bluuebunny/crossref_metadata_2025 huggingface dataset:
Reliability Demonstration
Authors: Mease David , Nair Vijayan N. , Robinson Jeffrey A.
Published: September 2008

Reliability demonstration test plans are used in industry to verify that the reliability of a product meets a specified target with a certain degree of confidence. This article provides an overview of reliability demonstration plans from a statistical perspective and gives some examples for illustration. Bayesian techniques and extreme testing, two general approaches for increasing the efficiency of test plans and reducing sample sizes, are also discussed.
Systems Reliability
Authors: Andrews John D.
Published: September 2008

It is necessary to make predictions of the failure frequency or likelihood of systems operating in many industrial sectors. The techniques available to conduct this type of assessment require the component failure and repair characteristics along with information defining the system structure. This article describes the features of some of the techniques that can be used to conduct such system reliability assessments. For each method discussed, an overview of its capability is provided. Consideration is given to the use of systems reliability assessment techniques in the context of risk assessment. Finally, a discussion addresses when each of the methods described should be used.
Reliability of Large Systems
Authors: Kołowrocki Krzysztof
Published: September 2008

This article is concerned with the application of limit reliability functions to the reliability evaluation of large systems. Two‐state large nonrepaired systems composed of independent components are considered. The asymptotic approach to the system reliability investigation and the system limit reliability function are defined. Two‐state homogeneous series and parallel systems are defined and their exact reliability functions are determined. The classes of limit reliability functions of these systems are presented. This article contains an exemplary application of the presented facts to the reliability evaluation of large technical systems. The accuracy of this evaluation is illustrated. Brief review and the latest references on limit reliability functions of two‐state and multistate homogeneous and nonhomogeneous series, parallel, and other systems are presented as well.
Repairable Systems Reliability
Authors: Rigdon Steven E.
Published: September 2008

Nonrepairable systems fail just once, so models for nonrepairable systems must account for random lifetimes. It is often reasonable to assume that different units have random lifetimes that are independent and follow the same distribution, leading to the usual i.i.d. (independent and identically distributed) assumption. By contrast, models for repairable systems must account for successive failures in time. For a given system, these times between failure are often not independent and not identically distributed. Various assumptions about the failure process lead to different models for repairable systems. In this article, we present the nonhomogeneous Poisson process (NHPP), the renewal process, the piecewise exponential model, and the modulated power law process (a compromise between renewal process and NHPP). Inference for a single system as well as for multiple copies of a system is discussed. We also discuss briefly the use of covariates or concomitant variables.
Parametric Probability Distributions in Reliability
Authors: Coolen Frank P.A.
Published: September 2008

In this paper, we present an overview of basic parametric probability distributions that are frequently used in reliability. We present some main characteristics of these distributions, and briefly discuss underlying assumptions related to their suitability as models for specific reliability scenarios.
Repair, Inspection, and Replacement Models
Authors: Coolen‐Schrijner Pauline
Published: September 2008

We discuss some basic maintenance models for stochastically deteriorating systems. Optimization of maintenance models with respect to a certain objective function gives the optimal maintenance policy over a predefined time horizon. We consider models involving repair, inspection, and replacement actions.
Human Reliability Assessment
Authors: Kirwan Barry
Published: September 2008

This chapter discusses the nature, role, and maturity of human reliability assessment (HRA). The origins of the approach are described, and the generic process of HRA is defined, focusing on its core components, namely, task analysis, error identification, and quantification of human error probabilities. Validation of methods is also summarized. Contemporary issues such as errors of commission, second generation HRA methods, and the relation between HRA and safety culture are also outlined. The conclusion is that HRA is sufficiently mature to help in many industries, though its evolution is far from over.
Ultrahigh Reliability
Authors: Resnick Marc L.
Published: September 2008

Ultrareliability is a system of systems approach to modeling and achieving reliability. It seeks to increase reliability metrics and mission success by an order of magnitude or more by going beyond traditional approaches to reliability. It involves a rigorous examination of the interacting relationships among system components, people, and the external context at all stages of the system life cycle from determining requirements to system disposal. Interactions are evaluated to quantify their effects on system reliability and mission success and to discover ways to mitigate sources of error and component failure. Interactions include communication, training, operating processes and procedures, and human factors. The external context includes customers, supply chains, and culture.

