bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidised plant sterols as well as oxycholesterol increase the proportion of severe atherosclerotic lesions in female LDL receptor+/ −mice
Authors: Plat Jogchum , Theuwissen Elke , Husche Constanze , Lütjohann Dieter , Gijbels Marion J. J. , Jeurissen Mike , Shiri-Sverdlov Ronit , van der Made Ingeborg , Mensink Ronald P.
Published: June 2013

Oxysterols (oxidised cholesterol) may play a role in the pathogenesis of CVD. Similar to cholesterol, plant sterols are susceptible to oxidation. However, less is known about the potential atherogenicity of oxidised plant sterols (oxyphytosterols). In the present study, the atherogenicity of a mixture of oxyphytosterols was examined by feeding female LDL receptor-deficient (LDLR+/ −) mice for 35 weeks a control diet (atherogenic high-fat diet;n9), an oxysterol diet (control diet+0·025 % (w/w) oxysterols;n12) or an oxyphytosterol diet (control diet+0·025 % (w/w) oxyphytosterols;n12). In the LDLR+/ −mice, serum levels of cholesterol, lipoprotein profiles, cholesterol exposure and inflammatory markers at the end of the experiment were comparable between the three diet groups. Nevertheless, the proportion of severe atherosclerotic lesions was significantly higher after oxysterol (41 %;P= 0·004) and oxyphytosterol (34 %;P= 0·011) diet consumption than after control diet consumption (26 %). Oxyphytosterol levels in the lesions were the highest in the oxyphytosterol group. Here, we show that not only dietary oxysterols but also dietary oxyphytosterols increase the proportion of severe atherosclerotic lesions. This suggests that plant sterols when oxidised may increase atherosclerotic lesion severity instead of lowering the size and severity of lesions when fed in their non-oxidised form. Therefore, this finding might give an indication as to where to find the answer in the current hot debate about the potential atherogenicity of plant sterols. However, to what extent these results can be extrapolated to the human situation warrants further investigation.
The Origins of Patronage Politics: State Building, Centrifugalism, and Decolonization
Authors: Kenny Paul D.
Published: June 2013

This article develops a two-part theory that accounts for both the origins and the persistence of patronage politics. First, greater centrifugal and disintegrative pressures at key moments in the state-building process give local elites more opportunity to institutionalize patronage at the subnational level. Second, decentralized patronage systems are more resistant to reform than centralized ones. Case studies of India and Ceylon illustrate how variation in centrifugal pressures allowed subnational elites to capture the state in the former but not the latter. Further data from the British Empire shows that greater centrifugal pressures faced by British colonies at the time of decolonization are correlated with the persistence of higher levels of patronage over time.
Predictable Dynamics in Higher-Order Risk-Neutral Moments: Evidence from the S&P 500 Options
Authors: Neumann Michael , Skiadopoulos George
Published: June 2013

We investigate whether there are predictable patterns in the dynamics of higher-order risk-neutral moments (RNMs) extracted from the market prices of Standard & Poor’s (S&P) 500 index options. To this end, we conduct a horse race among alternative forecasting models within an out-of-sample context over various forecasting horizons. We consider both a statistical and an economic setting. We find that higher RNMs can be statistically forecasted. However, only the 1-day-ahead skewness forecasts can be economically exploited. This economic significance vanishes once we incorporate transaction costs. The results have implications for the dynamics of implied volatility surfaces.
Brain regions related to fear extinction in obsessive-compulsive disorder and its relation to exposure therapy outcome: a morphometric study
Authors: Fullana M. A. , Cardoner N. , Alonso P. , Subirà M. , López-Solà C. , Pujol J. , Segalàs C. , Real E. , Bossa M. , Zacur E. , Martínez-Zalacaín I. , Bulbena A. , Menchón J. M. , Olmos S. , Soriano-Mas C.
Published: June 2013

Background

The size of particular sub-regions within the ventromedial prefrontal cortex (vmPFC) has been associated with fear extinction in humans. Exposure therapy is a form of extinction learning widely used in the treatment of obsessive-compulsive disorder (OCD). Here we investigated the relationship between morphometric measurements of different sub-regions of the vmPFC and exposure therapy outcome in OCD.

Method

A total of 74 OCD patients and 86 healthy controls underwent magnetic resonance imaging (MRI). Cortical thickness and volumetric measurements were obtained for the rostral anterior cingulate cortex (rACC), the medial orbital frontal cortex and the subcallosal cortex. After MRI acquisition, patients were enrolled in an exposure therapy protocol, and we assessed the relationship between MRI-derived measurements and treatment outcome. Baseline between-group differences for such measurements were also assessed.

Results

Compared with healthy controls, OCD patients showed a thinner left rACC (p = 0.008). Also, left rACC thickness was inversely associated with exposure therapy outcome (r – 0.32, p = 0.008), and this region was significantly thinner in OCD patients who responded to exposure therapy than in those who did not (p = 0.006). Analyses based on regional volumetry did not yield any significant results.

