Despite the fact that we commonly refer to artworks as 'meaningful' things, this is not to say that meaning is an objective property analogous to size or shape. If meaning is not a physical property then it follows that it can only be a way of using things, of treating them as if they were imbued with features that they do not actually possess. Meaning is thus an attribution in which we agree through social consensus to use objects as tokens of power, prestige, celebration, explanation, instruction and so on. I argue that such symbolic procedures originate in practices of tool-use in which tools are commonly employed in various different ways depending on context and opportunity. The purpose of this paper is to show that the ability to interpret artworks and more generally to ascribe meanings is a highly sophisticated cultural capacity and, more specifically, a verbal skill dependent upon a network of symbolic resources and techniques that only a socially evolved linguistic culture can provide and enable.


Previous studies have demonstrated that resistance to infection is decreased in Swiss Webster female mice maintained in the hindlimb-unloading model (Aviles H, Belay T, Fountain K, Vance M, and Sonnenfeld G. J Appl Physiol 95: 73-80, 2003; Belay T, Aviles H, Vance M, Fountain K, and Sonnenfeld G. J Allergy Clin Immunol 110: 262-268, 2002). This is a model of some of the aspects of spaceflight conditions, including lack of load bearing on hindlimbs and a fluid shift to the head. Active hexose correlated compound (AHCC), extracted from Basidiomycete mushrooms, has been shown to induce enhancement of immune responses, including enhanced natural killer activity. In the present study, AHCC was orally administered to mice to determine whether the treatment could decrease immunosuppression and mortality of mice maintained in the hindlimb-unloaded model and infected with Klebsiella pneumoniae. The results of the present study showed that administration of AHCC by gavage for 1 wk (1 g/kg body wt) before suspension and throughout the 10-day suspension period yielded significant beneficial effects for the hindlimb-unloaded group, including 1). decreased mortality, 2). increased time to death, and 3). increased ability to clear bacteria. The results suggest that AHCC can decrease the deleterious effects of the hindlimb-unloading model on immunity and resistance to infection.


Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD), and is associated with high morbidity and mortality rates. Key histological changes observed in DN include accumulation of extracellular matrix (ECM) proteins and tubulointerstitial fibrosis. Meprins are metalloproteinases that are abundantly expressed in the brush border membranes of proximal kidney tubules. Meprins are also expressed in leukocytes (monocytes and macrophages) and podocytes. Meprins cleave/degrade extracellular matrix (ECM) proteins such as collagen IV, collagen VI, fibronectin, laminin, and nidogen-1 in vitro. Meprins have been implicated in the pathology of DN. Sepsis is a complex medical condition, where the entire body undergoes an inflammatory state and the presence of a known or suspected infection leads to severe consequences such as multiple organ failure. Acute renal failure (ARF) is a common complication of sepsis. The objective of this study was to evaluate cecal ligation and puncture (CLP)-induced sepsis in meprin deficient mice with type 1 diabetes as a co-morbidity. Low dose Streptozotocin (STZ) was used to induce type-1 diabetes in wild-type (WT) C57BL/6 mice which express high levels of both meprin A and meprin B, and meprin α knockout mice on a C57BL/6 background, which are deficient in meprin A. Cecal ligation and puncture was performed 4 weeks post STZ injection. Blood was collected pre and post CLP to evaluate blood urea nitrogen (BUN) levels. The mice were sacrificed 18hr post CLP and kidney tissue processed for proteomic analysis. BUN levels were significantly higher in CLP mice and meprin α knockout mice had lower mortality rates in comparison to wild-type mice. The results show that meprin deficiency protected mice from kidney injury associated with CLP, suggesting that meprins play a role in kidney injury following CLP-induced sepsis.


Standard economic models of tax compliance have focused on enforcement-driven compliance. Notably, tax administrators also tend to place a great deal of emphasis on the importance of improving "tax morale" by encouraging voluntary compliance, creating a culture of compliance, and changing social norms. Tax morale does indeed appear to be an important component of compliance decisions, and there is strong evidence that tax morale operates through a variety of underlying channels. There is less evidence - to date - that indicates we know how to leverage these channels to improve compliance and revenue collection in a consistently successful way.


Abstract. Large climate feedback uncertainties limit the accuracy in predicting the response of the Earth's climate to the increase of CO2 concentration within the atmosphere. This study explores a potential to reduce uncertainties in climate sensitivity estimations using energy balance analysis, especially top-of-atmosphere (TOA) radiation imbalance. The time-scales studied generally cover from decade to century, that is, middle-range climate sensitivity is considered, which is directly related to the climate issue caused by atmospheric CO2 change. The significant difference between current analysis and previous energy balance models is that the current study targets at the boundary condition problem instead of solving the initial condition problem. Additionally, climate system memory and deep ocean heat transport are considered. The climate feedbacks are obtained based on the constraints of the TOA radiation imbalance and surface temperature measurements of the present climate. In this study, the TOA imbalance value of 0.85 W/m2 is used. Note that this imbalance value has large uncertainties. Based on this value, a positive climate feedback with a feedback coefficient ranging from −1.3 to −1.0 W/m2/K is found. The range of feedback coefficient is determined by climate system memory. The longer the memory, the stronger the positive feedback. The estimated time constant of the climate is large (70~120 years) mainly owing to the deep ocean heat transport, implying that the system may be not in an equilibrium state under the external forcing during the industrial era. For the doubled-CO2 climate (or 3.7 W/m2 forcing), the estimated global warming would be 3.1 K if the current estimate of 0.85 W/m2 TOA net radiative heating could be confirmed. With accurate long-term measurements of TOA radiation, the analysis method suggested by this study provides a great potential in the estimations of middle-range climate sensitivity.


For Fear of Pain offers a social history of the operating room in Britain during the final decades of painful surgery. It asks profound questions: how could surgeons operate upon conscious patients? How could patients submit? It presents a revisionist view of surgery, hygiene, nursing, military and naval surgery and the introduction of anaesthesia.


This article attempts a critical reappraisal of the part played by `trust' in management education. Our main contention is that trust is being perceptibly eroded by a range of factors that find their genesis in a wider set of social relations within contemporary capitalism. Accordingly, we set about trying to account for the diminution of trust in social theoretical terms. Having constructed an analytical matrix we then apply our reasoning to specific instances of mistrust in an educational context. Drawing on documented student reflections and other qualitative data we seek to demonstrate how broader social trends are being `holographically' rehearsed and reproduced in the micro-politics of the university classroom. Our `representative anecdotes' give the lie to the increasing regulation and legalization of educational relationships. The concluding section adopts a deliberately polemical tone and we end by asking some searching questions concerning the future of management education in universities.


We describe a multi-step CRISPR/Cas9 gene editing method to create endogenously tagged GFP-fusions of transcriptionally silent genes in human induced pluripotent stem cells (hiPSCs), allowing visualization of proteins that are only expressed upon differentiation. To do this, we designed a donor template containing the monomeric EGFP (mEGFP) fusion tag and an mCherry selection cassette delivered in tandem to a target locus via homology directed repair (HDR). mCherry expression was driven by a constitutive promoter and served as a drug-free, excisable selection marker. Following selection, the mCherry cassette was excised with Cas9, creating an mEGFP-fusion with the target gene. We achieved scarless excision by using repetitive sequences to guide microhomology-mediated end joining (MMEJ) and introduce linker sequences between the mEGFP tag and the target gene. Using this strategy, we successfully tagged genes encoding the cardiomyocyte sarcomeric proteins troponin I (TNNI1), alpha-actinin (ACTN2), titin (TTN), myosin light chain 2a (MYL7), and myosin light chain 2v (MYL2) with mEGFP in undifferentiated hiPSCs. This methodology provides a general strategy for scarlessly introducing tags to transcriptionally silent loci in hiPSCs.


The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and a major therapeutic target for the treatment of type II diabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides that interact with the receptor, including full-length (1–37) and truncated (7–37) forms of GLP-1 that can exist in an amidated form (GLP-1(1–36)NH2 and GLP-1(7–36)NH2) and the related peptide oxyntomodulin. In addition, the GLP-1R possesses exogenous agonists, including exendin-4, and the allosteric modulator, compound 2 (6,7-dichloro-2-methylsulfonyl-3-tert-butylaminoquinoxaline). The complexity of this ligand-receptor system is further increased by the presence of several single nucleotide polymorphisms (SNPs) that are distributed across the receptor. We have investigated 10 GLP-1R SNPs, which were characterized in three physiologically relevant signaling pathways (cAMP accumulation, extracellular signal-regulated kinase 1/2 phosphorylation, and intracellular Ca2+ mobilization); ligand binding and cell surface receptor expression were also determined. We demonstrate both ligand- and pathway-specific effects for multiple SNPs, with the most dramatic effect observed for the Met149 receptor variant. At the Met149 variant, there was selective loss of peptide-induced responses across all pathways examined, but preservation of response to the small molecule compound 2. In contrast, at the Cys333 variant, peptide responses were preserved but there was attenuated response to compound 2. Strikingly, the loss of peptide function at the Met149 receptor variant could be allosterically rescued by compound 2, providing proof-of-principle evidence that allosteric drugs could be used to treat patients with this loss of function variant.


This title was selected for "Sunday Times", "New Statesman" and "TLS" Books Of The Year. An obsession with the nature of death lies at the heart of the human experience. For most of our history religion provided a clear explanation for life and the afterlife. But in the late nineteenth and early twentieth centuries this framework came under relentless pressure as new ideas - from psychiatry to evolution to Communism - seemed to suggest that our fate was now in our own hands. We would ourselves become God. The "Immortalization Commission" raises a host of fascinating questions about what it means to be human. The great and terrible implication of Darwin's ideas was that natural selection made humans into animals like any other, doomed one day to disappear from the face of an uncaring Earth. The refusal to follow this logic and to insist instead on our immortality resulted in a series of experiments that carry on to the present day, some of which ravaged whole countries and some of which generated more private forms of pain. The implications of Gray's book will haunt the reader for the rest of their lives - and perhaps beyond.