There are many benefits when organizations achieve ultrareliability in their systems. Maintenance costs can often be reduced significantly because breakdowns become rare. Systems fail rarely and last longer. There are also indirect benefits such as streamlined development, increased customer satisfaction, and a better understanding of how systems operate. For many organizations, even the process of attempting ultrareliability yields several of these benefits, increasingly so as the organization develops its ultrareliability capability.
Risk Attitude
Authors: Munier Bertrand R. , Tapiero Charles
Published: September 2008

The concepts and analytical expressions of absolute and relative risk aversion, in both weak and strong senses, are explained and discussed. Examples are computed. The extension to multivariate risk aversion, the problem of background risk, and the relationship between mean‐variance and expected utility (EU) models are dealt with in an EU framework. Finally, new developments in relation to the question of generalized risk aversion in a non‐EU framework and to the measurement of risk aversion concepts in financial analysis are discussed.
Subjective Expected Utility
Authors: Munier Bertrand R.
Published: September 2008

Origins of expected utility are sketched. Uncertainty is distinguished from simple risk. The axiomatic foundation of subjective expected utility is then developed. Two main currents of thought are presented and discussed.
Subjective Probability
Authors: Curley Shawn P.
Published: September 2008

The need for subjective probabilities arises from the variability that is pervasive in our world. A subjective probability is intended to meaningfully communicate the degree of uncertainty in the face of variability. Surrounding this common theme are several different approaches to defining and using subjective probabilities. The mathematical theory of probability is summarized as a basis for understanding these approaches. This article then describes the alternative perspectives on subjective probability relative to the mathematical theory: subjective probability as one of several interpretations for mathematical probability theory, as a behavioral assessment, as an inherent aspect of all uses of probability theory, and as an uncertainty measure that can be detached from the mathematical theory. The issue of assessing the quality of subjective probabilities is also discussed as it relates to these approaches.
Supra Decision Maker
Authors: Morton Alec
Published: September 2008

Decisions about the regulation of risks typically impact on a number of different sectors of society, and so have to take cognizance of the views of a variety of stakeholders. One way to conceptualize such decisions is to think of the regulatory or governmental decision maker as a “supra decision maker” (supra DM). The notion of a supra DM represents a distinctively decision‐theoretic take on the aggregation of individual preferences, whereby stakeholders' value functions are arguments in the supra DM's utility function. A normative theory of the supra DM exists, which provides conditions for an additive representation of the supra DM's value function, but this theory avoids key questions about securing honest statements of stakeholders' values, and about the comparability of these statements. Despite this drawback, the idea of a supra DM is a useful frame for thinking about, and for private analysis of, decisions that impact multiple stakeholders.
Cross‐Species Extrapolation
Authors: Benignus Vernon A. , Boyes William K. , Bushnell Philip J.
Published: September 2008

The practice of cross‐species extrapolation (CSE) in toxicology is a special case of comparative physiology in which experimental data collected in nonhumans are used to estimate or predict effects of toxicants in humans. Conceptually, data from nonhumans are adjusted to account for physiological differences between species and applied to humans. The components of the process are as follows: (a) adjust for differences in internal doses that result from differences in physiology due to body size and pharmacokinetic differences, (b) account for differences in the sensitivity of species due to physiological processes, and (c) make the adjustments in numerical terms with confidence limits. Steps (a) and (b) are usually done by applications of mathematical/mechanistic physiological models to the extent possible. Step (c) is sometimes done using mechanistic models and sometimes empirically. The state of practice and limitations are discussed. The practice is in early stages of development.
1,3‐Butadiene
Authors: Henderson Rogene F.
Published: September 2008

1,3‐Butadiene (CAS #106‐99‐00) (BD) is a gaseous monomer used in large volumes in the manufacture of synthetic rubber and plastics. It is a four carbon compound with two double bonds, making it ideal for production of polymers and also for oxidation by enzymes in the body to form reactive epoxides that can bind to large molecules such as proteins and DNA. Acute exposures to high concentrations of BD can lead to irritation of the respiratory tract and to narcotic effects on the central nervous system. Animal studies on the effects of chronic exposure to lower concentrations of BD give varying results. In mice, BD is a potent multisite carcinogen and leads to atrophy of ovaries in females and testes in males, in addition to induction of a macrocytic anemia. In rats, BD is a weak carcinogen in endocrine‐related organs and does not affect the reproductive organs or the hematopoietic system. Epidemiology studies indicate that work in the butadiene‐styrene rubber industry is associated with an increase in leukemia (all types), but the data do not allow a separation of BD as the single causative agent.
Life Insurance Markets
Authors: Driver Rebecca
Published: September 2008