Conclusions

OCD patients showed cortical thickness reductions in the left rACC, and these alterations were related to exposure therapy outcome. The precise characterization of neuroimaging predictors of treatment response derived from the study of the brain areas involved in fear extinction may optimize exposure therapy planning in OCD and other anxiety disorders.
Distinguishing benchmarks of biological status from management reference points: A case study on Pacific salmon in Canada
Authors: HOLT CARRIE A. , IRVINE JAMES R.
Published: June 2013

For fisheries with multiple, competing objectives, identifying and applying reference points for management can present difficult trade-offs between long-term biological and shorter-term socioeconomic considerations. The term biological benchmarks is proposed to demarcate zones of population status based on conservation and production considerations. These scientifically derived benchmarks contrast with management reference points that generally require additional shorter-term socioeconomic information best obtained through public consultations. This paper illustrates the distinction between biological benchmarks and management reference points with a case study on Pacific salmon (Oncorhynchusspp.). In Canada, the management and assessment of wild Pacific salmon are guided by a major 2005 conservation policy, which calls for the identification of biological benchmarks to categorize status of demographically isolated populations, and decision-support tools, such as management reference points, to integrate biological information with appropriate social and economic information. In the Fraser River (British Columbia, Canada), the selection of management reference points for sockeye salmon (O. nerka) fisheries explicitly considered trade-offs between the probability of meeting long-term biological objectives on component populations and harvest objectives on population aggregates. Decisions about reference points were made in a consultative process that included extensive stakeholder engagement. Other agencies are urged to distinguish biological benchmarks from management reference points to ensure transparency in the relative influence of biological versus socioeconomic information in decision making.
Estimating tree biomass and changes in root biomass following clear-cutting ofBrachystegia-Julbernardia(miombo) woodland in central Zambia
Authors: CHIDUMAYO EMMANUEL N
Published: June 2013

This study aimed at developing allometric models from destructive sample field data for estimating both aboveground and belowground tree biomass and assessing changes in root biomass after old-growthBrachystegia-Julbernardia(miombo) woodland clearing in central Zambia. Logarithmic linear models were selected for estimating tree biomass because they gave the most accurate (low mean error) predictions. On average aboveground and belowground biomass in regrowth woodland represented 29% and 41%, respectively, of the biomass in old-growth woodland. The root:shoot ratios were 0.54 and 0.77 in old-growth and regrowth woodland, respectively. Ten years after clear-cutting old-growth woodland, root biomass loss was about 60% of the original biomass. The main cause of post clearing root biomass loss was fire which at the study sites occurred annually or biannually. Control of fire in cleared sites should be encouraged in forest management for carbon storage and sequestration in miombo woodland of southern Africa.
Consideration of reference points for the management of renewable resources under an adaptive management paradigm
Authors: IRWIN BRIAN J. , CONROY MICHAEL J.
Published: June 2013

The success of natural resource management depends on monitoring, assessment and enforcement. In support of these efforts, reference points (RPs) are often viewed as critical values of management-relevant indicators. This paper considers RPs from the standpoint of objective-driven decision making in dynamic resource systems, guided by principles of structured decision making (SDM) and adaptive resource management (AM). During the development of natural resource policy, RPs have been variously treated as either ‘targets’ or ‘triggers’. Under a SDM/AM paradigm, target RPs correspond approximately to value-based objectives, which may in turn be either of fundamental interest to stakeholders or intermediaries to other central objectives. By contrast, trigger RPs correspond to decision rules that are presumed to lead to desirable outcomes (such as the programme targets). Casting RPs as triggers or targets within a SDM framework is helpful towards clarifying why (or whether) a particular metric is appropriate. Further, the benefits of a SDM/AM process include elucidation of underlying untested assumptions that may reveal alternative metrics for use as RPs. Likewise, a structured decision-analytic framework may also reveal that failure to achieve management goals is not because the metrics are wrong, but because the decision-making process in which they are embedded is insufficiently robust to uncertainty, is not efficiently directed at producing a resource objective, or is incapable of adaptation to new knowledge.
ROOSEVELT AND PRESCOTT COME TO AN AGREEMENT
Authors: Caliendo Frank N. , Guo Nick L.
Published: June 2013

Edward C. Prescott has argued that mandatory saving is socially desirable because it solves the problem of people intentionally free riding and becoming a welfare burden. Inspired by Prescott's argument, we develop a model in which rational individuals choose between saving and free riding. We find that free riding is a robust outcome for a significant share of the population and that everyone, including the free riders, benefits from the elimination of free riding through mandatory saving. Our results strengthen Prescott's position that free riding is a serious problem and that mandatory saving is socially desirable.
Carers and Empowerment in the UK: A Critical Reflection
Authors: Larkin Mary , Milne Alisoun
Published: June 2013

This article provides a critical reflection on carer empowerment in the UK, an issue which has received limited attention in policy and research. The arena is characterised by considerable conceptual confusion around key terminology, carer, care and caring, and by limited understanding of the meaning and outcomes of carer empowerment. Despite increased national acknowledgment of carers, a politically active carers' movement and a number of policies intended to enhance the recognition and rights of carers, many carers remain invisible and receive little support from services, to the detriment of their own health and well-being. Addressing these challenges, alongside developing a robust theoretical foundation for taking the ‘carers' agenda’ forward, is needed if carers are to move towards a more empowered status in the twenty-first century.
Making the World Safe for Eugenics: The Eugenicist Harry H. Laughlin's Encounters with American Internationalism
Authors: McDonald Jason
Published: June 2013