Abstract. Multiannual satellite measurements of tropospheric NO 2 columns are used for evaluation of CO 2 emission changes in China in the period from 1996 to 2008. Indirect top-down annual estimates of CO 2 emissions are derived from the satellite NO 2 column measurements by means of a simple inverse modeling procedure involving simulations performed with the CHIMERE mesoscale chemistry–transport model and the CO 2 -to-NO x emission ratios from the Emission Database for Global Atmospheric Research (EDGAR) global anthropogenic emission inventory and Regional Emission Inventory in Asia (REAS). Exponential trends in the normalized time series of annual emissions are evaluated separately for the periods from 1996 to 2001 and from 2001 to 2008. The results indicate that the both periods manifest strong positive trends in the CO 2 emissions, and that the trend in the second period was significantly larger than the trend in the first period. Specifically, the trends in the first and second periods are best estimated to be in the range from 3.7 to 8.3 and from 11.0 to 13.2% per year, respectively, taking into account statistical uncertainties and differences between the CO 2 -to-NO x emission ratios from the EDGAR and REAS inventories. Comparison of our indirect top-down estimates of the CO 2 emission changes with the corresponding bottom-up estimates provided by the EDGAR (version 4.2) and Global Carbon Project (GCP) glomal emission inventories reveals that while acceleration of the CO 2 emission growth in the considered period is a common feature of both kinds of estimates, nonlinearity in the CO 2 emission changes may be strongly exaggerated in the global emission inventories. Specifically, the atmospheric NO 2 observations do not confirm the existence of a sharp bend in the emission inventory data time series in the period from 2000 to 2002. A significant quantitative difference is revealed between the bottom-up and indirect top-down estimates of the CO 2 emission trend in the period from 1996 to 2001 (specifically, the trend was not positive according to the global emission inventories, but is strongly positive in our estimates). These results confirm the findings of earlier studies that indicated probable large uncertainties in the energy production and other activity data for China from international energy statistics used as the input information in the global emission inventories. For the period from 2001 to 2008, some quantitative differences between the different kinds of estimates are found to be in the range of possible systematic uncertainties associated with our estimation method. In general, satellite measurements of tropospheric NO 2 are shown to be a useful source of information on CO 2 sources collocated with sources of nitrogen oxides; the corresponding potential of these measurements should be exploited further in future studies.


DOI: 10.2174/138920291766616110209 5508 Abstract: In eukaryotes, mitosis is tightly regulated to avoid the generation of numerical chromosome aberrations, or aneuploidies. The aneuploid phenotype is a consequence of chromosomal instability (CIN), i.e., an enhanced rate of chromosome segregation errors, which is frequently found in cancer cells and is associated with tumor aggressiveness and increased tumor cell survival potential. To avoid the generation of aneuploidies, cells rely on the spindle assembly checkpoint (SAC), a widely conserved mechanism that protects the genome against this type of error. This signaling pathway stops mitotic progression before anaphase until all chromosomes are correctly attached to spindle microtubules. However, impairment of the SAC cannot account for the establishment of CIN because cells bearing this phenotype have a functional SAC. Hence, in cells with CIN, anaphase is not triggered until all chromosomes are correctly attached to spindle microtubules and congressed at the metaphase plate. Thus, an interesting question arises: What mechanisms actually mediate CIN in cancer cells? Recent research has shown that some pathways involved in chromosome segregation are closely associated to centromere-encoded non-coding RNA (cencRNA) and that these RNAs are deregulated in abnormal conditions, such as cancer. These mechanisms may provide new explanations for chromosome segregation errors. The present review discusses some of these findings and proposes novel mechanisms for the establishment of CIN based on regulation by cencRNA.


Only about one-third of the deaths worldwide are assigned a medically-certified cause, and understanding the causes of deaths occurring outside of medical facilities is logistically and financially challenging. Verbal autopsy (VA) is a routinely used tool to collect information on cause of death in such settings. VA is a survey-based method where a structured questionnaire is conducted to family members or caregivers of a recently deceased person, and the collected information is used to infer the cause of death. As VA becomes an increasingly routine tool for cause-of-death data collection, the lengthy questionnaire has become a major challenge to the implementation and scale-up of VAs. In this paper, we propose a novel active questionnaire design approach that optimizes the order of the questions dynamically to achieve accurate cause-of-death assignment with the smallest number of questions. We propose a fully Bayesian strategy for adaptive question selection that is compatible with any existing probabilistic cause-of-death assignment methods. We also develop an early stopping criterion that fully accounts for the uncertainty in the model parameters. We also propose a penalized score to account for constraints and preferences of existing question structures. We evaluate the performance of our active designs using both synthetic and real data, demonstrating that the proposed strategy achieves accurate cause-of-death assignment using considerably fewer questions than the traditional static VA survey instruments.


OBJECTIVES: biomarkers refer to indicators measured by chemical or biologic tests using blood or urine .  The predicts physiologic or disease states, or increased disease risk.Risk stratification of persons at risk of future vascular event can separate subpopulations that would benefit most from established and emerging stoke preventive therapies. METHODS: Biomarkers representing various components of the inflammatory cascade, including: 1-systemic inflammation (c-reactive protein{CRP}, interleukin 6, monocyte chemotactic protein1,tumor necrosis factor α1,tumor necrosis factor recepror2{TNFR2}, osteoprotegrin, fibrinogen) 2-vascular inflammation/ endothelial dysfunction (intercellular adhesion molecule1,CD40 ligand, P-selectin,lipoprotein associated phospholipaseA  mass and activity,total homocysteine (tHcy),and vascular growth factor(VEGF),oxidative stress(myeloperoxidase) RESULTS : circulating biomarkers of inflammation and endothelial dysfunction are associated with ischemic stroke in stroke free community- dwelling individuals and they can be used to refine stroke prediction models inclusion of 4 biomarkers (CRP-TNFR2-tHcy-VEGF) DISCUSSION : Athough the roles of biomarkers are basically diagnosing the disease and predicting the outcome , biomarkers inpatients with stroke can also provide a large variety of other information about the risk of future stroke, possible stroke mechanisms for biomarker-guided treatment. Among circulating biomarkers  VEGF was the biomarker that had the greatest individual degree of discrimination for future ischemic stroke. Data from studies  have recently demonstrated  the relation between  VEGF and ischemic stroke pathogenesis is, however not well established.total homocysteine and CRP are well established markers of increase stroke risk , the former via its role in accelerated atherosclerotic disease and the latter marking systemic inflammation and plague instability. It has been demonstrated independent association between TNFR2 and ischemic stroke, preliminary data have shown the lower vascular events, in patients with rheumatoid arthritis on TNF inhibitors , particularly in patients with longer duration of use, and characterizing the protective effects Of TNF inhibitors in stroke patients CONCLUSIONS: recent study reported that multiple microparticle biomarkers in addition to existing protein biomarkes are valuable for predicting future of cerebrovascular events


The OTiS (Online Teaching in Scotland) programme, run by the now defunct Scotcit programme, ran an International e-Workshop on Developing Online Tutoring Skills which was held between 8–12 May 2000. It was organised by Heriot–Watt University, Edinburgh and The Robert Gordon University, Aberdeen, UK. Out of this workshop came the seminal Online Tutoring E-Book, a generic primer on e-learning pedagogy and methodology, full of practical implementation guidelines. Although the Scotcit programme ended some years ago, the E-Book has been copied to the SONET site as a series of PDF files, which are now available via the ALT Open Access Repository. The editor, Carol Higgison, is currently working in e-learning at the University of Bradford (see her staff profile) and is the Chair of the Association for Learning Technology (ALT).


The research work presented here is concerned with numerical simulations of two different electrical phenomena: Long gap electrical discharges under switching impulses and the lightning attachment process associated with positive upward leaders. The development of positive upward leaders and the progression of discharges in long gaps are attributable to two intertwined physical phenomena, namely, the leader channel and the streamer zone. The physical description and the proposed calculations of the above-mentioned phenomena are based on experimental tests conducted in long spark gaps. The methodology presented here proposes a new geometrical approximation for the representation of the streamer and the calculation of the accumulated electrical charge. Furthermore, two different approaches to representing the leader channel are applied and compared. Statistical delays before the inception of the first corona, and random distributions to represent the tortuous nature of the path taken by the leader channel were included based on the behavior observed in experimental tests, with the intention of ensuring the discharge behaved in a realistic manner. A reasonable agreement was found between the physical model and the experimental test results. A model is proposed to simulate the negative discharges produced by switching impulses using the methodology developed to simulate positive leader discharges and the physics underlying the negative leader phenomena. The validation of the method demonstrated that phenomena such as the pilot leader and negative leader currents are successfully represented. In addition, based on previous work conducted on the physics of lightning and the lightning attachment process, a new methodology is developed and tested. In this new approach, the background electric field and the ionized region, considered in conjunction with the advance of the leader segment, are computed using a novel method. The proposed methodology was employed to test two engineering methods that are accepted in international standards, the mesh method and the electro-geometrical method. The results demonstrated that the engineering approximations are consistent with the physical approach. In addition to the electrical phenomena mentioned above, one should remember that, to simplify the calculation, there are certain real effects arising from the lightning attachment process that have not been considered. In fact, when a structure is subjected to a strong electric field, it is possible to generate multiple upward leaders from that structure. This effect has not been taken into account in the numerical models available previously, and therefore the process of generating multiple upward leaders incepted over a structure is incorporated here. The results have shown that a slight advantage from the background electric field is enough for one upward connecting leader to take over, thereby forcing the others to abort the attachment process.