This section reviews the life insurance market, looking at both protection and investment policies. It discusses the role of life insurance products in helping households smooth their consumption and the impact of the bequest motive. It considers whether households are under‐ or overinsured, for example, in the context of mandatory annuitization. It discusses the extent to which individuals can commit to life insurance policies and the impact of this on policy design. It looks at longevity risk and investigates the extent to which adverse selection exists in annuity markets. Finally, it discusses distribution and the impact of the Internet in reducing search costs.
Comparative Efficacy Trials (Phase
III
Studies)
Authors: Goldberg Judith D. , Shao Yongzhao
Published: September 2008

A comparative efficacy trial (a phase III study) is a clinical trial that is designed to compare the efficacy of an experimental treatment with that of a control treatment (active or a placebo). This article provides a brief introduction to the design and analysis of phase III trials. The issues discussed include randomization and blinding, selection of populations for study, selection of efficacy endpoints, the risk of type I and II errors, the determination of sample size, multicenter trials, interim analysis, and the assessment and comparison of treatment effects between/among different treatment groups.
Effect Modification and Interaction
Authors: Greenland Sander
Published: September 2008

This article discusses definitions and concepts of effect modification, interaction, synergism, and related concepts and terms.
Scenario Simulation Method for Risk Management
Authors: Jamshidian Farshid , Zhu Yu
Published: September 2008

The scenario simulation method described in this article is a computationally efficient alternative to the traditional Monte Carlo method. The method applies principal component analysis to select key factors, and approximates a multidimensional lognormal distribution of interest rates and exchange rates by a multinomial distribution of key factors. The computational efficiency is further enhanced by stratified sampling at multicurrency stage. Because of the efficiency, the model can afford a large sample size to obtain a satisfactory representation of return distribution for multicurrency fixed‐income and derivative portfolios. The method has wide applications in risk management.
Basic Concepts of Insurance
Authors: Kunreuther Howard
Published: September 2008

Insurance is an economic institution that allows the transfer of financial risk from an individual to a pooled group of risks by means of a two‐party contract. Insurance markets can exist because of
the law of large numbers
, which states that, for a series of independent and identically distributed random variables (such as automobile insurance claims), the variance of the average amount of a claim payment decreases as the number of claims increases. However, natural hazards‐such as earthquakes, floods, and hurricanes—are classified as
catastrophic risks
. There is a high probability that many structures would be damaged or destroyed at the same time. One way that insurers reduce the magnitude of their catastrophic losses is by employing high deductibles. The use of coinsurance, whereby the insurer pays a fraction of any loss that occurs, produces an effect similar to a deductible. Another way of limiting potential losses is for the insurer to place caps on the maximum amount of coverage on any given piece of property. An additional option is for the insurer to buy reinsurance.
Moral Hazard
Authors: Kunreuther Howard
Published: September 2008

Moral hazard refers to an increase in the probability of loss caused by the behavior of the policyholder. Providing insurance protection to an individual may lead that person to behave more carelessly than he or she did before having coverage. If the insurer cannot predict this behavior and relies on past loss data from uninsured individuals to estimate rates, the resulting premium is likely to be too low to cover losses. Ways to avoid moral hazard are to raise the premium, introduce deductibles or coinsurance as part of the insurance contract, place upper limits on the amount of coverage an individual or enterprise can purchase, or require specific mitigation measures as a condition of insurance.
Protection of Infrastructure
Authors: Banks David L. , Hengartner Nicholas
Published: September 2008

Critical infrastructure consists of the basic mechanisms and services essential for a society to function. It must be protected against natural and deliberate damage. These protective efforts should be selected according to careful risk analysis, with consideration of opportunity costs and the interactions between different kinds of investment. For natural threats, there is a large literature that often focuses on the extreme events; for deliberate threats, one must also consider game theory.
Ethical Issues in Using Statistics, Statistical Methods, and Statistical Sources in Work Related to Homeland Security
Authors: Seltzer William , Anderson Margo
Published: September 2008

