeneous graph of Web pages, wrappers, seeds and candidates is able to rank the candidates according to their relevance to the seeds. We evaluate the performance of the approach and show that it is efficient, effective and practical.


Tumors of glial origin consist of a core mass and a penumbra of invasive, single cells, decreasing in numbers towards the periphery and still detectable several centimeters away from the core lesion. Several decades ago, the diffuse nature of malignant gliomas was recognized by neurosurgeons when super-radical resections using hemispherectomies failed to eradicate these tumors. Local invasiveness eventually leads to regrowth of a recurrent tumor predominantly adjacent to the resection cavity, which is not significantly altered by radiation or chemotherapy. This raises the question of whether invasive glioma cells activate cellular programs that render these cells resistant to conventional treatments. Clinical and experimental data demonstrate that glioma invasion is determined by several independent mechanisms that facilitate the spread of these tumors along different anatomic and molecular structures. A common denominator of this cellular behavior may be cell motility. Gene-expression profiling showed upregulation of genes related to motility, and functional studies demonstrated that cell motility contributes to the invasive phenotype of malignant gliomas. There is accumulating evidence that invasive glioma cells show a decreased proliferation rate and a relative resistance to apoptosis, which may contribute to chemotherapy and radiation resistance. Interestingly, interference with cell motility by different strategies results in increased susceptibility to apoptosis, indicating that this dynamic relationship can potentially be exploited as an anti-invasive treatment paradigm. In this review, we discuss mechanisms of glioma invasion, characteristics of the invasive cell, and consequences of this cellular phenotype for surgical resection, oncologic treatments, and future perspectives for anti-invasive strategies.


The paper starts by examining the concept of social security in Tanzania, showing that there are three key issues in social security which have not been adequately addressed by existing social security schemes and need immediate attention. The paper then examines the nature and forms of social security in Tanzania in a historical perspective. It shows that non-conventional social security instruments hClVefailed to promote equitable economic growth and have been heavily biased in favour of the well-off at the expense of the poor. The effectiveness of traditional and informal social security systems has been impaired by changes that have taken place since the colonial period. Formal social security schemes are riddled with problems. The development of formal social security has been gradual and the introduction of structural acijustment programmes has led to the decline of formal security schemes. In terms of coverage, formal social security schemes cover only 6% of the population and focus on only afew risks.


A decade after the Global Financial Crisis, there is little consensus on its primary cause. Some blame bad actors, à la The Big Short. Others finger the collapse of residential real estate prices. More nuanced views consider prolonged policy framework uncertainties in the 2000s, including monetary, accountancy, and home ownership policies as factors. This article looks at the role of academic finance. This argument is similar to the theme of Michael Lewis's 2004 book Moneyball: The Art of Winning an Unfair Game, where Oakland A's manager Billy Beane can't afford to pay market prices for highly ranked players—prices that are shaped by conventional baseball statistics. Beane uses Bill James' evolved baseball statistics ("sabermetrics") to game the market by picking up valuable players for a song and reaps extraordinary results. In the same way, savvy securitization market participants turned the archaic playbook of academic finance on itself and profited exorbitantly, with serious consequences.


A simple method for texture-based seg- mentation of colored images combining the Hotelling transform and an unsupervised neural network is presented. The method separates the image into n regions representing n possible existing textures. The Hotelling transform is used to improve the color contrast and achieve uncorrelated color components. Auto-contrast is then applied to get a better color spreading. Finally, a set of features extracted from the transformed image is submitted to a competitive neural network for training. Once nished, the neu- ral network parameters are used to label the image regions according to their textures.


While sailing towards the waves of hierarchy and authory, neither men nor women knew of their unfortunate fate on a deserted piece of land where no traces of civilisation had been encountered before. The characters in Timberlake Wertenbaker's play ''Our Country's Good" did not know what was awaiting for them behind the grey clouds of the ocean. In this paper, the aim is to demonstrate power relations in terms of authority and obedience between characters of the play coming to for with efforts to interact with one another after a long-lasting voyage to Autralia. In the first part of the paper, the characters and setting are analyzed with a focus on main concepts from post-structural and post-colonial ways of thinking. In the second part, references to authority and obedience are shown and analyzed with an insight into everyday life of the characters in the play. With this two-phased process of analysis, it has been concluded that imposition of power on people through the colonial way of life makes people identify themselves with the roles of strong/weak, logical/emotional, civilized/natural helping the oppositions win over them on this new, shattered piece of land.