This article attempts to investigate the use of request perspectives in Yemeni Arabic. The sample of the current study consists of 336 undergraduate students, namely 168 male respondents and 168 female respondents. They were asked to respond in Yemeni Arabic to twelve different situations in which they carried out the speech act of request. The data were collected using a Discourse Completion Test (DCT). They were analyzed according to the models proposed by Blum-Kulka, et al. (1989), whose analytical framework classified request perspective into four types: hearer-oriented request, speaker-oriented request, inclusive, and impersonal. The results of the study revealed that native speakers of Yemeni Arabic that used the direct head acts of requests were mostly from the hearer-oriented perspective. The respondents employed a hearer-oriented perspective either in the direct strategies or conventionally indirect strategies in order to show solidarity and paying attention to others. However, the indirect head act of request used various perspectives such as hearer-oriented, speaker-oriented, inclusive, or impersonal. The respondents employed speaker-oriented perspective, inclusive or impersonal in order to be free from the imposition of others and to show that they respected the rights of others to their own autonomy and freedom of movement or choice. Furthermore, the results revealed that in general, the respondents in M-M and F-F interactions and M-F and F-M interactions employed hearer-oriented and speaker-oriented perspective more than other perspectives. In particular, the results revealed that the respondents in M-M and F-F interactions and M-F and F-M interactions had a great tendency to use hearer-oriented perspective only in direct requests.


Photo-induced excited-state reactions stand in the center of function of the photosensitive biological systems. These reactions can be accompanied by structural changes of the chromophore (for example isomerization) which are influenced by the nearest environment of the chromophore, and vice versa. In bacteriorhodopsin (bR), the effects of the protein environment are crucial to assure high rate and outstanding bond selectivity of isomerization. In order to identify if these effects are of steric or electrostatic origin, we carried out an extensive femtosecond time resolved fluorescence study on the retinal chromophore of bR in a large class of solvents. The latter differ in viscosity, dielectric constant, polarizability and hydrogen bonding abilities. To carry out this study a novel experimental setup – the polychromatic fluorescence up-conversion, has been designed and constructed that allows broad band detection of the fluorescence spectra, with the time resolution of 100 fs. It is found that in all studied solvents here essential part of the ultrafast excited-state dynamics is dominated by intramolecular processes. Indeed, the relaxation times and the period of the vibrational coherences, which are the markers of the protein-solvent difference, do not show significant dependence with respect to viscosity and/or to dielectric constant of studied solvents. Additionally, we find that in solvents that are able to evacuate the excess energy from the Franck-Condon zone, the chromophore is less likely to take a non-reactive path (return to the initial state). Consequently, the photoisomerization efficiency gets enhanced. Nevertheless, this solvent-induced enhancement is far smaller than the enhancement induced by the photocatalytic effect of the protein binding pocket. These observations lead us to conclude that in fact the dynamics of isomerization in protein are essentially determined by steric effects.


Background: With increased cigarette smoking worldwide, greater numbers of inflammatory diseases have been recorded. Coronary diseases, pulmonary diseases, and cancers of different types are all associated with cigarette smoking. In Saudi Arabia, people start smoking at an early age, which could lead to acceleration in immune system issues. The presence of biological parameters that could be used to diagnose possible inflammatory mechanisms would speed the discovery of new therapeutic approaches. Methodology: In this study, we examined the concentration of AAT, TNF-α and MMP-9 in serums for smokers and nonsmokers in the young Saudi male population, aged 19 to 35 years old. Results: The recorded data showed a significant increase in both TNF-α and MMP-9, with mean ± SEM as 239.5 ± 43.14 vs. 83.02 ± 11.96 with P values of 0.0004 (3571 ± 542.5 vs. 1718 ± 137.3) and 0.0430, respectively. The AAT was higher in smokers compared with the control group, even though it did not reach a significant level (7.039 ± 093 vs. 4.465 ± 0.3901). We did not record any correlation between the measured parameters and packs/year of smokers. Conclusion: In conclusion, our results confirmed the possibility of using AAT, TNF-α and MMP-9 in the early diagnosis of immune system alterations associated with smoking. Understanding the mechanisms behind the development of chronic inflammatory disease would help in the prevention of complications and enable the discovery of therapeutic agents.


In 1996 a hunting test for British gun dogs was started in Sweden, based on a similar one al-ready in place in Norway. The aim of the new test was to describe the hunting ability of the dog and to use the results as a basis for selection. However, up to now, no genetic study of these data has been done. Therefore the aim of this study was to estimate genetic parameters for the traits measured in the hunting test and to investigate whether the traits can summarized into fewer overall measures.
Data from trails of British gundogs between 1996 and 2005 in Sweden were used to estimate genetic parameters and environmental effects in hunting performance. British gundogs consist of five different breeds: Pointer, English setter (ES), Gordon setter (GS), Irish red setter (Irl S) and Irish red and white setter. The study used 7251 competition results were dogs and bitches had equal hunting performance. The pedigree data was collected from the Swedish kennel club. Because the data set was very small for Irish red and white setter, no calculations were made regarding genetic correlations and heritability.
The hunting performance included 13 different traits. Due to the few observations for five of the traits, only eight traits were used in the analysis: speed, style, hunting eagerness, bird find-ing, independence, seeking width, ability to work in the field, and cooperation. Factor analysis of these traits extracted two factors, named energy and an independent ability. Seven different traits, with the exception for the trait bird finding, were evaluated using a mixed animal model using the Restricted Maximum Likelihood method (REML). In the model, adjustment was made for year, season, class and type of performance test.
Earlier studies made by Vangen and Klemetsdal (1988) regarding hunting potential in English setters have shown that some hunting traits have a rather low to moderate heritability: 0.22 for hunting eagerness, 0.18 for field work, and style and speed, and 0.09 for cooperation. They also showed that some of the traits correlated very strongly. Vangen and Klemetsdal (1988) also indicated that hunting traits were heritable and that better systems of assessing such traits might lead to an even higher heritability which leads to a greater potential progress in selec-tion (Serpell, 1995).
The results suggested large difference in breeds regarding heritability. The estimated herita-bility for pointer was low for all traits (0.02-0.09). Gordon setter (GS) was the only breed that showed a high heritability 0.51 (independence). Except for the trait cooperation (0.01) all traits had moderate heritability in the breed GS. However, GS had few data in the study, and for that reason no firm conclusion could be drawn. Irish setter had moderate heritability (0.15-0.27) for four traits (speed, style, hunting eagerness and seeking width), whereas independ-ence, ability to work in the field and cooperation all showed low heritability (0.01-0.08). Al-most the same results were found in English setter: 0.13 (speed), 0.11 (style) and 0.12 (hunt-ing eagerness). The remaining traits showed very low heritabilities.
The repeatability was very variable (0.03-0.51), where GS had the highest values. A high re-peatability can partly be explained by a high additive variance, but also from the fact that the performance test and the judge are relatively reliable.
The genetic correlations were positive and very high for almost all traits. Correlations close to 1.0 were found in ES and GS (hunting eagerness and independence), but also between the traits seeking width and independence (ES). The phenotypic correlations were lower in com-parison with the genetic correlations and showed almost the same results for all breeds: speed, style and hunting eagerness correlated very strongly. Regarding permanent environmental correlations, GS showed high negative values in some traits, possibly owing to too few dogs in the study.
The new traits created based on the factor analysis, named energy and independent ability, showed heritabilities of 0.14 (ES), 031 (GS), 0.22 (Irl S) and 0.06 (pointer), and 0.1 (ES), 0.18 (GS), 0.15 (Irl S) and 0.07 (pointer), respectively. The correlations between the new compo-site traits were all positive, moderate to high.
Because of the low to moderate heritabilities in nearly all traits the evaluation of breeding values should be based on progeny and sib testing instead of performance testing only. The animal model, Best Linear Unbiased Prediction (BLUP) would be a useful method when breeding for hunting traits. Furthermore, more records have to be collected before any further conclusions can be drawn.


School theatre productions are performed throughout Australian secondary schools each year. Currently Broadway model musicals are often performed as the content of these school productions. The examination of the secondary school production involved in this research focuses upon a Victorian coeducational government secondary school's collaborative rewrite, rehearsal and performance of A Midsummer Night's Dream.
Drawing from literature in Drama in Education, Theatre in Education, Applied Theatre, Australian Curriculum documents, Pedagogy, Authentic Learning, Extra-curricular education and Creativity, the question, 'The school production – To be or not to be?' Deals with the very nomenclature of the school production by examining the following two questions:
1. What are the experiences and benefits for the students involved in the authentic model of school production?
2. What is the teacher's experience while working on an authentic school production?