The article emphasizes that there are distinctive ethical, as well as scientific and legal, issues involved in deploying statistical methods and data for homeland security, even as we note the overlaps between science and ethics on the one hand and law and ethics on the other hand. The article discusses (a) ethical challenges that arise from using inappropriate methods, whether they are “quick‐fix” shortcuts and approximations or elaborate models; (b) the ethical imperative to avoid causing harm to innocent people embodied in the need to respect the principle of statistical confidentiality and the need to take into account the intermediary and long‐term substantive objectives of any risk assessment; and (c) the common ethical failure involved in using only the technical indicator, “risk of disclosure”, rather than its ethically informed counterpart “the harm arising, given the disclosure”, in the assessment of the efficacy alternative approaches. The special ethical challenges that arise when data systems are used to target individuals or population subgroups based on racial, ethnic, religious, or similar attributes are also discussed. The article concludes by stressing the importance of establishing a mechanism for appropriate ethical review and oversight lest, in our untempered zeal for the value of the data and methods we employ or the important objectives of work on homeland security, we become complicit in harming innocent individuals or vulnerable population subgroups.
Cancer Risk Evaluation from Animal Studies
Authors: Melnick Ronald L. , Kissling Grace E.
Published: September 2008

Data from properly designed and evaluated studies in experimental animals have been and continue to be reliable sources of information for the identification of potential human health hazards and the estimation of risks in exposed human populations. Properly designed studies must include (a) animal models that are sensitive to the endpoints under investigation, (b) adequately challenging doses, (c) adequate durations of exposure (at least 2 years for carcinogenicity studies in rats and mice), (d) sufficient numbers of animals per dose group to have adequate statistical power to detect a true effect, (e) multiple dose groups to allow characterization of dose–response relationships, (f) complete and peer‐reviewed histopathological diagnoses, and (g) pair‐wise comparisons with the control group and analyses of trends based on survival‐adjusted tumor rates. Mechanistic information and pharmacokinetic models that have been adequately tested may have an impact on the characterization of dose–response relationships and the estimation of cancer risk at human exposure levels. Setting occupational or environmental exposure standards based on animal carcinogenicity data provides a prudent public health approach to reduce the burden of cancer in exposed populations. More work is necessary to understand the basis for interindividual differences in susceptibility and to properly establish health‐based exposure standards that protect the most vulnerable segments of the general population.
Operational Risk Development
Authors: Davies Brandon J.
Published: September 2008

This paper looks at the application of operational risk ‘models’ under Pillar 1 of the Basel II regulatory framework. It looks both at the conceptual problems underlying the definition of operational risk and the practical issues of data collection associated with modeling operational risk events. It also looks at operational value at risk (Op. VaR) as a measure of operational risk and the issues associated with implementing such a measure; it contrasts Op. VaR with an expected shortfall approach as used in the insurance industry. When managing operational risk, it is proposed that a process control approach operational risk management has many advantages especially when implemented through conformance to ISO and similar standards.
Sampling and Inspection for Monitoring Threats to Homeland Security
Authors: Thompson Colin , Fox David R.
Published: September 2008

In this paper, we describe a simple mathematical model for identifying an appropriate sample size for surveillance programs for monitoring threats to homeland security associated with “objects” passing an inspection point—typically a port of entry.
Dioxin Risk
Authors: Charnley Gail
Published: September 2008

The term
dioxin
refers to a large group of structurally related chemicals that are unintentional byproducts of combustion and certain industrial processes. They are environmentally and biologically persistent. They produce a variety of adverse effects in laboratory animals, but the extent to which environmental levels of dioxin pose a risk to humans is controversial.
Genetic admixture of eight Mexican indigenous populations: Based on five polymarker, HLA‐DQA1, ABO, and RH loci
Authors: Buentello‐Malo Leonora , Peñaloza‐Espinosa Rosenda I. , Salamanca‐Gómez Fabio , Cerda‐Flores Ricardo M.
Published: September 2008