Harry H. Laughlin's main claim to fame was as director of the Eugenics Record Office at Cold Spring Harbor, Long Island, from which position he exerted considerable influence upon early twentieth-century campaigns to restrict immigration and to institute compulsory sterilization of the socially inadequate. Laughlin also had an absorbing fascination for the idea of a single world government. Over the course of forty years, he produced a voluminous body of mostly unpublished work on the subject. In examining Laughlin's musings on internationalism, this article provides a glimpse into how a leading American eugenicist would have projected onto the world stage the policies he was zealously endeavoring to implement at the domestic level. Laughlin sent samples of his work to many of America's leading internationalists. Their responses to Laughlin's ideas reveal much about the character of internationalism in the United States during the era of World War I, especially the extent to which his racist and imperialist assumptions were shared by other members of the internationalist movement. Consequently, this article provides yet another example of how liberal and conservative impulses were neither easily distinguishable nor mutually exclusive during the Progressive Era.
Tauchen – Tauchtauglichkeit: Ein Thema für die Hausarztpraxis
Authors: Wendling Jürg
Published: June 2013

Immer mehr Taucher suchen die Hausarztpraxis für ein Tauchtauglichkeitszeugnis auf. Dabei handelt es sich um eine Begutachtung mit Risikobeurteilung, wozu neben der Krankengeschichte auch die Kenntnis der Tauchtechnik, der Motivation und der eingegangenen Risiken vorausgesetzt ist. Typische Charakteristiken werden vorgestellt, ebenso tauchmedizinische Weiterbildungsmöglichkeiten für Grundversorger, Hilfestellungen und Ressourcen für spezifische Abklärungen.
Abklärung der Proteinurie
Authors: Nowak Albina , Serra Andreas L.
Published: June 2013

Die Proteinurie ist ein abklärungsbedürftiger Zufallsbefund in der hausärztlichen Praxis. Da viele Nierenerkrankungen zu Beginn asymptomatisch verlaufen, gehört die Bestimmung der Proteinurie sowohl zum Screening von Risikogruppen wie Patienten mit Diabetes mellitus und arterieller Hypertonie als auch zum Monitoring des Verlaufs einer bekannten Nephropathie. Die frühzeitige Diagnose einer Proteinurie ist wichtig, da Therapien von Nierenerkrankung meist zu Beginn des Krankheitsverlaufs besser wirken, als im Spätstadium der chronischen Niereninsuffizienz. Der Grundversorger trägt daher einen entscheidenden Beitrag zur Früherkennung und Vorabklärung von Nierenerkrankungen bei. Harmlose Formen der Proteinurie, wie transiente und orthostatische Proteinurie, sollten von prognostisch ungünstigen Formen unterschieden werden. Der gewöhnliche Urin-Papierstreifentest ist wenig sensitiv für Nicht-Albumine. Sensitiver und spezifischer ist die quantitative Protein- und Albuminbestimmung im Spontanurin, die eine gute Abschätzung der pro 24 Stunden ausgeschiedenen Proteinmenge erlaubt.
Die Autonomie der Hebamme
Authors: Yang Hie-Sun , Roes Martina
Published: June 2013

In der Arbeit der Hebamme bestehen auffällige Parallelen zu „Advanced Nursing Practice“ (ANP). Inhaltlich, juristisch sowie wirtschaftlich arbeiten Hebammen autonom und definieren einen eigenverantwortlichen Handlungsbereich. Was bedeutet dies für die Zukunft der Hebammenprofession?
Gewichtsveränderung in der Berufsausbildung: Wo besteht Handlungsbedarf?
Authors: Wiens Dana , Coers Sarah
Published: June 2013

Zeigen Pflegende während der Berufsausbildung häufiger Gewichtsveränderungen als Auszubildende technischer Berufe? Dieser Frage ist eine Forschungsarbeit nachgegangen. Die Resultate stimmen nachdenklich: Auszubildende der Pflege nehmen deutlich an Gewicht zu.
Youth and Video Games
Authors: Evans Michael A. , Norton Anderson , Chang Mido , Deater-Deckard Kirby , Balci Osman
Published: June 2013

Recent research suggests that video games and social media may influence youths’ lives in ways that deserve attention from psychologists, mathematics educators, and learning scientists. For example, positive effects on engagement, which can increase probability of mathematics proficiency, have been reported in the literature. We examine this issue with emphasis on the effects of video game play on youth learning and engagement; what features, attributes, and mechanisms of video games have been identified as most salient for these factors; and how scholarship in the domain might design more rigorous studies to determine the effects of video game play on learning, achievement, and engagement. We include a description of our work developing educational games for middle school youth struggling to become algebra-ready.
Sample Preparation and Profiling: Mass‐Spectrometry‐Based Profiling Strategies
Authors: Kim Yeoun Jin , Domon Bruno
Published: June 2013