The soil bacterium Streptomyces peucetius produces two widely used anticancer antibiotics doxorubicin and daunorubicin. Present within the biosynthesis gene cluster in S. peucetius is the drrAB operon which codes for a dedicated ATP-binding cassette type transporter for the export of these two closely related antibiotics. DrrAB system was believed to be the single-drug transporter due to its dedicated nature; however, our study demonstrated under both in vivo and in vitro conditions that DrrAB system can transport not only doxorubicin but also Hoechst 33342 and ethidium bromide. Moreover, many other well-studied multi-drug resistance proteins substrates (including verapamil, vinblastine and rifampicin) inhibit DrrAB-mediated doxorubicin transport, indicating they are also substrates of DrrAB pump. Kinetic studies show competitive inhibition of doxorubicin transport by Hoechst 33342 and rifampicin and noncompetitive inhibition by verapamil, suggesting the possibility of more than one drug binding site in the DrrAB system. This is the first in-depth study of a drug resistance system from a producer organism, and it shows that a dedicated efflux system like DrrAB contains specificity for multiple drugs. Our study also provides the first direct evidence for the dual role of the metalloprotease FtsH in the biogenesis of membrane proteins. We found that FtsH is not only responsible for proteolysis of unassembled DrrB protein but it also plays a much broader role in biogenesis of the DrrAB complex. DrrA and DrrB proteins expressed together in a temperature sensitive ftsH mutant strain were found to be non-functional due to their incorrect assembly. Simultaneous expression of wild-type FtsH in trans resulted in normal doxorubicin efflux. Strikingly, doxorubicin efflux could be restored in mutant cells irrespective of whether FtsH was expressed simultaneously with DrrAB or expressed after these proteins had already accumulated in an inactive conformation, thus providing crucial evidence for the ability of FtsH to refold the misassembled proteins. Complementation experiments also showed that the catalytic ATP binding domain of FtsH contains a chaperone-like activity, however both the catalytic and the proteolytic domains of FtsH are required to be present and work coordinately to participate in biogenesis of DrrAB complex in the membrane. INDEX WORDS: Multi-drug Resistance, ABC transporter, DrrAB, FtsH, Drug efflux CHARACTERIZATION OF DRRAB COMPLEX FROM STREPTOMYCES PEUCETIUS AS A MULTIDRUG TRANSPORTER


The step of urbanization and modern civilization fosters different functional zones in a city, such as residential areas, business districts, and educational areas. In a metropolis, people commute between these functional zones every day to engage in different socioeconomic activities, e.g., working, shopping, and entertaining. In this paper, we propose a data-driven framework to discover functional zones in a city. Specifically, we introduce the concept of latent activity trajectory (LAT), which captures socioeconomic activities conducted by citizens at different locations in a chronological order. Later, we segment an urban area into disjointed regions according to major roads, such as highways and urban expressways. We have developed a topic-modeling-based approach to cluster the segmented regions into functional zones leveraging mobility and location semantics mined from LAT. Furthermore, we identify the intensity of each functional zone using Kernel Density Estimation. Extensive experiments are conducted with several urban scale datasets to show that the proposed framework offers a powerful ability to capture city dynamics and provides valuable calibrations to urban planners in terms of functional zones.


The purpose of the paper is to evaluate the validity of purchasing power parity (PPP) for eight countries from the Emerging Europe: Hungary,Czech Republic, Poland, Romania, Lithuania, Latvia, Serbia and Turkey. Monthly data for euro and U.S. dollar based real exchange rate time series are considered covering the period: January, 2000 - August, 2011. Given significant changes in these economies in this sample it seems plausible to assume that real exchange time series are characterized by more than one time structural break. In order to endogenously determine the number and type of breaks while testing for the presence of unit roots we applied the Lee-Strazicich approach. For two euro based real exchange rate time series (in Hungary and Turkey) the unit root hypothesis has been rejected. For the U.S. dollar based real exchange rate time series in Poland, Romania and Turkey the presence of unit root has been rejected. To assess the adjustment dynamics of those real exchange rates that were detected to be stationary with two breaks, the impulse response function is calculated and half-life is estimated. Our overall conclusion is that the persistence of real exchange rate in Emerging Europe is still substantially high. The lack of strong empirical support for PPP suggests that careful policy actions are needed in this region to prevent serious exchange rate misalignment.


This second volume of The Details of Modern Architecture continues the study of the relationships of the ideals of design and the realities of construction in modern architecture, beginning in the late 1920s and extending to the present day. It contains a wealth of new information on the construction of modern architecture at a variety of scales from minute details to general principles. There are over 500 illustrations, including 130 original photographs and 230 original axonometric drawings, arranged to explain the technical, aesthetic, and historical aspects of the building form. Most of the modern movements in architecture have identified some paradigm of good construction, arguing that buildings should be built like Gothic cathedrals, like airplanes, like automobiles, like ships, or like primitive dwellings. Ford examines the degree to which these models were followed, either in spirit or in form, and reveals much about both the theories and techniques of modern architecture, including the extent to which the current constructional theories of High Tech and Deconstruction are dependent on the traditional modernist paradigms, as well as the ways in which all of these theories differ from the realities of modern building. Individual chapters treat the work of Eliel and Eero Saarinen, Eric Gunnar Asplund, Richard Neutra, Alvar Aalto, Le Corbusier, and Louis Kahn, as well as the Case Study, High Tech, Postmodern, and Deconstructivist architects. Among the individual buildings documented are Eliel Saarinen's Cranbrook School, Asplund's Woodland Cemetery, Fuller's Dymaxion house, the Venturi house, the Eames and other Case Study houses, the concrete buildings of Le Corbusier, Aalto's Saynatsalo Town Hall, and Kahn's Exeter Library and Salk Institute -- with many details published for the first time.


Oil is a major source of income for Nigeria and it is the mainstay of the country's economy. Nigeria's intensive oil sector accounts for nearly 40% of its gross domestic product, but declined steadily to an average of 14.71% of the country's total export between 2006 and 20111; and contributed about 80% of budgetary revenues that all tiers of government heavily depend on.2 Oil spills and gas flaring are some of the effects of the unregulated exploratory activities of the oil multinational companies that have contributed immensely to the physical and mental illness of the local inhabitants of the Niger Delta region and violated most of their rights as guaranteed under international and regional human rights instruments and the Constitution of the Federal Republic of Nigeria 1999 (as amended) 1999. In view of the growing threats to human health and the environment (posed by human activities), the international community has agreed to a number of treaties to respond to the health and human rights challenges posed by environmental degradation. Although Nigeria is a party to most of these instruments,3 it has done little or nothing to regulate the conduct of the oil companies that negatively impact on the health of the Niger Delta people. While the impact of oil extraction affects both men and women, the article focuses on its implications for women's reproductive well-being. This is because women are a disadvantaged and marginalised group and have continued to experience discriminatory practices in many parts of the country, including the Niger Delta area. The article discusses the health challenges associated with oil exploitation in the Niger Delta, paying attention to the position of women. It then proffers suggestions on measures and steps that could be taken by the Nigerian government and other stakeholders in ensuring the adequate protection of the health rights of local inhabitants.


1 The collective efficiency model contends that joint action is essential for coping with new challenges. This paper discusses how enterprises in the Lake Victoria fish cluster operate, interact and address common challenges facing the industry. It suggests that the lack of effective institutions and the existing power relations explain the inability of the cluster to respond effectively to recent crises. Both the Co-operative Society and the Fisheries Department are weak, whereas the existing welfare based associations merely exploit social capital in sub-ethnic groups. These groupings have not transcended welfare concerns into the economic realm, and their potential for taking strategic joint action is limited. The cluster's strongest joint action has been vertical, between one successful trader and one Industrial Fish Processor (IFP). This action saved the cluster from imminent collapse, but it did not result in the creation of institutions or organisations capable of dealing with other problems. The results uphold the collective efficiency model in the sense that they underscore the need for joint action in the face of new challenges. The findings also call for extension of the model to consider more explicitly the institutional framework that appears necessary for effective joint action to take place.


Background and Purpose: Fluoride is a natural element essential for human nutrition due to its benefits for dental enamel. It is well-documented that standard amounts of fluoride in drinking-water can decrease the rate of dental caries. This study was conducted with the aim of measuring fluoride concentration of drinking-water supplies and urban distribution system in Qom, Iran. Materials and Methods: Results were subsequently compared against national and international standards. All sources of drinking-water of rural and urban areas were examined. To measure fluoride, the standard SPADNS method and a DR/4000s spectrophotometer were used . Results: Results showed that the mean of fluoride concentration in rural areas, mainly supplied with groundwater sources, was 0.41 mg/L, that of the urban distribution system 0.82 mg/L, that of Ali-Abad station 0.11 mg/L, and that of the private water desalination system 0.24 mg/L. Due to the hot climate of Qom, fluoride concentration means of all sources were lower than the permissible standards set by Iranian Standards and the WHO guidelines (except those of some of the groundwater sources and urban distribution systems). Conclusion: It seems that in most of the drinking-water sources the average fluoride concentration is not enough to prevent dental caries or strengthen dental enamel. It is concluded that Qom's drinking-water would require at least 0.4 mg/L to reach the minimum desirable standard.