The role of NF- (cid:1) B in regulating human cytomegalovirus (HCMV) replication and gene transcription remains controversial. Multiple, functional NF- (cid:1) B response elements exist in the major immediate-early promoter (MIEP) enhancer of HCMV, suggesting a possible requirement for this transcription factor in lytic viral replication. Here we demonstrate by generating and analyzing HCMVs with alterations in the MIEP-enhancer that, although this region is essential for HCMV growth, none of the four NF- (cid:1) B response elements contained within the enhancer are required for MIE gene expression or HCMV replication in multiple cell types. These data reveal the robustness of the regulatory network controlling the MIEP enhancer. The major immediate-early promoter (MIEP) of human cytomegalovirus (HCMV) is responsive to a multitude of transcription factors and plays a pivotal role in initiating the viral


Background Little is known about the characteristics of emergency patients transported to hospital while participating in sports activity. Hence, we identified characteristics of emergency patients transported to hospital by emergency medical service (EMS) while participating in sports activity in Osaka City. Methods Population-based ambulance records of Osaka Municipal Fire Department were reviewed. All sports-related emergency transport cases (ie, patients experiencing external injury or illness during/immediately after participation in sports activity and then transported to hospital by the EMS) were enrolled, including both athletes and recreational sports participants. The study was performed from January 1, 2013 to December 31, 2015. Data of patient characteristics were described according to the type of sports. Results During the study, 661,190 patients required emergency transport in Osaka city; 2,642 (0.4%) were sports-related emergency transport, including 2,453 external injuries and 298 illnesses. Overall, 79.0% of patients were men and 44.4% were less than 18 years. Emergency transport during ball games accounts for the majority of cases (71.5%, 1,888/2,642), including baseball (n = 380), soccer (n = 368), and futsal (n = 209). The leading diagnosis/symptom of external injury was fracture/bone contusion (n = 701) and that of illness was heatstroke/dehydration (n = 184). Serious acute illness, such as sudden cardiac arrest, accounted for 0.6% (16/2,751) of all accidents, with half of them (n = 8) related to long-distance running. Conclusion Characteristics of sports-related accidents widely varied by type of sports. Measures to prevent serious accidents during sports activities should be established based on the information on patient characteristics of each type of sports.


Data platform of data sharing and service provide technical support for high-speed railway transportation organization, it provide data parameter and data support for high-speed railway operation management, and it plays an important role in promoting national economic development. In this paper, the metadata theory is used for data storage, data cataloging, data retrieval and data discovery in the management of the Beijing-Shanghai high-speed railway transportation equipment, analyze and propose key technologies of the establishment of data sharing platform based on metadata management of high-speed railway transportation equipment, correlation analysis is made and the result of analysis indicates that data platform can greatly improve the utilization and ability to obtain high-speed railway transportation equipment data. It can also improve the ability to support organizational decision-making of high-speed railway transportation.


Ten years have passed since the release of the final report of the World Health Organization (WHO) Commission on Social Determinants of Health (CSDH),1 a landmark document that provided a global blue‐print for the health promotion community and the stakeholders we work with. Three overarching recommendations were outlined, improving daily living conditions; tackling the inequitable distribution of power, money and resources; and measuring and understanding the problem and assessing the impact of action.1 The extent to which progress has been, and continues to be, made is contested. This editorial briefly reflects on what has been achieved over the past decade—in broad terms—about action on the social determinants of health (SDH) in Australia. We deliberately take a balanced view by highlighting the weaknesses and strengths in what has been achieved by governments, non‐government organisations, research institutions, peak bodies and civil society. We also reflect on the ongoing role that the Australian Health Promotion Association (AHPA) has played in advancing our understanding about, and action on, the SDH.