In proteomics-based biomarker discovery, mass spectrometry (MS) has become an essential technology for both qualitative and quantitative analyses of proteins. In conjunction with separation methods, such as liquid chromatography (LC) or electrophoresis, the systematic peptide identification and quantification has expedited the profiling of protein components in biological samples. Numerous studies aiming at the discovery of clinically meaningful biomarker candidates have employed such MS-based proteome profiling approaches. The robustness of mass spectrometric methods has in addition facilitated large-scale analyses required for the verification and validation stages of biomarker discovery studies. In this chapter, LC-MS based profiling strategies for the discovery of protein biomarkers are discussed. In addition to reviewing the experimental strategies widely employed in the field, a specific example of biomarker discovery is discussed in this chapter.
Bioinformatics and Statistics: LC‐MS(/MS) Data Preprocessing for Biomarker Discovery
Authors: Horvatovich Péter , Suits Frank , Hoekman Berend , Bischoff Rainer
Published: June 2013

This chapter provides an overview of the main steps of LC-MS(/MS) data pre-processing workflows. It discusses the main characteristics of these steps and provides a detailed functional description of the currently available algorithmic approaches. As an example, the chapter presents the main steps of the Threshold Avoiding Proteomics Pipeline, which includes several novel concepts to increase the accuracy of peptide quantification and to increase the extracted dynamic concentration range of compounds. The chapter further outlines a quality control method to assess and compare the relative performance of various LC-MS(/MS) data pre-processing workflows integrated in the msComapre framework using a set of differentially spiked LC-MS datasets. The chapter discusses the most common quantitative data pre-processing errors and provides visualization methods to identify these errors. Finally the chapter provides an overview of future development trends of LC-MS(/MS) data pre-processing algorithm development stressing the need for easy-to-use high-throughput bioinformatics platforms using modern parallel computational resources to alleviate current data pre-processing and analysis bottlenecks.
Bioinformatics and Statistics: Statistical Analysis and Validation
Authors: Hoefsloot Huub C. J.
Published: June 2013

In this chapter guidelines are given for the selection of a few biomarker candidates from a large number of compounds with a relative low number of samples. The main concepts concerning the statistical validation of the search for biomarkers are discussed. These complicated methods and concepts are discussed without using difficult mathematics. So the people who are involved in biomarker research but have no statistical or informatics background are able to understand this chapter. Also for the specialist all the concepts to avoid the problem of false‐positives, these are findings that turn out to be wrong, are discussed and practical advice is given. The situation where no biomarkers are found is discussed and suggestions are made as to how to investigate whether this is due to the statistical method or to the data.
Bioinformatics and Statistics: Computational Discovery, Verification, and Validation of Functional Biomarkers
Authors: Zhang Fan , Drabier Renee
Published: June 2013

The advent of omics technologies such as genomics and proteomics has the hope of discovering novel biomarkers that can be used to diagnose, predict, and monitor the progress of disease. The enormous amount of data generated by high‐throughput proteomics, metabolomics, and genomics technologies requires sophisticated statistical techniques to differentiate between disease individuals and healthy individuals and identify candidate biomarkers. Many novel methods have been developed and applied for the purpose of identifying and using biomarkers to improve disease understanding, and to tailor medication use in individual patients with the goals of enhancing efficacy and minimizing toxicity. High‐dimensional investigations where thousands of genotypes, transcripts, methylation markers, and metabolites are measured together with environmental risk factors and clinical information are considered powerful tools to achieve these goals and are, therefore, an important focus of current research in clinical application.
Discovery and Validation Case Studies, Recommendations: A Pipeline that Integrates the Discovery and Verification Studies of Urinary Protein Biomarkers Reveals Candidate Markers for Bladder Cancer
Authors: Chen Yi‐Ting , Parker Carol E. , Chen Hsiao‐Wei , Chen Chien‐Lun , Domanski Dominik , Smith Derek S. , Wu Chih‐Ching , Chung Ting , Liang Kung‐Hao , Chen Min‐Chi , Chang Yu‐Sun , Borchers Christoph H. , Yu Jau‐Song
Published: June 2013

There are currently no widely accepted biomarkers for non-invasive diagnosis or screening of bladder cancer. There is, therefore, a compelling need to develop more reliable bladder cancer biomarkers, particularly those which can be measured in body fluids. In this book chapter, we describe the proteomic workflow which we used to develop a non-invasive assay for the detection of human bladder tumor in urine specimens. A six-protein biomarker panel was generated by a combination of untargeted mass-spectrometry-based biomarker discovery using an “isobaric tags for relative and absolute quantitation” (iTRAQ) platform, and subsequent biomarker verification using a targeted multiple-reaction-monitoring mass spectrometry (MRM-MS) approach.
Discovery and Validation Case Studies, Recommendations: Discovery and Development of Multimarker Panels for Improved Prediction of Near‐Term Myocardial Infarction
Authors: Juhasz Peter , Lynch Moira , Paniagua Manuel , Campbell Jennifer , Adourian Aram , Guo Yu , Li Xiaohong , Nordestgaard Børge G. , Gordon Neal F.
Published: June 2013