Article outlining concept of 'refraction' developed as part of the RIAIPE3 study – an inter-university programme exploring equity and social cohesion policies in higher education. In much of our experiences of, and research in, educational policy we see how global and national policies are often reinterpreted and redirected at local and classroom level. In this paper, we highlight some initial thoughts relating to the development of the concept of 'refraction' as a lens for both theoretical development and for informing methodological approaches and empirical investigation that may provide rich and contextualised understandings of schools and practice. As an emerging concept 'refraction' draws on a range of existing traditions and approaches in the social sciences with several key areas for exploration and investigation. Broadly however, refraction in education may be seen as a change in direction arising from individuals' and groups' own beliefs, practice and trajectories that are at odds with dominant waves of reform and policies introduced into the field. This type of 'bending' or mediation occurs in various ways and for numerous reasons and must be viewed as crucial elements for analysis, as not only do they highlight alternative and pre-figurative antecedents, forms and models of practice, they also illustrate the interaction between ideology and structures and individual and collective practice and action. Firstly, from this perspective, we suggest that research in the field should be contextualised and analysed in relation to historical periodisation and the broader movements, cycles and waves of reform. Secondly, in researching current practice within a broader social-historical context, we can better understand and illuminate the effects of ideology and power and how these are exerted through policies. However, such analyses alone would imply a sense of determinism, with power and ideology as totalising and actors as merely passive and subject to its effects. Analyses therefore, need to account for and examine alternative discourse, movements and practice and the conditions under which they occur. Moreover, in attempting to address the dichotomy of structure and agency, there is a need to elicit qualitative accounts of practitioners in order to explore how, and to what extent, their own trajectories, life histories and professional identities influence their practice, mediate policies and negate the effects of ideology and power. Furthermore, approaches that elucidate pre-figurative practice, politics, discourse and language through narrative inquiry, and the ways in which actors make meaning of their own lives and professional practice, not only offer us detailed pictures of subjective realities but also allow us to highlight alternative practices and oppositional discourses that are often overlooked, or brushed aside, in official discourse. Set against the current period of significant social and political upheaval and uncertainty, we are witnessing threats to the prevailing and dominant perspectives and related policies that have orientated the form of education in the neo-liberal era. Whether the current financial crisis will result in the continued reassertion of more efficacious forms of neo-liberalism and privatisation, or whether competing discourses, ideologies and traditions will begin to influence the organisation and form of education remains to be seen. However, given such unprecedented changes, it is vital we develop conceptual tools that will enable us to investigate and explore changes in policy and practice and the conditions that inform acts of refraction between them, thereby placing context and history as central to explorations (Goodson & Norrie, 2005). As we shall see, the historical periodisation depends a good deal on cultural factors and these are refracted in very different ways in different continents and cultures.


Predictions about global climate change have produced both stark scenarios of environmental catastrophe and purportedly pragmatic ideas about adaptation. This book takes a different perspective, exploring the idea that the challenge of adapting to global climate change is fundamentally an ethical one, that it is not simply a matter of adapting our infrastructures and economies to mitigate damage but rather of adapting ourselves to realities of a new global climate. The challenge is to restore our conception of humanity -- to understand human flourishing in new ways -- in an age in which humanity shapes the basic conditions of the global environment. In the face of what we have unintentionally done to Earth's ecology, who shall we become? The contributors examine ways that new realities will require us to revisit and adjust the practice of ecological restoration; the place of ecology in our conception of justice; the form and substance of traditional virtues and vices; and the organizations, scale, and underlying metaphors of important institutions. Topics discussed include historical fidelity in ecological restoration; the application of capability theory to ecology; the questionable ethics of geoengineering; and the cognitive transformation required if we are to "think like a planet."


This paper is made to describe the Site Aspects category which is one of the main categories of the proposed sustainable rating & certification system for new construction in Egypt presented by the accredited Ph.D. research made by the above author and coauthors for the purpose of promoting the sustainable building practices and embracing the potential of green buildings in Egypt.

Some of the current international sustainable rating systems segregate the site elements into two categories; the first category is concerned with selection of site location, and the second category is concerned with sustainable sites design matters for the site development proposed works, while both categories are combined together in one uniform category called the Site Aspects in the accredited Ph.D. research to avoid the overlap and similarity of scope of some credits/issues and to offer a complete sustainable framework of all site requirements.

The Site Aspects category, as described below, is having an assembly of mandatory and scoring credits based on the sustainability three bottom lines; environmental, social, and economical aspects which can help in a better selection of project site location and can participate in more appropriate sustainable designs for the project's site development.


Globalisation has set in a new trend in Indian news media wherein the once leading news agencies are steadily losing their traditional hold on daily newspapers and slowly getting marginalised in the process. The shrinking presence of news stories from leading news agencies in news dailies is a sure indicator of the ill-effects of globalisation on Indian news media. The role of news agencies, as the main supplier of news, has steadily declined over the past two decades. The present study considers the quantum of news stories from the Indian news agencies to critically examine their position in the overall news coverage, both from temporal and cross-sectional perspective. The study utilises content analysis, a specific research approach used frequently in all areas of the media, to examine the contents of the newspapers to test the validity of the argument that the role of Indian news agencies is shrinking in the wake of globalisation. The study aims at identifying and analysing distinct trends in the world of news agency journalism with the help of data generated after content analysis of five leading dailies -- four in English and one in Hindi. Four English dailies representing four regions of the country are The Times of India from the West, The Tribune from the North, The Statesman from the East, and The Hindu from the South. The Hindi daily is Punjab Kesari. National news agencies covered under the study are PTI, UNI (English) and Hindusthan Samachar (Hindi). Specifically, the study examines the quantum and percentage of news items taken from Indian news agencies both before and after globalisation. The temporal axis analysis covers a period of 20 years beginning with 1985 at a five year gap, i.e. 1985, 1990, 1995, 2000 and 2005 for a period of one week each for content analysis.


We obtain a new solution of the star-triangle relation with positive Boltzmann weights which contains as special cases all continuous and discrete spin solutions of this relation, that were previously known. This new master solution defines an exactly solvable 2D lattice model of statistical mechanics, which involves continuous spin variables, living on a circle, and contains two temperature-like parameters. If one of the these parameters approaches a root of unity (corresponds to zero temperature), the spin variables freezes into discrete positions, equidistantly spaced on the circle. An absolute orientation of these positions on the circle slowly changes between lattice sites by overall rotations. Allowed configurations of these rotations are described by classical discrete integrable equations, closely related to the famous $Q_4$-equations by Adler Bobenko and Suris. Fluctuations between degenerate ground states in the vicinity of zero temperature are described by a rather general integrable lattice model with discrete spin variables. In some simple special cases the latter reduces to the Kashiwara-Miwa and chiral Potts models.


INTRODUCTION: Gallstone disease (GSD) represents a significant burden for health-care systems worldwide and is one of the most common disorders among patients presenting to emergency rooms with abdominal discomfort. This study was aimed to know the association of biochemical parameters and development of GSD. MATERIALS AND METHODS: We conducted a case–control study from January 2013 to December 2013 among patients attending outpatient department of general surgery at a tertiary care hospital of Delhi, North India; we recruited 120 cases and the same number of controls in the study. Data collection for both cases and controls was done on a self-designed pretested interview schedule and all the patients were investigated for relevant biochemical parameters. Logistic regression was used for univariate and multivariate analyses to find out different correlates and analyze the independent effects of these correlates on GSD. RESULTS: We have included 120 cases and the same number of age- and sex-matched controls in the study and final analysis. Almost 70% of the cases were females and 30% were males. In multivariate logistic regression, we have found maximum significant association with serum total cholesterol (odds ratio [OR]: 1.013, confidence interval [CI]: 1.003–1.024, P = 0.041) followed by low-density lipoprotein (LDL) cholesterol (OR: 1.017, CI: 1.001–1.034, P = 0.04) and triglycerides (OR: 1.009, CI: 1.001–1.018, P = 0.049). Fasting blood sugar (P = 0.18), high-density lipoprotein cholesterol (P = 0.07), aspartate transaminase (P = 0.21), alanine transaminase (P = 0.29), and total bilirubin (P = 0.13) were not found to be independently associated with GSD. CONCLUSION: Biochemical parameters such as plasma total cholesterol, triglycerides, and LDL cholesterol level were independently associated with GSD.


ABSTRACT This paper builds on recent work on "third spaces" to analyze political talk in comments on news about nonpublic affairs. It draws on content and discourse analyses of comments on news published by a leading Costa Rican media organization on Facebook. The article develops five categories of issues that triggered political talk (institutionality, identity, political inclinations, factual aspects, and criticism of the media) and examines the discursive strategies through which these comments became political. This allowed to broaden understanding of the political relevance of discussions about nonpublic affairs on social media.


The field of non-invasive ventilation continues to expand rapidly since publication of the second edition of Non-Invasive Respiratory Support, new controversies have arisen and numerous practical guidelines have been issued. This expanded third edition with new international contributors has been fully revised and updated. It builds on the success of the highly-regarded previous editions, detailing the role of non-invasive ventilation (NIV) in acute and chronic ventilatory failure, and the outcome of the intervention across a wide range of respiratory disorders in adults and children. The book provides clear, step-by-step, evidence-based guidance on the practicalities of all the principal techniques, and advice is offered on indications for NIV, how to choose equipment, when to initiate therapy, and when to discontinue therapy. From a highly respected international author team, this book provides invaluable guidance to respiratory physicians, intensivists, anaesthetists, nurses, physiotherapists and medical technicians working in this area.