Since the 1980s, elite and public discourses emphasizing the unpredictability and uncontrollability of the mass movement of labor have been cast and recast in China. Mobility is constructed as a central feature of the marginalized migrant worker population in China. Focused on the relationship between social structures and discursive construction, this article is a critical analysis of the discourse of mobility in the context of migrant labor in China. Mobility has been (a) understood as a necessity to relocate and use surplus agrarian labor, (b) interpreted as a personal opportunity for escaping the rigid urban–rural dichotomy, and (c) mystified as a threat to the privileged, highly subsidized urban form of living. In outlining these themes, I juxtapose the discourse of mobility with discussions of specific social issues such as deindustrialization and left-behind children/elderly, and broader issues of structural exploitation and disenfranchisement. In the discussion section, I propose that the interaction of mobility, fixity, emplacement, and displacement can serve as an entry point for understanding workers' disenfranchisement and marginalization.


BACKGROUND
Inwardly-rectifying potassium channel protein Kir4.1 is encoded by Kcnj10 which maps to a quantitative trait locus on chromosome 1 for the voluntary alcohol consumption phenotype in mice. Kcnj10 brain expression differences have been established between ethanol-preferring C57Bl/6J and ethanol-avoiding BALB/cJ mice, but its differential expression in other tissues and strains have largely been overlooked. A nonsynonymous single nucleotide polymorphism exists between C57Bl/6J and ethanol-avoiding DBA/2J mice which changes amino acid 262 from threonine (C57Bl/6J) to serine (DBA/2J). This Kcnj10 SNP and its expression may serve as valuable markers in predicting the ethanol preference phenotype in mice.

METHODS
The evolutionary divergence of the Kir gene family was characterized using phylogenetic analysis involving the 16 mouse Kir channels. Kcnj10 expression differences in the brain, liver, lung, heart, spleen, kidney, testes, and muscle of male C57Bl/6J and DBA/2J mice at different developmental stages were examined using semiquantitative RT-PCR analysis. A SNP analysis was conducted to assess the association of Kcnj10 Thr262Ser SNP and the ethanol preference phenotype in F2 mice derived from the reciprocal crosses of the C57Bl/6J and DBA/2J strains.

RESULTS
Evolutionary analysis supports gene duplication and genetic recombination as likely sources of diversity within the Kir gene family. Semiquantitative RT-PCR analysis revealed significantly higher Kcnj10 expression in the brain, spleen, and kidney of both strains when compared to other tissues from the same strain. There were no significant differences in tissue-specific mRNA levels between strains except in the testes. Genotype distributions of the Kcnj10 Thr262Ser SNP were different between low- and high-drinkers. A significant difference in the average ethanol preference level of each genotype was also observed.

CONCLUSION
Our results suggest a role for Kcnj10 in ethanol preference determination in mice. However, further experiments are needed to establish if this association is due to the nonsynonymous SNP or other additional factors associated with Kcnj10.


An increasing number of applications such as risk evaluation in banking or inventory management require support for temporal data. After more than a decade of standstill, the recent adoption of some bitemporal features in SQL:2011 has reinvigorated the support among commercial database vendors, who incorporate an increasing number of relevant bitemporal features. Naturally, assessing the performance and scalability of temporal data storage and operations is of great concern for potential users. The cost of keeping and querying history with novel operations (such as time travel, temporal joins or temporal aggregations) is not adequately reflected in any existing benchmark. In this paper, we present a benchmark proposal which provides comprehensive coverage of the bitemporal data management. It builds on the solid foundations of TPC-H but extends it with a rich set of queries and update scenarios. This workload stems both from real-life temporal applications from SAP's customer base and a systematic coverage of temporal operators proposed in the academic literature. In the accompanying paper [6] we present preliminary results of our benchmark on a number of temporal database systems, also highlighting the need for certain language extensions. In the appendix of this technical report we provide all details required to implement the benchmark.