This report is a case study of the complex process of designing and performing a biomarker discovery study, validating its preliminary findings, and translating these into a clinical utility that would be suitable for the requirements of FDA clearance. The process is illustrated on the development of a multianalyte (protein) panel that can significantly enhance the prediction of the risk of near‐term myocardial infarction (MI) over traditional risk factors. The utilized clinical material is a subset of the Copenhagen General Population Study consisting of a matched set 252 cases, defined as fatal or nonfatal MI within four years of blood collection, and 499 controls. For discovery, we utilized high‐resolution mass‐spectrometric profiling of pooled samples complemented with multiplexed immunoassays. Discoveries were validated by using multiple reaction monitoring (MRM) liquid chromatography‐mass spectrometry (LC‐MS). It was demonstrated that a six‐protein panel comprised of analytes measured by MRM and immunoassays could significantly improve risk prediction over that provided by traditional risk factors alone. The path of developing a “submission package” for FDA clearance is also discussed.
Respiratory Syncytial Virus Fusion Inhibitors
Authors: Sperandio David , Mackman Richard
Published: June 2013

Infections with the respiratory syncytical virus (RSV) are the leading cause of lower respiratory tract infections and a serious health concern in infants less than 2 years of age, the immunocompromised and the geriatric population. Numerous research programs directed at small‐molecule inhibitors of RSV have been initiated over the last 50 years. RSV inhibitors that target the fusion event have shown a lot of promise and are reviewed in this chapter. However, none of these programs have yet reached the market or late‐stage clinical development. Therefore, focus in this review is given to the challenges in the preclinical development phase and the ideal target product profile. The challenges in clinical development are also discussed, including the use of a new RSV challenge strain (Memphis 37), clinical trial design in immunosupressed patients, patients with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) and clinical trials in infants.
Discovery and Development of Antiviral Drugs for Treatment of Pathogenic Human Orthopoxvirus Infections
Authors: Jordan Robert
Published: June 2013

Smallpox, a devastating disease with mortality rates of upwards of 30%, ravaged humanity for thousands of years until it was eradicated in the latter half of the twentieth century by a successful vaccination campaign sponsored by the World Health Organization. Smallpox was caused by infection with variola virus, one of several orthopoxviruses that infect humans and cause disease. Although smallpox no longer exists in the environment, concern that variola virus or a related orthopoxvirus could be developed into a bioweapon prompted the US government to sponsor research into developing antiviral drugs to treat variola virus infection. Antiviral drug development for orthopoxvirus infections is hampered by the lack of human disease, requiring the use of animal models to establish pharmacokinetic–pharmacodynamic relationships to guide effective human dosing strategies. Cidofovir, CMX001 and ST‐246 are clinical‐stage compounds currently being evaluated for the treatment of pathogenic orthopoxvirus infections. Cidofovir is an acyclic nucleoside phosphonate that targets the viral polymerase and CMX001 is an oral prodrug of cidofovir designed to improve oral bioavailability and safety. ST‐246 is a novel chemical entity that blocks viral egress. Although all three compounds are effective at treating orthopoxvirus infections in animal models, and are safe and well tolerated in human clinical trials, establishing effective human dosing strategies using animal efficacy data remains a major challenge for the development of these therapeutics.
HIV Integrase Inhibitors
Authors: Johns Brian A. , Kawasuji Takashi , Velthuisen Emile J.
Published: June 2013

This chapter presents the discovery, development and evolution of integrase strand transfer inhibitors. A brief overview of the first‐generation inhibitors raltegravir and elvitegravir serves to describe their landmark advancement of the field and also outline areas for further improvement. The remainder of the discussion revolves around the strategy in designing a series of carbamoylpyridines that ultimately led to the discovery of dolutegravir, an investigational integrase inhibitor in late‐stage clinical development. In addition, an intriguing approach to the development of a related compound, S/GSK744, as a long‐acting parenteral agent is presented. Finally, an exciting new area of non‐catalytic site integrase inhibitors is included.
HCV NS3/4a Protease Inhibitors: Simeprevir (TMC‐435350), Vaniprevir (MK‐7009) and MK‐5172
Authors: McCauley John A. , Rudd Michael T. , Liverton Nigel J.
Published: June 2013

Hepatitis C virus (HCV) infection continues to represent a major health issue, with estimates of 130–170 million people infected worldwide. Recent developments in the HCV NS3/4a protease inhibitor area have significantly improved treatment options for patients. However, a more dramatic paradigm shift in the treatment of HCV infection appears all but certain in coming years, with a move to all oral combination therapy with direct‐acting antivirals (DAAs). HCV protease inhibitors have the potential to play a significant role in these DAA combination therapies. This chapter discusses in detail the design and discovery of three HCV NS3/4a protease inhibitors in clinical development: simeprevir (TMC‐435350), vaniprevir (MK‐7009) and MK‐5172.
Design and Development of NS5B Polymerase Non‐nucleoside Inhibitors for the Treatment of Hepatitis C Virus Infection
Authors: Beaulieu Pierre L.
Published: June 2013