A series of numerical simulations of tropical cyclones in idealized large-scale environments is performed to examine the effects of vertical wind shear on the structure and intensity of hurricanes. The simulations are performed using the nonhydrostatic Pennsylvania State University‐National Center for Atmospheric Research fifth-generation Mesoscale Model using a 5-km fine mesh and fully explicit representation of moist processes. When large-scale vertical shears are applied to mature tropical cyclones, the storms quickly develop wavenumber one asymmetries with upward motion and rainfall concentrated on the left side of the shear vector looking downshear, in agreement with earlier studies. The asymmetries develop due to the storm's response to imbalances caused by the shear. The storms in shear weaken with time and eventually reach an approximate steady-state intensity that is well below their theoretical maximum potential intensity. As expected, the magnitude of the weakening increases with increasing shear. All of the storms experience time lags between the imposition of the large-scale shear and the resulting rise in the minimum central pressure. While the lag is at most a few hours when the storm is placed in very strong (15 m s21) shear, storms in weaker shears experience much longer lag times, with th e5ms 21 shear case showing no signs of weakening until more than 36 h after the shear is applied. These lags suggest that the storm intensity is to some degree predictable from observations of largescale shear changes. In all cases both the development of the asymmetries in core structure and the subsequent weakening of the storm occur before any resolvable tilt of the storm's vertical axis occurs. It is hypothesized that the weakening of the storm occurs via the following sequence of events: First, the shear causes the structure of the eyewall region to become highly asymmetric throughout the depth of the storm. Second, the asymmetries in the upper troposphere, where the storm circulation is weaker, become sufficiently strong that air with high values of potential vorticity and equivalent potential temperature are mixed outward rather than into the eye. This allows the shear to ventilate the eye resulting in a loss of the warm core at upper levels, which causes the central pressure to rise, weakening the entire storm. The maximum potential vorticity becomes concentrated in saturated portions of the eyewall cloud aloft rather than in the eye. Third, the asymmetric features at upper levels are advected by the shear, causing the upper portions of the vortex to tilt approximately downshear. The storm weakens from the top down, reaching an approximate steady-state intensity when the ventilated layer can descend no farther due to the increasing strength and stability of the vortex at lower levels.


Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. ALS is a fatal neurodegenerative disease and clinical diagnosis typically takes many months to complete. Early disease diagnosis through the use of biomarkers may aid in correct clinical management of patients and possibly delay time to ventilator and morbidity. This review explores the progress of biomarker discovery efforts for ALS and the many challenges that remain. Included are different technologies utilized in biomarker discovery efforts (proteomic, genomic and metabolomic) and putative biomarkers uncovered using these techniques. These studies have discovered genetic mutations leading to familial forms of ALS, and specific protein alterations that occur in biological fluids (cerebrospinal fluid and blood) and/or tissues of ALS subjects. More recent high-throughput technologies have revealed panels of proteomic or metabolic biomarkers that can discriminate between ALS and control groups. The identification of disease-specific biomarkers will provide opportunities to develop early diagnostic measures as well as surrogate markers to monitor disease progression and test drug efficacy in clinical trials.


Supercritical extraction using carbon dioxide was carried out in a semi-continuous mode on the binder and its components of an acrylate-based system, the results of which were compared with a poly (vinyl butyral)-based system. To investigate the contribution of each of the binder components to overall weight loss of the acrylic-based binder, pure components as well as combination of different components were subjected to supercritical extraction. To enhance the extraction of binder, co-solvents were evaluated on the most extractable binder component and an optimal co-solvent loading was determined. Supercritical extraction experiments were then carried out and the effect of the co-solvent on the extraction profiles was examined. Enhancement in extraction was observed for the acrylic-based system whereas no overall enhancement was observed for the poly (vinyl butyral)-based system. To interpret the dynamics of supercritical extraction, diffusivities of the binder components of the acrylic-based and the poly (vinyl butyral based) multilayer ceramic capacitors were calculated, and were found to be in the same order of magnitude. Finally, visual analysis was performed on the acrylic-based system to suggest a mechanism that led to defects in these green ceramic bodies after the extraction process. Supercritical extraction with carbon dioxide at 10-40 MPa and 55-90°C was used to remove binder from multilayer green ceramic bodies. Defects such as cracking and delamination were occasionally observed in the green bodies following the extraction process, and these defects were attributed to pressure gradients that arise during depressurization from conditions of supercritical extraction. A model based on flow in porous media was thus developed to describe the temporal and spatial distribution of pressure within the green body during depressurization. The model incorporated the Peng-Robinson cubic equation of state to describe the pressurevolume-temperature behavior of the supercritical carbon dioxide, and the effect of changes in the viscosity of the supercritical fluid. The effects of the body size and gas-phase permeability on the pressure within the green body were examined.


A single turbiditic coarse limestone layer (thickness up to 10 cm), interpreted as distal calciturbidite, is described for the first time from the Lower Cretaceous Schrambach Formation of the Lunz Nappe (Kaltenleutgeben section, Northern Calcareous Alps). It is composed almost exclusively of bioclasts derived from echinoids (about 50 %), bryozoans, coralline red algae, foraminifers, and remains of stromatoporoids and belemnoids; calcareous green algae are missing. The stratigraphic age of this layer is Late Hauterivian based on the findings of the Euptychoceras Abundance Zone. The biota, indicate a source area in an upper slope position marking the transition to shallow-water areas. This is the first record of a shallow-water evolution in the Northern Calcareous Alps from the time-interval between the Barmstein limestones (Late Tithonian—Late Berriasian), the Plassen Formation (up to Early/ Middle Berriasian) and the allochthonous Urgonian limestones (since Late Barremian onwards). A relationship to equivalent biodetritus within the Rossfeld Formation, which currently lacks biostratigraphic data, is possible. Finally, transportation from southern directions is assumed due to the occasional occurrence of chrome spinel and the nappe tectonic position of the locality.


Theoretical and empirical models of legislative decision making in parliamentary democracies typically neglect the policy preferences of individual MPs and instead focus on political parties and possible institutional constraints. We argue that MPs actually make judgments and decisions on the basis of their preferences, which are shaped by their personal characteristics. However, given the strength of parties in most parliamentary systems, the impact of personal characteristics on legislative behavior is rarely visible. Therefore, we examine a moral issue. Looking at cosponsorship, parliamentary speeches, and votes in the German Bundestag, we analyze the legislative procedure on the regulation of preimplantation genetic diagnosis (PGD) in Germany in 2011. We show that the legislative behavior of MPs does not only reflect partisan conflict but is also influenced by the preferences of the constituents and MPs' own personal characteristics such as: religious denomination, gender, and parental status.


The Mediterranean is an invented cultural space, on the frontier between North and South, West and East. Modern Art and the Idea of the Mediterranean examines the representation of this region in the visual arts since the late eighteenth century, placing the 'idea of the Mediterranean' - a cultural construct rather than a physical reality - at the centre of our understanding of modern visual culture. This collection of essays features an international group of scholars who examine competing visions of the Mediterranean in terms of modernity and cultural identity, questioning and illuminating both European and non-European representations. An introductory essay frames the analysis in terms of a new spatial paradigm of the Mediterranean as a geographic, historical, and cultural region that emerged in the late eighteenth century, as France and Britain colonized the surrounding territories. Essays are grouped around three vital themes: visualization of the space of the new Mediterranean; varied uses of the classical paradigm; and issues of identity and resistance in an age of modernity and colonialism. Drawing on recent geographical, historical, cultural and anthropological studies, contributors address the visual representation of identity in both the European and the 'Oriental,' the colonial and post-colonial Mediterranean.


This paper presents a method to detect buildings in terrestrial images. High resolution terrestrial images are normally taken from land survey vehicles. These images and other surveyed data along roads are needed by many agencies that require new data as time passes by. Land use in rural area is an example that needs information about buildings and can benefit from terrestrial images. The proposed method was aimed to detect buildings in terrestrial images to benefit the above needs. The method consists of two stages. The first stage removes unwanted objects, performs image segmentation, and finds regions of interest. Image processing techniques such as greenness extraction, sky detection, color segmentation, color detection, shape detection are used. The second stage performs building detection. It includes the possible building parts detection, projection profiles finding, and the building determination. The method can identify a partial building if the whole building is not shown in an image. The proposed method was tested on 936 images (332 images with buildings and 604 images without buildings). The images were from Google Street View. The accuracy was determined by human inspection. The method gave promising results with an average accuracy of 82.5%. Positive faults were 4.7% average. 


The paper commences with a briefing on the state of telecommunications in developing countries, Nepal being the prime example. The paper goes on to examine the procedures followed to establish Nepal Internet Users' group(NIUG); a non-profit NGO established to facilitate access to internet technologies through intranet in a cost-effective manner.

In establishing this network, the group was assisted by the Electronic Networking Project of the International Center for Integrated Mountain Development (ICIMOD)—a project funded by International Development Research Center (IDRC), Canada and responsible for establishing NepalNet , a group of development organisations through which a joint home page was registered on the worldwide web. The backward and forward linkages are explored—and this includes the difficulties of establishing IT networks in countries in which governments maintain a monopoly on telecommunication facilities. How these were overcome, the equipment acquired, and the partnerships formed are all given a place in this paper. The paper concludes with a brief on costs and the plans for the future, especially the role of IT in development research.


A 63-year-old male patient with hematuria and flank pain was admitted. Radiological evaluation revealed S-shaped, left-to-right cross-renal ectopia with a renal mass localized in the upper pole of the right kidney. Three-dimensional computed tomography (3D-CT) showed that the orthotopic moiety had 1 artery and 2 veins, and the ectopic moiety had 1 artery and 1 vein. A nephron-sparing partial nephrectomy was performed. The pathological diagnosis was collecting duct carcinoma with sarcomatoid differentiation. Using 3D-CT, we were able to achieve the appropriate preoperative surgical planning for this challenging case. To our knowledge, this is the first case report of collecting duct carcinoma with sarcomatoid differentiation in a cross-fused renal ectopic kidney.