This study explores the genetic admixture of eight Mexican indigenous populations (Otomi‐Ixmiquilpan, Otomi‐Actopan, Tzeltales, Nahua‐Milpa‐Alta, Nahua‐Xochimilco, Nahua‐Zitlala, Nahua‐Ixhuatlancillo, and Nahua‐Coyolillo) on the basis of five PCR‐based polymorphic DNA loci (LDLR, GYPA, HBGG, D7S8, GC), HLA_DQA1, and the blood groups ABO and Rh (CcDEe). Among the indigenous populations, the highest gene frequencies for O and D were 0.9703 and 1.000 for Zitlala (State of Guerrero) and 0.9955 and 0.9414 for Tzeltales (State of Chiapas), respectively. Maximum likelihood estimates of admixture components yield a trihybrid model with Amerindian (assuming that Nahua‐Zitlala is the most representative indigenous population), Spanish, and African ancestry with the admixture proportions: 93.03, 6.03, and 0.94 for Tzeltales, and 28.99, 44.03, and 26.98 for Coyolillo. A contribution of the ancestral populations of Ixhuatlancillo, Actopan, Ixmiquilpan, Milpa‐Alta, and Xochimilco were found with the following average of admixture proportions: 75.84, 22.50, and 1.66. The findings herein demonstrate that the genetic admixture of the Mexican indigenous populations who at present speak the same Amer‐Indian language can be differentiated and that the majority of them have less ancestral indigenous contribution than those considered as Mestizo populations. Am. J. Hum. Biol., 2008. © 2008 Wiley‐Liss, Inc.
High fitness is associated with a healthier programming of body composition at adolescence
Authors: Ortega Francisco B. , Ruiz Jonatan R. , Labayen Idoia , Redondo Carlos , Breidenassel Christina , Gómez Sonia , Moreno Luis A. , Castillo Manuel J.
Published: September 2008

The programming effect of birth weight on later body composition has become of increasing interest in recent years. This programming effect is affected by factors such as gender. Physical fitness could be another factor of influence. This study aimed to examine whether handgrip strength (HG) or cardiovascular fitness (CVF) modify the associations between birth weight and body composition in adolescents. A sample of 1,740 (942 females) adolescents aged 13 to 18.5 years, born at more than 35 weeks of gestation, from the AVENA study was studied. Waist circumference was measured, percentage body fat was calculated from skinfold thicknesses and fat free mass was derived by subtracting fat mass from total body weight. HG and CVF were assessed using the HG test and the 20 m shuttle run test, respectively. Birth weight was positively associated with fat free mass in females with high (above the median) CVF (P < 0.001), but not in those with low (below the median) CVF. In contrast, birth weight was positively associated with total and central adiposity in males with low HG (both P = 0.002), but not in those with high HG. These results suggest that the programming effect of birth weight on later body composition is dependent on gender and fitness level. A high birth weight may have a healthy programming effect on body composition in those adolescents with a high fitness level, being associated with increased fat free mass levels in females and not showing the increased adiposity levels observed in unfit males. Am. J. Hum. Biol., 2008. © 2008 Wiley‐Liss, Inc.
Further investigation into the secrets of successful and unsuccessful mediators
Authors: Goldberg Stephen B. , Shaw Margaret L.
Published: September 2008

Stephen B. Goldberg, of Chicago, brings Alternatives' readers up to date with his survey research on mediation room dynamics. With collaborator and coauthor Margaret L. Shaw, of New York, the research pinpoints why representatives of disputing parties believe they succeeded in mediation. Then, the authors detail a second follow‐up study that asked the same group why mediations fail. Their analysis provides concrete preparation steps for mediation parties and advocates, grounded in the practical results their surveys reveal.
Final call for reservations: Next month's corporate leadership awards dinner
Authors: Bleemer Russ
Published: September 2008

Last call for next month's Corporate Leadership Awards Dinner in NYC honoring Microsoft Corp. and its general counsel, Brad Smith. Also, details about CPR's new website; the free International Dispute Negotiation podcasts, and a call for nominations for the 2008 CPR Institute Awards for Excellence in ADR.
California's supreme court first reasserts an arbitrator power…
Authors: Hunt Jillian Lee , Bleemer Russ , Klimpl Timothy
Published: September 2008

Two significant opinions on mediation confidentiality from opposite coasts emerged this summer. Alternatives' editor Russ Bleemer, and Timothy Klimpl, of New York, analyze the result in the closely watched California Supreme Court Simmons v. Ghaderi case, which provides strong support for the state's mediation protection statutes. Confidentiality is on shakier ground in the hands of New York's top court, with details provided about the Court's affirmance of a subpoena for a mediator's testimony and records. Jillian Lee Hunt, of New York, looks at another California Supreme Court case on the limits of arbitrator power, and there is a report on a United Kingdom survey revealing an insufficient use of employment mediation.
Die Entdeckung und Synthese von marinen Polyethern
Authors: Nicolaou K. C. , Frederick Michael O. , Aversa Robert J.
Published: September 2008