Electronics devices such as electric motors generate enormous amount of heat, which disturbs the normal performance of the devices and reduces their reliability. This temperature rise has to be limited for two reasons: mechanical stress and the deterioration of the insulating materials. Heat generation is also caused the life span of the motors to decrease and its cause a new replacement which normally cost high. To overcome the heat transfer problems, many cooling methods were applied to the electric motors but still it cannot be solve effectively due to some limitations in these methods. To improve the heat transfer rate, the water or the other liquids such as ethylene glycol were dispersed and suspended with nanoparticles. This new class of heat transfer fluids is called nanofluids where the high thermal conductivity solid particles were mixed into the heat transfer liquids to gain a higher heat transfer rates. Therefore, a study was conducted and encompasses in cooling of the electric motors by nanofluids. The study has shown that by replacing nanofluids to the base fluids, the heat transfer rate can be improved. Also, this study has opened the opportunity for the researchers to do researches under nanofluids for cooling purposes.


Rice Milling Agroindustry was a business engaged in time after rice harvest that would process dry milled rice (GKG) into rice. This study aims to obtained cost, income, income and break even point (BEP) in unit (Kg) and price (Rp) of small agroindustry rice mill in Sragen regency. The basic method of research used analytical descriptive method with survey technique. Determination of location of sample sub- district was done by purposive, that was Kedawung, Masaran and Tanon Subdistrict. Respondents were taken with purposive sampling of 30 people. The types and sources of data used from the primary and secondary data. Technical data was done by interview, observation and documentation. The results showed the average amount of operating revenues of IDR 3,440,880,724/year and IDR 478,41,.307/year. The fficiency of the business were 1.16 and can be said to be efficient because the R/C ratio was more than one. Break even point (BEP) of Small rice milling agroindustry business on the basis of price (IDR) has their breakeven business position broken down by the main output of brown rice from IDR 508,027,645, white rice IDR 30,825,245, gloss rice at IDR 181,746,850. BEP on the basis of unit with main product of white rice was equal to66,610 Kg, 36,588 kg of gloss of rice, brown rice of 109.963 Kg.


Entity standardization maps noisy mentions from free-form text to standard entities in a knowledge base. The unique challenge of this task relative to other entity-related tasks is the lack of surrounding context and numerous variations in the surface form of the mentions, especially when it comes to generalization across domains where labeled data is scarce. Previous research mostly focuses on developing models either heavily relying on context, or dedicated solely to a specific domain. In contrast, we propose CoSiNES, a generic and adaptable framework with Contrastive Siamese Network for Entity Standardization that effectively adapts a pretrained language model to capture the syntax and semantics of the entities in a new domain. We construct a new dataset in the technology domain, which contains 640 technical stack entities and 6,412 mentions collected from industrial content management systems. We demonstrate that CoSiNES yields higher accuracy and faster runtime than baselines derived from leading methods in this domain. CoSiNES also achieves competitive performance in four standard datasets from the chemistry, medicine, and biomedical domains, demonstrating its cross-domain applicability. Code and data is available at https://github.com/konveyor/tackle-container-advisor/tree/main/entity_standardizer/cosines


UNLABELLED
We investigated and compared findings on combined 99mTc pertechnetate-201Tl with those of [99mTc]pertechnetate-67Ga scintiscans to elucidate the advantages of 201Tl in detecting various salivary glands disorders.

METHODS
We studied 23 patients: 6 had sialadenitis, 12 had benign tumors and 5 had malignant tumors. All but four patients had undergone [99mTc]pertechnetate (before and after lemon stimulation), 201Tl (early and delayed) and 67Ga imaging.

RESULTS
Five of six sialadenitis patients showed various degrees of diffuse uptake of 99mTc. All six except one showed early uptake without retention of 201Tl on delayed imaging. The 67Ga scan showed uptake in all patients except one. Nine of 12 benign tumors showed a cold defect on 99mTc scans. Patients with Warthin's tumors and plasmacytoma showed increased 99mTc uptake at the tumor with retention. The 201Tl scan showed early uptake without retention in benign tumors except in three patients, two of whom had Warthin's tumor. Five of the benign tumors, however, were positive on 67Ga scan. None of the malignant tumors showed any uptake of 99mTc. The 201Tl scan showed uptake with tumor retention on delayed images in three patients; three other patients also had positive 67Ga scans. Overall, sensitivity and specificity of 201Tl in detecting malignant tumors were 60% and 73%, respectively, with a negative predictive value of 85%. Sensitivity and specificity for 67Ga were 60% and 47%, respectively, with a negative predictive value of 80%.