"There is more value on a single page of Seeds of Change than in a yeara's worth of Rush Limbaugh screeds combined with a lifetime of Sarah Palin sneers at community organizers.ai?? --Todd Gitlin. Seeds of Change goes beyond the headlines of the last Presidential campaign to describe what really happened in ACORN's massive voter registration drives, why it triggered an unrelenting attack by Fox News and the Republican Party, and how it confronted its internal divisions and scandals. Based on Atlas's own eyewitness original reporting, as the only journalist to have access to ACORN's staff and board meetings, this book documents the critical transition from founder Wade Rathke, a white New Orleans radical to Bertha Lewis, a Brooklyn African American activist. The story begins in the 1970s, when a small group of young men and women, led by a charismatic college dropout, began a quest to help the powerless help themselves. In a tale full of unusual characters and dramatic conflicts, the book follows the ups and downs of ACORN's organizers and members as they confront big corporations and unresponsive government officials in Albuquerque, Brooklyn, Chicago, Detroit, Little Rock, New Orleans, Philadelphia, and the Twin Cities. The author follows the course of local and national campaigns to organize unions, fight the subprime mortgage crisis, promote living wages for working people, struggle for affordable housing and against gentrification, and help Hurricane Katrina's survivors return to New Orleans. The book dispels the conservative myth that we can only help the poor through private soup kitchens and charity and the liberal myth that the solution rests simply with more government services. Seeds of Change, not only provides a gripping look at ACORN's four decades of effective organizing, but also offers a hopeful analysis of the potential for a revival of real American democracy.


Between 1814 and 1831, French slave traders trafficked approximately 200,000 individuals. Among those, a small but still surprising number stopped over in Haiti on their return voyage after selling captives elsewhere in the Americas. Using the case of the brigantine the Marcelin as its prime example, this article shows how legitimate commodity trading with Haiti served as a cover for illicit French slaving in the era of slave-trade abolition. The article situates the Marcelin within a "second slave trade," which emerged as European countries abolished the transatlantic trade on paper but continued it in practice. Because the second slave trade was illegal, it left a very limited historical trace. This article reconstructs its contours from fragmentary archival evidence, while arguing that, ultimately, the archive itself does violence to the history of the nineteenth-century slave trade.


The viscous seminal plasma (SP) is currently a major impediment to the handling of ejaculate and the development of some biotechnologies in South American camelids. The vas deferens-collected spermatozoa of alpacas is a useful technique to avoid this problem. On the other hand, SP contains a large protein component that has been implicated in the function of spermatozoa within the female reproductive tract. In this sense, the low fertility achieved using transcervical insemination with frozen-thawed spermatozoa in alpacas could be improved by adding SP. This study aimed to evaluate the effect of the whole SP on some in vitro parameters of alpaca spermatozoa after the freezing-thawing-process and the fertility after artificial insemination. It would contribute to a better understanding of the interaction between thawed sperm cells and SP. Spermatozoa were obtained by surgically diverted vas deferens. The samples were diluted with a Tris-based extender, packaged in straws, and frozen. At thawing, each straw was divided into two post-thawing conditions: with the addition of 10% of PBS (control) or with 10% SP (treatment). The sperm cells were evaluated using dynamic parameters, sperm cell morphology, and morphometry. Fertility was assessed by an artificial insemination trial. All in vitro parameters were analyzed by ANOVA. A heterogeneity test was scheduled for the fertility trial. After the freezing-thawing process, motility and plasma membrane functionality was improved when SP was added. No differences were found for post-thaw viability between the control and treatment samples. The percentage of normal cells was higher with SP at post-thawing, and a decrease of the presence of bent tailed spermatozoa with a droplet in the SP group was observed. The length of the head spermatozoa was 3.4% higher in the samples with PBS compared to those in which SP was added. Females pregnant at day 25 post-insemination were 0/12 (with SP inside the straw) and 1/10 (without SP inside the straw). In conclusion, the presence of 10% SP at post-thawing improves sperm cells' motility, functionality, and morphology, indicating that it would be beneficial to improve the frozen-thawed alpaca's physiology spermatozoa. More fertility trials must be developed to increase this knowledge.


Diffusion-based generative models are extremely effective in generating high-quality images, with generated samples often surpassing the quality of those produced by other models under several metrics. One distinguishing feature of these models, however, is that they typically require long sampling chains to produce high-fidelity images. This presents a challenge not only from the lenses of sampling time, but also from the inherent difficulty in backpropagating through these chains in order to accomplish tasks such as model inversion, i.e. approximately finding latent states that generate known images. In this paper, we look at diffusion models through a different perspective, that of a (deep) equilibrium (DEQ) fixed point model. Specifically, we extend the recent denoising diffusion implicit model (DDIM; Song et al. 2020), and model the entire sampling chain as a joint, multivariate fixed point system. This setup provides an elegant unification of diffusion and equilibrium models, and shows benefits in 1) single image sampling, as it replaces the fully-serial typical sampling process with a parallel one; and 2) model inversion, where we can leverage fast gradients in the DEQ setting to much more quickly find the noise that generates a given image. The approach is also orthogonal and thus complementary to other methods used to reduce the sampling time, or improve model inversion. We demonstrate our method's strong performance across several datasets, including CIFAR10, CelebA, and LSUN Bedrooms and Churches.


In his book, America's Unwritten Constitution, Akhil Reed Amar contends that to properly engage the written Constitution, scholars and laymen alike must look to extratextual sources: among them America's founding documents, institutional practices, and ethos, all of which constitute Amar's "unwritten Constitution." In this Article, I argue that contemporary originalist constitutional theory is consistent with reliance on extraconstitutional sources in certain circumstances. I establish a framework for revaluating the use of extratextual sources. That framework categorizes extratextual sources and explains their relevance to constitutional interpretation (the meaning of the text) and constitutional construction (elaboration of constitutional doctrine and decision of constitutional cases). I conclude by applying the framework to a question posed by Akhil Amar: Can vice presidents preside over their own trial upon impeachment? A negative answer to this question is consistent with an originalist constitutional theory that carefully cabins the use of extratextual sources in constitutional interpretation and construction.


The design, synthesis, characterization and biological properties of a Pt(iv) complex containing the very active inhibitor of histone deacetylase (2-propynyl)octanoic acid, POA, as an axial ligand are reported here. The title complex, namely (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(iv), 1, containing POA in racemic or in enantiomeric forms, was one/two orders of magnitude more active than cisplatin, depending on the chemo-sensitivity of the cancer cell lines. Moreover, 1 exhibited similar or even better antiproliferative activity than (OC-6-33)-diamminedichloridobis(2-propylpentanoato)platinum(iv), 2, containing two molecules of the well-known histone deacetylase inhibitor 2-propylpentanoic (valproic) acid. The high potency of 1 is likely due to its high cellular accumulation and to the synergism between the DNA-damaging cisplatin and the histone deacetylase inhibitor POA, both released upon the intracellular reduction of 1. Prodrug 1, after oral administration, caused an impressive reduction of the tumor mass (94%) in a model of solid tumor (murine Lewis lung carcinoma), compared to that of the control, whereas (intraperitoneal) cisplatin induced a tumor regression of 75% only. A good accumulation of 1 was observed in the tumor mass. The time course of the body weight attested that cisplatin induced elevated anorexia, whereas treatment with 1 did not induce significant body weight loss throughout the therapeutic experiment.


In 1976 Maxine Hong Kingston burst into American literature with the publication of The Woman Warrior: Memoirs of a Girlhood Among Ghosts. Since then her subsequent works--China Men (1980) and Tripmaster Monkey: His Fake Book (1989)--have startled readers with their complex projections of Asian-American life as a bi-cultural and bilingual adventure filled with contemporary confusions and ancient legends, inherited values, and new loyalties. Kingston has written of her family upbringing in Stockton, California, of the stories her mother told her as advice and warning, of her father's illegal arrival in the United States, of the exploits of grandfathers who worked on the rails in California, of San Francisco street life in the 1960s, and of traditional Chinese legends. Whatever her subject, she claims America for herself and other Asian Americans whose histories are an essential part of the larger American tapestry. In this collection of interviews Kingston talks about her life, her writing, and her objectives. From the first, her books have hovered along the hazy line between fiction and nonfiction, memoir and imagination. As she answers her critics and readers, she both clarifies the differences and exults in the difficulties of distinguishing between the remembered and the re-created. She explains how she worked to bridge her parents' Chinese dialect with American slang, how she learned to explore her inheritance and find new relevance in her mother's "talk stories," and how she developed the complex juxtapositions of myths and memoir that fill her books. Always savvy, often provocative, constantly amused and amusing, Kingston provides a vivid commentary on her writing and offers insight into a body of her work.


This dissertation explores how female gender identity is continually created and re-created in Egypt through a number of daily practices, of which female circumcision is central. In order to do so, the study inquires into the lived experiences and social meanings of female circumcision and femininity as narrated by women from lower class neighbourhoods in Cairo. The study seeks to understand how the experiences of femininity and female circumcision are shaped and challenged by the social and political changes that impinge on these women's lives.Female circumcision has become a global political minefield with 'Western' interventions affecting Egyptian politics and social development, not least in the area of democracy and human rights. The global human rights discourse brings about change by portraying female circumcision as mutilation. These discourses and other political and social changes both in Egypt and elsewhere, such as modernization, the aftermath of 9/11 and regional instability have together begun to dis-embed female circumcision from its socio-cultural context. This thesis focuses upon the way in which these women understand and respond to these complex changes and it looks particularly at how different actors, in their construction of female identity, contest, resist, subvert or embrace female circumcision.The study explores how the subject is made through the interplay of global hegemonic structures of power and the most intimate sphere, which has been exposed in the international arena. The need to understand agency as the capacity to act according to the exigencies of the specific sociocultural forms the main premise of this dissertation; the Egyptian context comprises the complex interaction between the local and a variety of wider global forces.