The hepatitis C virus (HCV) infects an estimated 130–170 million people worldwide and is associated with life‐threatening liver diseases. The recent introduction of the first two HCV direct‐acting antivirals (DAAs) as a complement to the interferon/ribavirin standard of care has provided patients with improved outcomes. Still, 25–30% of subjects infected with genotype 1 HCV do not respond adequately to treatment owing to the emergence of resistant virus and many suffer from severe side effects. A paradigm shift towards the development of interferon‐free combinations of DAAs with complementary modes of action is currently taking place. Virally encoded proteins and enzymes have become the target of HCV drug discovery efforts and several promising new agents are currently being evaluated in the clinic for treatment of chronic HCV infection. The NS5B RNA‐dependent RNA polymerase is responsible for replication of viral RNA and plays a pivotal role in the virus life cycle. NS5B is undoubtedly the most druggable HCV target and is susceptible to several classes of allosteric inhibitors that bind to four distinct sites on the enzyme. This chapter describes successful strategies that have led to the discovery of HCV NS5B antivirals. It is divided according to allosteric sites and describes how each of the known families of inhibitors was discovered, characterized and optimized to provide clinical candidates. When available, the strategies adopted by medicinal chemists to optimize initial leads and address challenges and liabilities encountered on the path to candidate selection are described, along with reported clinical outcomes.
Optimization of Cyclophilin Inhibitors for Use in Antiviral Therapy
Authors: Peel Michael , Scribner Andrew
Published: June 2013

Cyclophilins are members of the Propyl Peptidase Isomerase (PPIase) family of proteins and have recently been found to be required for efficient replication and/or infectivity of several viruses. Cyclosporine A (CsA), the prototypical inhibitor of cyclophilins has shown good activity against several key viruses, including HIV‐1 and HCV, however the immunosuppressive activity of CsA precludes its use as an effective anti‐viral agent. Structural information derived from the ternary complex formed by CsA, cyclophilin A and calcineurin has allowed the design of non‐immunosuppressive derivatives of CsA that retain, and in some cases improve, antiviral activity toward hepatitis C. Chemical modification of CsA has led to compounds with improved pharmacokinetic properties and with reduced drug‐drug interaction potential. Non‐CsA derived inhibitors of cyclophilin A have recently been identified and hold promise as synthetically more tractable leads for cyclophilin‐based discovery projects.
Prodrugs in the Treatment of Viral Diseases
Authors: Sofia Michael J.
Published: June 2013

Prodrug strategies have played a prominent role in the development of drugs to treat viral diseases. Implementation of prodrug approaches has been shown to improve the drug characteristics of agents to treat a wide range of viral diseases, including HIV, HBV, HCV, CMV, VZV, EBV, HSV and influenza. Prodrugs of antiviral agents have been used to address issues such as poor intestinal absorption because of the lack of membrane permeability or poor solubility. Prodrugs have also been used to enable tissue targeting. This chapter addresses the issues and challenges associated with prodrug design and development and highlights a number of case studies where prodrugs of antiviral agents have been used to solve pharmacokinetic or pharmaceutics problems that limited the development of the parent drug.
Implementing a Robust Methodology: Experimental Designs and Optimisation
Authors: Tomàs‐Morer Xavier , González‐Sabaté Lucinio , Fernández‐Ruano Laura , Paz Gómez‐Carracedo María
Published: June 2013

The aim of any atomic spectroscopist, as of any analytical chemist, is to develop robust and efficient measurement procedures. Experimental design, sequential optimisation and response surface methodology are three critical tools to extract maximum information from a limited number of systematised and planned sets of experimental trials. The basics of these methodologies are introduced here and some common strategies presented in a user‐friendly, practical way and their advantages and drawbacks explained, from full factorial designs to saturated designs, which allow minimum performance of experiments. Tagughi’s designs and their philosophy, optimisation techniques and main response surface designs are introduced as well. Several matrices of experiments are presented so that they can be used directly by the reader. In addition, an updated review of published works, with comments related to applications in atomic spectrometry, is included.
Ordinary Multiple Linear Regression and Principal Components Regression
Authors: Ferré‐Baldrich Joan , Boqué‐Martí Ricard
Published: June 2013

Calibration based on a classical univariate regression requires completely selective measurements. Therefore, predictions may be biased severely when this requirement is not fulfilled. Multivariate regression is presented as a means to overcome these limitations. Three different approaches to multivariate calibration are presented: the classical least‐squares model, the inverse least‐squares model, and the regression on principal components. Their advantages (mainly their ability to yield correct predictions for non‐selective measurements) and limitations are discussed. This introduction to multivariate calibration offers a basis for understanding the partial least‐squares model described in Chapter 5.
Partial Least‐Squares Regression
Authors: Andrade‐Garda José Manuel , Carlosena‐Zubieta Alatzne , Boqué‐Martí Ricard , Ferré‐Baldrich Joan
Published: June 2013

This chapter presents the most widely applied and, probably, satisfactory multivariate regression method used nowadays: partial least squares (PLS). Graphical explanations of many concepts are given to complement the more formal mathematical background. Several approaches to solving current problems are suggested. The development of a satisfactory regression model can alleviate the typical laboratory workload (preparation of many standards, solutions with concomitants, etc.) but only when a strict and serious job is performed with the PLS methodology. Iteration is the key word here as the analyst has to iterate the data within the software capabilities. Validation is essential, as can never be stressed sufficiently enough, and it will be explained here in detail. Two approaches to deal with the new concepts of ‘limit of detection’ and ‘limit of quantification’ (these terms will be used although they have been superseded) given by International Organization for Standardization (ISO) and the European Union (EU) are presented. Finally, a comprehensive review of practical applications that have used PLS within the atomic spectrometry field is presented.
Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts
Authors: Liang Qiuli , Benavides Gloria A. , Vassilopoulos Athanassios , Gius David , Darley-Usmar Victor , Zhang Jianhua
Published: June 2013