CONCLUSION
In view of sensitivity, specificity and convenience of 201Tl as well as future prospects for dual-isotope acquisition, 67Ga may be replaced by 201Tl in detecting salivary gland disorder.


The aim of this study is to establish the net-shape forming of titanium matrix composites (TMCs) shot sleeve for Al alloys die-casting using a casting route. In-situ synthesis and casting of TMCs were carried out in a vacuum induction melting furnace. The synthesized (TiC+TiB) TMCs were examined using an scanning electron microscopy and electron probe micro-analyzer. The thermo-physical variables estimated by casting process were applied to the modeling of TMCs shot-sleeve casting using the Magmasoft®. The results of the investment casting and modeling of TMCs confirm that the casting route can be an effective approach for the economic net-shape forming of TMCs shot sleeve.


Various radiolabeled monoclonal antibodies have been developed for the treatment and diagnosis of malignancies. Rituximab is a chimeric mouse-human monoclonal antibody. Rituximab selectively binds with high affinity to the CD20 antigen (human B-lymphocyte restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and on >90% of B cell non-Hodgkin's lymphomas. These properties make the CD20 receptor a suitable target for radioactive therapy. 177Lu has been considered as a promising radionuclide for developing therapeutic radiopharmaceuticals, esp. radiolabeled monoclonal antibodies, owing to its suitable decay characteristics, as well as the feasibility of large-scale production in adequate specific activity and radionuclidic purity.
In order to obtain 177Lu anti-CD20 radioimmunoconjugates for using in therapeutic studies, different bifunctional chelating agents-antiCD20 (rituximab) (BFCA-rituximab) were labeled by "cold" 177Lu chloride for preliminary chemical characterization. Rituximab, conjugated with three different BFCA, p-SCN-Bn-DOTA, p-SCN-Bn-DTPA and 1B4M-DTPA in a form of freeze-dried preparation was dissolved with sterile saline, and subsequent labelled with 1.0709 µg Lu chloride which is equievalent to MTD for 177Lu (118.3 mCi) in a total volume of 1mL at pH 7.0, and incubation for 30 min at room temperature (p-SCN-Bn-DTPA-rituximab and 1B4M-DTPA-rituximab) and 60 min at 40°C (p-SCN-Bn-DOTA-rituximab). Characterization of the conjugated BFCA-MoAb and determination of the average number of BFCA attached to each antibody molecule was performed by Matrix-Assisted Laser Desorption Ionization time-of-flight (MALDI-ToF) mass spectrometry. MALDI-TOF experiments revealed the presence of two major peaks corresponding to a MW of conjugated and unconjugated rituximab equivalent to an average of 7.7 (p-SCN-Bn-DOTA), 11 (p-SCN-Bn-DTPA) and 9.8 (1B4M-DTPA) groups per molecule of antibody. In order to examine relevant quality parameters, including detection, and purity assessment, SDS-PAGE experiments, under reducing conditions, were performed. All three BFCA-rituximab conjugates (labeled and non-labeled) were resolved in two distinct Mr species which migrated in two bands (upper band at ~50 kDa and lower band ~30 kDa) confirming the migration behavior typical for IgG antibodies which are composed of two identical subunits each composed by two polypeptide chains: two heavy and two light chains, linked via disulfide bonds.
The next step is radio labeling of BFCA-rituximab conjugates and their evaluation in order to find the most appropriate form for potential radiopharmaceutical for treatment of patients of relapsed and refractory non Hodgkin's lymphoma.


Depending on your confidence and skillset, you can either assist teachers or take your own lessons. Either way, you will be making a real difference.