Die beispiellose Struktur des marinen Naturstoffs Brevetoxin B wurde 1981 von den Arbeitsgruppen um Nakanishi und Clardy aufgeklärt. Das leiterförmige Molekülgerüst dieses kondensierten Polyethers, die starke Toxizität und der faszinierende Wirkmechanismus durch Angriff am spannungsgesteuerten Natriumkanal sorgten für Aufmerksamkeit. Syntheseversuche führten zur Entwicklung zahlreicher neuer Methoden und Strategien zum Aufbau von Etherringen und wurden schließlich durch die Totalsynthesen von Brevetoxin B und einigen verwandten, ähnlich anspruchsvollen Zielverbindungen gekrönt. Unter den marinen Polyethern nimmt Maitotoxin als kompliziertester und giftigster Vertreter eine Sonderstellung ein; die Verbindung ist der größte bekannte nichtpolymere Naturstoff überhaupt. Dieser Aufsatz beginnt mit einer kurzen Geschichte zur Isolierung der Biotoxine und beleuchtet ihre biologischen Eigenschaften und Wirkmechanismen. Dann werden Syntheseversuche beschrieben, wobei besonders neue Methoden berücksichtigt werden, die im Laufe dieser Studien entwickelt wurden. Den Abschluss bilden eine Diskussion der noch nicht abgeschlossenen Totalsynthese von Maitotoxin sowie ein Ausblick auf die weitere Entwicklung des Forschungsgebiets.
The Continuing Saga of the Marine Polyether Biotoxins
Authors: Nicolaou K. C. , Frederick Michael O. , Aversa Robert J.
Published: September 2008

The unprecedented structure of the marine natural product brevetoxin B was elucidated by the research group of Nakanishi and Clardy in 1981. The ladderlike molecular architecture of this fused polyether molecule, its potent toxicity, and fascinating voltage‐sensitive sodium channel based mechanism of action immediately captured the imagination of synthetic chemists. Synthetic endeavors resulted in numerous new methods and strategies for the construction of cyclic ethers, and culminated in several impressive total syntheses of this molecule and some of its equally challenging siblings. Of the marine polyethers, maitotoxin is not only the most complex and most toxic of the class, but is also the largest nonpolymeric natural product known to date. This Review begins with a brief history of the isolation of these biotoxins and highlights their biological properties and mechanism of action. Chemical syntheses are then described, with particular emphasis on new methods developed and applied to the total syntheses. The Review ends with a discussion of the, as yet unfinished, story of maitotoxin, and projects into the future of this area of research.
Improvement of thermal and fire properties of polypropylene
Authors: Goodarzi Vahabodin , Monemian Seyed Ali , Angaji Mahmood Torabi , Motahari Siamak
Published: September 2008

In the present research, the thermal stability and fire properties of polypropylene (PP) have been improved through direct melt intercalation of PP, organically modified montmorillonite (OMMT), calcium carbonate (CaCO3) nanoparticles, and conventional flame retardants, i.e., decabromodiphenyl oxide (DB) and antimony trioxide (AO). The morphology of the compound was characterized by means of X‐ray diffractometry and transmission electron microscopy. Thermogravimetry analysis (TGA), cone‐calorimetry, limiting oxygen index, UL‐94, and tensile tests were also employed to investigate thermal and mechanical properties as well as the flammability of the compounds. Data, obtained from TGA, indicated that simultaneous incorporation of both OMMT and CaCO3 nanoparticles forms a synergistic effect to improve both the thermal and thermo‐oxidative stability. The kinetic analysis of polymer degradation showed that the presence of nanoparticles hindered the thermal degradation of PP. The combination of OMMT and CaCO3 was more effective to improve fire properties than OMMT and DB/AO. The experimental results indicated that the incorporation of OMMT and CaCO3 improved both the tensile (i.e., the increase of yield strength, tensile strength, and Young's modulus) and thermal properties. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Diastereoselective Synthesis of N‐Boc‐Norpandamarilactonine‐B and Pandamarilactonine‐A
Authors: Honda Toshio , Katoh Misugi , Ushiwata Makoto , Shigehisa Hiroki
Published: September 2008