Sirt3 (sirtuin 3) is an NAD-dependent deacetylase localized to mitochondria. Sirt3 expression is increased in mouse muscle and liver by starvation, which could protect against the starvation-dependent increase in oxidative stress and protein damage. Damaged proteins and organelles depend on autophagy for removal and this is critical for cell survival, but the role of Sirt3 is unclear. To examine this, we used Sirt3-KO (knockout) mouse embryonic fibroblast cells, and found that, under basal conditions, Sirt3-KO cells exhibited increased autophagy flux compared with WT (wild-type) cells. In response to nutrient deprivation, both WT and KO cells exhibited increased basal and ATP-linked mitochondrial respiration, indicating an increased energy demand. Both cells exhibited lower levels of phosphorylated mTOR (mammalian target of rapamycin) and higher autophagy flux, with KO cells exhibiting lower maximal mitochondrial respiration and reserve capacity, and higher levels of autophagy than WT cells. KO cells exhibit higher phospho-JNK (c-Jun N-terminal kinase) and phospho-c-Jun than WT cells under starvation conditions. However, inhibition of JNK activity in Sirt3-KO cells did not affect LC3-I (light chain 3-I) and LC3-II levels, indicating that Sirt3-regulated autophagy is independent of the JNK pathway. Caspase 3 activation and cell death are significantly higher in Sirt3-KO cells compared with WT cells in response to nutrient deprivation. Inhibition of autophagy by chloroquine exacerbated cell death in both WT and Sirt3-KO cells, and by 3-methyadenine exacerbated cell death in Sirt3-KO cells. These data suggest that nutrient deprivation-induced autophagy plays a protective role in cell survival, and Sirt3 decreases the requirement for enhanced autophagy and improves cellular bioenergetics.
Singular linear parameter‐varying observer for composition estimation in a binary distillation column
Authors: Aguilera‐González Adriana , Astorga‐Zaragoza Carlos‐Manuel , Adam‐Medina Manuel , Theilliol Didier , Reyes‐Reyes Juan , García‐Beltrán Carlos‐Daniel
Published: June 2013

The aim of this study is to provide a full comprehensive study of the singular linear parameter‐varying (LPV) systems and observer synthesis in a real process. The states and unknown inputs estimation problem for a binary distillation column is solved by using an LPV proportional‐integral observer (PI‐Observer). A singular LPV model of the process is developed. This model facilitates the design of the PI‐Observer for singular LPV systems. The observer proposed is tested using experimental data of a distillation column separating an ethanol–water mixture. The results indicate that the observer is able to accurately reconstruct the product composition dynamics and the unknown inputs of the process.
Robust control design for automatic regulation of blood pressure
Authors: Malagutti Nicolò , Dehghani Arvin , Kennedy Rodney Andrew
Published: June 2013

The problem of automatic administration of vasoactive drugs to a patient can be treated as a regulation problem of a system, which is characterised by large parametric uncertainty, non‐Gaussian disturbances and unmodelled dynamics, yet carries strict requirements in terms of robustness and performance. A number of approaches have been proposed in the past to tackle this problem, particularly for the postoperative management of blood pressure in cardiac surgery patients. We describe the design of a robust multiple‐model adaptive control (RMMAC) architecture and investigate whether this can overcome some issues observed with earlier methods. Key features of RMMAC are robust optimal controller design using an iterative μ synthesis algorithm and improved system estimation. Simulation results indicate that RMMAC is capable of avoiding transient instability and delivering performance in the face of significant parameter changes over time and large disturbances including non‐zero‐mean signals. The findings support further research into RMMAC as a potentially viable approach to the design of safer automatic closed‐loop drug administration technologies capable of operating under challenging clinical conditions such as may arise in an intraoperative setting.
Further improvement in stability criteria for linear systems with interval time‐varying delay
Authors: Souza Fernando O.
Published: June 2013

The delay‐dependent stability problem for systems with time‐delay varying in an interval is addressed in this study. Based on Lyapunov–Krasovskii theory the proposed methods formulated as linear matrix inequality problems are able to check the stability interval when the time‐varying delay d (t) belongs to an interval [τ1, τ2]. The Lyapunov–Krasovskii functional (LKF) selected in the present paper is simpler than some ones considered in the literature. However, the criteria obtained, based on this simple LKF, outperformed the similar existing ones in all numerical tests accomplished in this paper.