Background/Aims The International Council of Ophthalmology (ICO) offers fellowship programmes to help young ophthalmologists, mainly from low-resource countries, improve their practical or research skills in ophthalmology subspecialty areas. Using questionnaires, the objective of the present study was to evaluate how the ICO Fellowship Programme has impacted on improving knowledge, skills and the careers of young ophthalmologists from low-resource countries. Methods From 2001 to 2019 overall 1140 ICO fellowships were awarded. A questionnaire was sent to ICO fellows after the conclusion of their fellowship and another 3 years later. Part 1 contained 26 questions, while Part 2 had 21 questions. The answers were collected through an online platform and analysed descriptively thereafter. Results 1101 Part 1 questionnaires had been sent to former fellows, with a return rate of 47% (516 responses) and 829 Part 2 questionnaires with a return rate of 47% (390 responses). Overall, 98.3% strongly or somewhat agreed that knowledge in their subspecialty has improved considerably. Whereas only 19% of them held a lecturer, senior lecturer or head of subspecialty department position prior to the fellowship, 46% of them held such a position 3 years after the fellowship was completed. Conclusions The ICO Fellowship Programmes aim to promote the enhancement of eye care delivery and eye health in low-resource countries, the professional development of young leaders and the improvement of eye care. The results of the current study confirm the expectation of such a positive impact. Moreover, almost half of the responding participants have been appointed to a local leadership position in their home country.


. We prove that the conformal automorphism group of a countably connected circular region of connectivity at least three is either a Fuchsian group or a discrete elementary group of M¨obius transformations.


An inverse analysis based on the artificial neural network technique is introduced for effective identification of crack damage in aluminum plates. The concepts of digital damage fingerprints and damage parameter database, which are prerequisites for neural network developing and training, are presented. Parameterized modeling for finite element analysis and an information mapping approach are applied to constitute the damage parameter database cost-effectively. The generalization performance of the neural network is examined by a process of `leave-one-out' cross-validation and diverse factors are discussed, based on which the optimization of the neural network architecture is evaluated. The capability of this inverse approach is assessed by two crack cases from experiments, with good accuracy obtained in damage parameters (central position, size, and orientation).


In this paper we propose a hardware version for two-dimensional cellular automata. Since cellular automata are parallel systems containing a large number of simple processing elements, their hardware version is necessary for their real-time study and applications. A cellular automata chip is described both at the architectural and cell level. The paper outlines the main functions of the cellular automata chip and describes how they operate. We also present some quantitative aspects that determine the chip dimension. The chip can be succesfully used for experiments with large CA implying long-time evolution.


The notion that information has a different value based on the time of its first availability is at the heart of being able to quantify the value of any stock market indicators. Compared to using investors' trading data to predict liquidity and volatility in the stock market, the use of investors' information-seeking behavior before the actual trading has an important advantage in time value. This article investigates the online search frequency of Google users to explore how traders' response to information asymmetry would predict future market liquidity. The findings show that the Google Insight for Search (GIS) daily index is an effective measure of the level of information asymmetry and inversely predicts the future liquidity level. This predictive power is significant at the 1% level. More importantly, the GIS indicators remain strong and significant even after including traditional information asymmetry variables in all the regressions. Last but not least, we find that the GIS index can capture the change in investors' attention and provide indications on future stock return at the 1% significance level.


Flame synthesis of carbon nanotubes and nanocapsules is demonstrated via a pyramid-shaped pyrolysis flame. The mixture of CO, H2, and nebulized catalyst raw material reacts in a high temperature environment formed inside the frustum of pyramid-shaped reactor heated by premixed flame of C2H2 and air outside. A sampling substrate inserted into the incomplete combusting flame of central reacting mixtures can gain the samples of carbon nanotubes and nanocapsules. The effect of sampling time and catalyst concentration is revealed via Field emission scanning electron microscope (FE-SEM) and High-resolution transmission electron microscopy (HR-TEM). 5-mins sampling time and 0.5/50 (Fe(CO)5/C2H5OH, volume ratio) of catalyst concentration is the most appropriate for carbon nanotubes synthesis. In addition, it is to say that catalyst concentration is the most important one among all the factors that can be used to determine whether the main products are carbon nanotubes or nanocapsules, and the structures of nanocapsules are also analyzed in detail.