Optically pure N‐Boc‐norpandamarilactonine‐B was diastereoselectively synthesized starting from L‐serine by employing a double ring closing metathesis (RCM) of a tetraene derivative as a key reaction. N‐Boc‐norpandamarilactonine‐B obtained was further converted to pandamarilactonine‐A.
Structure‐Activity Relationships Study of Bastadin 6, an Anti‐Angiogenic Brominated‐Tyrosine Derived Metabolite from Marine Sponge
Authors: Kotoku Naoyuki , Hiramatsu Atsushi , Tsujita Hiroaki , Hirakawa Yoichi , Sanagawa Mami , Aoki Shunji , Kobayashi Motomasa
Published: September 2008

A structure‐activity relationship (SAR) study of bastadin 6 (1), a brominated tyrosine‐derived metabolite from Indonesian marine sponge having a potent anti‐angiogenic activity, was executed. The syntheses and their biological evaluation of the oxime‐modified analogues and bromine‐modified analogues revealed that both the oxime moieties and bromine atoms in bastadin 6 (1) play an important role to show the potent and selective anti‐proliferative activity against human umbilical vein endothelial cells (HUVECs).
Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases
Authors: Nguyen Jeffrey‐Tri , Hamada Yoshio , Kimura Tooru , Kiso Yoshiaki
Published: September 2008

In this retrospective, personal review covering our research from the late 1980s until 2007, we outline nearly two‐decade worth of our own work on several aspartic protease inhibitors including those affecting renin, HIV‐1 protease, plasmepsins, β‐secretase, and HTLV‐I protease and we report on aspartic protease inhibitors as potential drugs to treat hypertension, AIDS, malaria, Alzheimer's disease and adult T‐cell leukemia, HTLV‐I associated myelopathy / tropical spastic paraparesis, and various, respectively, associated diseases. Herein, we describe our methods for rational substrate‐based drug design of peptidomimetics that potently inhibit the activity of renin, HIV‐1 protease, plasmepsins, β‐secretase, and HTLV‐I protease accordingly, using an appropriately selected inhibitory residue that contained a hydroxymethylcarbonyl isostere. Although this non‐hydrolyzable isostere mimics the transition state that is formed during protein cleavage of a substrate, the isostere‐containing inhibitor is not cleaved. We highlight our optimization studies in which we used various techniques and tools such as truncation studies, natural and non‐natural amino acid substitution studies, various moieties to promote chemical and pharmacological stability, X‐ray crystallography, computer‐assisted docking and dynamic simulations, quantitative structure‐activity relationship studies, and various other methods that this review can barely mention.
Structure‐Activity Relationships of Pyrazine‐Based CK2 Inhibitors: Synthesis and Evaluation of 2,6‐Disubstituted Pyrazines and 4,6‐Disubstituted Pyrimidines
Authors: Suzuki Yamato , Cluzeau Jérôme , Hara Takafumi , Hirasawa Akira , Tsujimoto Gozoh , Oishi Shinya , Ohno Hiroaki , Fujii Nobutaka
Published: September 2008

Structually related to the known CK2 inhibitors, 2,6‐disubstituted pyrazine and 4,6‐disubstituted pyrimidine derivatives were synthesized and their inhibitory activities toward CK2α and CK2α′ were evaluated. Structure‐activity relationship study has revealed that several pyrazine derivatives bearing a (pyrrol‐3‐yl)acetic acid and a monosubstituted aniline possess potent inhibitory activities.
Evaluation of potential modifiers of the cardiac phenotype in the 22q11.2 deletion syndrome
Authors: Goldmuntz Elizabeth , Driscoll Deborah A. , Emanuel Beverly S. , McDonald‐McGinn Donna , Mei Minghua , Zackai Elaine , Mitchell Laura E.
Published: September 2008

BACKGROUND:

The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion.

METHODS:

Data from 343 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the cardiac phenotype in this disorder. Subjects with and without cardiac malformations, and subjects with and without aortic arch anomalies were compared with respect to sex and race. In addition, in the subset of subjects from whom a DNA sample was available, genotypes for variants of four genes that are involved in the folate‐homocysteine metabolic pathway and that have been implicated as risk factors for other birth defects were compared. Five variants in four genes were genotyped by heteroduplex or restriction digest assays. The chi‐square or Fisher's exact test was used to evaluate the association between the cardiac phenotype and each potential modifier.