Notation: Through out this paper the superscript T stands for transpose. 0 refers to a null matrix with appropriate dimensions. For a real symmetric matrix M, the notation M > 0 (< 0) means that M is the positive (negative) definite. The symmetric term in a matrix is denoted by *.
Set‐point regulation of monotone systems using the monotone small‐gain theorem
Authors: Agahi Hamed , Yazdanpanah Mohammad Javad
Published: June 2013

Monotone dynamical systems are those with solutions preserving specific orderings, relative to the associated initial states. This study shows that, under negative output feedback control, a monotone single‐input single‐output system with well‐defined static characteristics is able to globally asymptotically regulate its solution at desired constant set‐points, while the boundedness of all solutions are successfully guaranteed. This valuable result is obtained only through limited amount of qualitative and quantitative data, which may be provided from relatively simple experiments for real applications. The design procedure, in the cast of a new theorem, is mainly derived from the specific version of Small Gain Theorem for autonomous monotone systems; which ensures the global attractivity of the desired set‐point. A biological simulation example illustrates the effectiveness and applicability of the proposed control strategy.
Tracking and rejection of periodic signals for discrete‐time linear systems subject to control saturation
Authors: Flores Jeferson Vieira , da Silva Joao Manoel Gomes , Sartori Renan
Published: June 2013

This work addresses the tracking and rejection problem of periodic signals for discrete‐time linear systems subject to control saturation. To ensure the periodic tracking/rejection an internal model‐based controller is considered. Based on this control structure, conditions allowing the simultaneous synthesis of a stabilising state feedback gain and an anti‐windup gain are proposed. Provided that references and disturbances belong to the interior of a certain admissible set, these gains guarantee that the trajectories of the closed‐loop system starting in an ellipsoidal set contract to the linearity region of the closed‐loop system, where the presence of the internal model ensures the periodic tracking/rejection. To compute the gains, an LMI‐based optimisation problem aiming at the maximisation of the set of admissible states and/or the set of admissible references/disturbances is proposed.
An improved rolled strip pulse forming line
Authors: Li Song , Qian Bao-Liang , Yang Han-Wu , Gao Jing-Ming , Liu Zhao-Xi
Published: June 2013

The rolled strip pulse forming line (RSPFL) has advantages of compactness, portability, and long pulse achievability which could well meet the requirements of industrial application of the pulse power technology. In this paper, an improved RSPFL with an additional insulator between the grounded conductors is investigated numerically and experimentally. Results demonstrate that the jitter on the flat-top of the output voltage waveform is reduced to 3.8% due to the improved structure. Theoretical analysis shows that the electromagnetic coupling between the conductors of the RSPFL strongly influences the output voltage waveform. Therefore, the new structure was designed to minimize the detrimental effect of the electromagnetic coupling. Simulation results show that the electromagnetic coupling can be efficiently reduced in the improved RSPFL. Experimental results illustrate that the improved RSPFL, with dimensions and weight of Φ 290 × 250 mm and 16 kg, when used as a simple pulse forming line, could generate a well shaped quasi-square pulse with output power of hundreds of MW and pulse duration of 250 ns. Importantly, the improved RSPFL was successfully used as a Blumlein pulse forming line, and a 10.8 kV, 260 ns quasi-square pulse was obtained on a 2 Ω dummy load. Experiments show reasonable agreement with numerical analysis.
Breakdown-prone volume in terahertz wave beams
Authors: Nusinovich G. S. , Qiao F. , Kashyn D. G. , Pu R. , Dolin L. S.
Published: June 2013

This study was motivated by the recently proposed concept of remote detection of concealed radioactive materials by a focused terahertz (THz) radiation [V. L. Granatstein and G. S. Nusinovich, J. Appl. Phys. 108, 063304 (2010)]. According to this concept, a high-power THz radiation should be focused in a small spot where the field intensity exceeds the breakdown threshold. In the presence of free electrons in such a breakdown-prone volume, a THz discharge will occur there. However, this volume should be so small that in the absence of ionizing sources in its vicinity the probability to have there any free electrons is low. Then, the increased breakdown rate in a series of THz pulses would indicate the presence of hidden radioactive materials in the vicinity of the focused spot. For this concept, it is important to accurately determine the breakdown-prone volume created by a focused THz radiation. This problem is analyzed in this paper, first, for the case of a single wave beam and, then, for the case of crossing wave beams of different polarizations. The problem is studied first ignoring the diffraction spread of wave beams in the vicinity of the focal plane and, then, with the account for the diffraction spreading. Then, relations between the THz wave power, the range of such a system and the breakdown-prone volume are analyzed. Finally, the effect of the atmospheric turbulence on propagation and focusing of THz wave beams in air is considered.
Large antisymmetric magnetoresistance across chemically etched GaMnAs nanoconstrictions
Authors: Eid K. F. , Ocola L. E. , Liu X. , Furdyna J. K.
Published: June 2013

We report the observation of a highly antisymmetric magnetoresistance in GaMnAs specimens with lateral nano-constrictions. The experiments were carried out on samples with an in-plane easy axis of magnetization, in in-plane applied magnetic field. We attribute this behavior to the formation of isolated nano-sized islands at the nano-constrictions, whose magnetization can undergo out-of-plane reorientation during switching. The change in resistance is up to 50%, which cannot be explained by the normal anisotropic magnetoresistance in GaMnAs. We propose tunneling anisotropic magnetoresistance as the most likely mechanism for this effect.