It has been shown that the monoclonal antibody Ki-67 reacts with a nuclear antigen that is expressed only by proliferating cells. The feasibility of using image analysis to quantitate Ki-67 staining (proliferation index [PI]) of epithelial ovarian cancers was investigated. The PI was determined in 50 advanced-stage primary ovarian cancers. Frozen sections were immunostained with the Ki-67 monoclonal antibody, and the PI was calculated using static image analysis. Among 35 stage III ovarian carcinomas, the median PI was 8.9%, compared with 17.7% in 15 stage IV cancers (P = 0.06). There was no relationship between PI and histologic grade. The median survival time of 32 patients whose cancers had a high Ki-67 expression (> or = 7.5%) was 16.8 months, which differed significantly (P < 0.01) from the median survival of 31.5 months observed in patients whose tumors demonstrated low Ki-67 expression (< 7.5%). Quantitative image analysis of Ki-67-stained fresh-frozen ovarian cancers may provide useful prognostic information. Further studies are warranted to investigate the relationship between Ki-67 expression and other known clinicopathologic and genetic features of ovarian cancer.


Abstract. Volcanic eruptions are rare but potentially catastrophic phenomena, affecting societies and economies through different pathways. The 2010 Eyjafjallajökull eruption in Iceland, a medium-sized ash-fall-producing eruption, caused losses in the range of billions of dollars, mainly to the aviation and tourism industries. Financial risk transfer mechanisms such as insurance are used by individuals, companies, governments, etc., to protect themselves from losses associated with natural catastrophes. In this work, we conceptualize and design a parametric risk transfer mechanism to offset losses to building structures arising from large, ash-fall-producing volcanic eruptions. Such a transfer mechanism relies on the objective measurement of physical characteristics of volcanic eruptions that are correlated with the size of resulting losses (in this case, height of the eruptive column and predominant direction of ash dispersal) in order to pre-determine payments to the risk cedent concerned. We apply this risk transfer mechanism to the case of Mount Fuji in Japan by considering a potential risk cedent such as a regional government interested in offsetting losses to dwellings in the heavily populated prefectures of Tokyo and Kanagawa. The simplicity in determining eruptive column height and ash fall dispersal direction makes this design suitable for extrapolation to other volcanic settings worldwide where significant ash-fall-producing eruptions may occur, provided these parameters are reported by an official, reputable agency and a suitable loss model is available for the volcanoes of interest.


This work was supported by FCT – "Fundacao para a Ciencia e a Tecnologia", within ISISE, project UID/ECI/04029/2013 as well Project Scope: UID/CEC/00319/2013 and through the post-doctoral Grant fellowship with reference SFRH/BPD/94792/2013. This work was also partly financed by FEDER funds through the Competitivity Factors Operational Programme - COMPETE and by national funds through FCT within the scope of the project POCI-01-0145-FEDER-007633. This work has been also supported by COMPETE: POCI-010145-FEDER-007043. A special thanks goes to Network Rail that kindly make available the data (basic earthworks examination data and the Earthworks Hazard Condition scores) used in this work.


Psychological ideas had always played a role on the formation of economic thought as can be seen in the works of many influential pre-classical and classical authors. Up to the beginning of the 20th century, there was almost no methodological objection regarding the incorporation of ideas from psychology into economic theories. After this period, a fundamental shift in mainstream economics took place which is also known as the Paretian turn. This conceptual change, initiated mainly by Vilfredo Pareto and completed with the emergence of the theories of choice in the first decades of the 20th century, attempted to expel all psychological notions from economic theory. However, in the last three decades, the increasing appeal of subjective well-being research and especially of the new behavioral economics, re-brought the topic onto the surface. In order to better comprehend and to contribute to the recent discussion concerning the relationship between the two disciplines, the study of relevant views found in history of economic thought is necessary. The paper starts with a brief sketch of the history of the relationship between economics and psychology, focusing also to the recent literature which points to a reconsideration of this relationship. After an examination of psychological ideas found in influential pre-marginalist writers, the paper discusses the arguments supporting the case for the interaction between the two fields. It also suggests that the work of Richard Jennings can be seen as the peak of the early interaction between economics and psychology. Finally, it considers the relevance of these arguments for the current debate concerning the relationship between economics and psychology.


We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).