Behavioral Economics is the combination of psychology and economics that investigates what happens in markets in which some of the agents display human limitations and complications. We begin with a preliminary question about relevance. Does some combination of market forces, learning and evolution render these human qualities irrelevant? No. Because of limits of arbitrage less than perfect agents survive and influence market outcomes. We then discuss three important ways in which humans deviate from the standard economic model. Bounded rationality reflects the limited cognitive abilities that constrain human problem solving. Bounded willpower captures the fact that people sometimes make choices that are not in their long-run interest. Bounded self-interest incorporates the comforting fact that humans are often willing to sacrifice their own interests to help others. We then illustrate how these concepts can be applied in two settings: finance and savings. Financial markets have greater arbitrage opportunities than other markets, so behavioral factors might be thought to be less important here, but we show that even here the limits of arbitrage create anomalies that the psychology of decision making helps explain. Since saving for retirement requires both complex calculations and willpower, behavioral factors are essential elements of any complete descriptive theory.


Ecosystem services (ES) are increasingly recognized as a means to facilitate adaption to environmental change. However, the provisions of ES are likely to be impacted by changes in climate and/or changes in land use. In developing countries, where people are typically dependent on these services for their livelihoods, these impacts are of concern; however, very little is known about the changes in provisioning of ES over time. In this study, we assess the perceived changes on ES in the Panchase Mountain Ecological Region of western Nepal. The study area accommodates three distinct ecoregions, ranging from lowland to upland ecosystems and communities. Focus group discussions and key informant interviews were used to collect information on how ES may have changed in the landscape over time. This approach was supported by transect walks, field observations, and secondary sources of information, such as climatic and remote sensing data. Perceived changes on ES in the study region include reduced availability of water, reduced food production, degradation of forest ecosystems, and changes in species compositions. These changes are thought to have impacted other ES, and, in turn, local livelihoods. Management actions that can help local communities foster ES are recommended.


Amphiphilic block copolymers consisting of poly(ethylene oxide) and poly(lactide) have great potential for formulating drug delivery systems. Our approach was to synthesize poly(ethylene oxide-b-D,L-lactide), (PEO-b-PDLLA), block copolymers with controlled molecular weights and good functionality on the poly(ethylene oxide) end for the design of potential core-shell delivery vehicles for HIV drugs. PEO-b-PDLLA block copolymer was used as a polymeric nanocarrier to encapsulate the HIV protease inhibitor, Ritonavir, within magnetite nanoparticles. Well-defined multifunctional polymeric nanoparticles with controlled sizes and size distributions were fabricated by rapid nanoprecipitation using blends of the PEO-b-PDLLA block copolymer with poly(L-lactide), (PLLA) homopolymer. Heterobifunctional PEO oligomers were directly prepared by initiating ethylene oxide with functional alcohols bearing vinylsilane, vinylether and maleimide moieties to provide appropriate end groups for conjugating targeting ligands. The polyethers with narrow molecular weight distributions were utilized as macroinitiators for the synthesis of poly(lactide) block. Heterobifunctional diblock copolymers possessing carboxylic acids were prepared from ene-thiol addition reaction of mercaptoacetic acid across the vinyl group on the PEO end, while preserving the hydroxyl functionality on the other end. Additionally, PDLLAs bearing maleimide functionality with controlled molecular weights were synthesized using maleimide functional initiator. End group modification was performed via


To anticipate the response of fish populations to climate change, we developed a framework that integrates requirements in all life stages to assess impacts across the entire life cycle. The framework was applied on plaice (Pleuronectes platessa) and Atlantic herring (Clupea harengus) in the North Sea, Atlantic cod (Gadus morhua) in the Norwegian/Barents Seas and European anchovy (Engraulis encrasicolus) in the Bay of Biscay. In each case study, we reviewed habitats required by each life stage, habitat availability, and connectivity between habitats. We then explored how these could be altered by climate change. We documented environmental processes impacting habitat availability and connectivity, providing an integrated view at the population level and in a spatial context of potential climate impacts. A key result was that climate-driven changes in larval dispersion seem to be the major unknown. Our summary suggested that species with specific habitat requirements for spawning (herring) or nursery grounds (plaice) display bottlenecks in their life cycle. Among the species examined, anchovy could cope best with environmental variability. Plaice was considered to be least resilient to climate-driven changes due to its strict connectivity between spawning and nursery grounds. For plaice in the North Sea, habitat availability was expected to reduce with climate change. For North Sea herring, Norwegian cod and Biscay anchovy, climate-driven changes were expected to have contrasting impacts depending on the life stage. Our review highlights the need to integrate physiological and behavioural processes across the life cycle to project the response of specific populations to climate change.


Laser light excitation of fluorescent markers offers highly sensitive and specific analysis for bio-medical or chemical analysis. To profit from these advantages for applications in the field or at the point-of-care, a plastic lab-on-a-chip with integrated organic semiconductor lasers is presented here. First order distributed feedback lasers based on the organic semiconductor tris(8-hydroxyquinoline) aluminum (Alq3) doped with the laser dye 4-dicyanomethylene-2-methyl-6-(p-dimethylaminostyril)-4H-pyrane (DCM), deep ultraviolet induced waveguides, and a nanostructured microfluidic channel are integrated into a poly(methyl methacrylate) (PMMA) substrate. A simple and parallel fabrication process is used comprising thermal imprint, DUV exposure, evaporation of the laser material, and sealing by thermal bonding. The excitation of two fluorescent marker model systems including labeled antibodies with light emitted by integrated lasers is demonstrated.


We describe the design, manufacture, and performance of bare-fiber integral field units (IFUs) for the SDSS-IV survey Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) on the the Sloan 2.5 m telescope at Apache Point Observatory. MaNGA is a luminosity-selected integral-field spectroscopic survey of 104 local galaxies covering 360–1030 nm at R ∼ 2200 ?> . The IFUs have hexagonal dense packing of fibers with packing regularity of 3 μm (rms), and throughput of 96 ± 0.5% from 350 nm to 1 μm in the lab. Their sizes range from 19 to 127 fibers (3–7 hexagonal layers) using Polymicro FBP 120:132:150 μm core:clad:buffer fibers to reach a fill fraction of 56%. High throughput (and low focal-ratio degradation (FRD)) is achieved by maintaining the fiber cladding and buffer intact, ensuring excellent surface polish, and applying a multi-layer anti-reflection (AR) coating of the input and output surfaces. In operations on-sky, the IFUs show only an additional 2.3% FRD-related variability in throughput despite repeated mechanical stressing during plate plugging (however other losses are present). The IFUs achieve on-sky throughput 5% above the single-fiber feeds used in SDSS-III/BOSS, attributable to equivalent performance compared to single fibers and additional gains from the AR coating. The manufacturing process is geared toward mass-production of high-multiplex systems. The low-stress process involves a precision ferrule with a hexagonal inner shape designed to lead inserted fibers to settle in a dense hexagonal pattern. The ferrule ID is tapered at progressively shallower angles toward its tip and the final 2 mm are straight and only a few microns larger than necessary to hold the desired number of fibers. Our IFU manufacturing process scales easily to accommodate other fiber sizes and can produce IFUs with substantially larger fiber counts. To assure quality, automated testing in a simple and inexpensive system enables complete characterization of throughput and fiber metrology. Future applications include larger IFUs, higher fill factors with stripped buffer, de-cladding, and lenslet coupling.


The destructiveness of major (Category 3 to 5) hurricanes along the United States Atlantic Ocean seaboard has been recognized for centuries. While the effects of hurricanes on coastal ecosystems are well known, the influence of hurricanes on pelagic seabirds is difficult to assess. During the annual Atlantic hurricane season (~1 June to 30 November), the endangered black-capped petrel Pterodroma hasitata aggregates in Gulf Stream habitats from Florida to North Carolina. On at least 8 occasions over the past century, hurricanes have driven petrels far inland (sometimes as far as the Great Lakes), suggesting the demise of 10s to 100s of individuals. This paper models >100 yr of data to characterize and compare key aspects of hurricanes that did and did not drive petrels inland. Our model suggests that the predicted increase in the frequency of Category 3 to 5 hurricanes in the region due to climate change could nearly double the expected number of wrecked petrels over the next century and place an endangered species at greater risk of extinction.


We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy.


Nuclear factor κB (NF-κB) is well known for its activity as a transcription factor that contributes to stimulation of gene expression in response to various stimuli, including infection and inflammation. One of the genes stimulated by NF-κB appears to be involved in controlling mRNA stability, thus conferring a posttranscriptional mechanism of NF-κB-mediated inhibition of gene expression. Sitcheran et al. describe an RNA sequence that confers NF-κB-mediated mRNA destabilization. MyoD and Sox9 are two transcriptional regulators that contribute to mesenchymal differentiation to muscle and cartilage, respectively. The mRNA for Sox9 was found to be decreased after treatment of chondrocytic cells with tumor necrosis factor-α (TNF-α), and this effect was blocked by overexpression of an NF-κB signaling superrepressor (IκBα-SR). In nuclear run-on assays with samples from TNF-α-treated or control C2C12 cells, MyoD transcription was not inhibited by TNF-α despite a decrease in MyoD mRNA. Deletion analysis of the MyoD RNA sequence allowed a minimal region required for NF-κB-mediated destabilization to be identified, and within that region, a multiply occurring ACUACAG was responsible for NF-κB-mediated destabilization. This repeated motif was also present in Sox9 and conferred NF-κB-mediated mRNA destabilization to a transcript not normally regulated by NF-κB. NF-κB transcriptional activity is required for MyoD inhibition; thus, the authors propose that NF-κB stimulates the expression of factors that control mRNA stability, which allows NF-κB signals to lead to decreased expression of genes. R. Sitcheran, P. C. Cogswell, A. S. Baldwin Jr., NF-κB mediates inhibition of mesenchymal cell differentation through a posttranscriptional gene silencing mechanism. Genes Dev. 17, 2368-2373 (2003). [Abstract] [Full Text]