RESULTS:

The cardiac phenotype observed in individuals with a 22q11.2 deletion was not significantly associated with either sex or race. The genetic variants that were evaluated also did not appear to be associated with the cardiovascular phenotype.

CONCLUSIONS:

Variation in the cardiac phenotype observed between individuals with a 22q11.2 deletion does not appear to be related to sex, race, or five sequence variants in four folate‐related genes that are located outside of the 22q11.2 region. Birth Defects Research (Part A), 2009. © 2008 Wiley‐Liss, Inc.
The impact of protein exclusion on the purity performance of ion exchange resins
Authors: Zeid J. , Harinarayan C. , van Reis R.
Published: September 2008

Dynamic binding capacity (DBC) decreases with increasing conductivity in the equilibrium regime for ion exchange chromatography. An exclusion regime has been demonstrated in ion exchange resins where DBC increases with increasing conductivity and decreasing protein charge. The purpose of this work was to examine the impact of the exclusion regime on impurity removal. Resin performance was evaluated based on dynamic binding capacities and purity within the exclusion and equilibrium regimes. The results revealed that Chinese hamster ovary proteins (CHOP), a major impurity, exhibit similar exclusion trends as the MAb proteins. The results further the understanding of the exclusion regime and its impact on product purity, a critical area for IEX development and optimization. Biotechnol. Bioeng. 2009; 102: 971–976. © 2008 Wiley Periodicals, Inc.
In situ product recovery of n‐butanol using polymeric resins
Authors: Nielsen David R. , Prather Kristala Jones
Published: September 2008

Polymeric resins with high n‐butanol adsorption affinities were identified from a candidate pool of commercially available materials representing a wide array of physical and chemical properties. Resin hydrophobicity, which was dictated by the chemical structure of its constituent monomer units, most greatly influenced the resin‐aqueous equilibrium partitioning of n‐butanol whereas ionic functionalization appeared to have no effect. In general, those materials derived from poly(styrene‐co‐divinylbenzene) possessed the greatest n‐butanol affinity, while the adsorption potential of these resins was limited by their specific surface area. Resins were tested for their ability to serve as effective in situ product recovery (ISPR) devices in the n‐butanol fermentation by Clostridium acetobutylicum ATCC 824. In small‐scale batch fermentations, the addition of 0.05 kg/L Dowex® Optipore SD‐2 facilitated achievement of effective n‐butanol titers as high as 2.22% (w/v), well above the inhibitory threshold of C. acetobutylicum ATCC 824, and nearly twice that of traditional, single‐phase fermentations. Retrieval of n‐butanol from resins via thermal treatment was demonstrated with high efficiency and predicted to be economically favorable. Due to its modular nature, the proposed ISPR design exhibits strong potential for compatibility with future n‐butanol fermentation efforts. Biotechnol. Bioeng. 2009; 102: 811–821. © 2008 Wiley Periodicals, Inc.
The construction and characterization of two xylan‐degrading chimeric enzymes
Authors: Fan Zhanmin , Wagschal Kurt , Lee Charles C. , Kong Que , Shen Katherine A. , Maiti Indu B. , Yuan Ling
Published: September 2008

Degradation of xylan requires several enzymes. Two chimeric enzymes, xyln–ara and xyln–xylo, were constructed by linking the catalytic portion of a xylanase (xyln) to either an arabinofuranosidase (ara) or a xylosidase (xylo) with a flexible peptide linker. The recombinant parental enzymes and chimeras were produced in E. coli at high levels and purified for characterization of their enzymatic and kinetic properties as well as activities on natural substrates. The chimeras closely resemble the parental enzymes or their mixtures with regard to protein properties. They share similar temperature profiles and have similar catalytic efficiencies as the parental enzymes when assayed using substrates 4‐nitrophenyl‐α‐L‐arabinofuranoside or 2‐nitrophenyl‐ β‐D‐xylopyranoside. The chimeras also show unique enzymatic characteristics. In xylanase activity assays using Remazol Brilliant Blue‐xylan, while the parental xylanase has a pH optimum of pH 8, the chimeras showed shifted pH optima as a consequence of significantly increased activity at pH 6 (the optimal pH for ara and xylo). Both chimeras exhibited additive effects of the parental enzymes when assayed at wide ranges of pH and temperatures. The xyln–xylo chimera had the same activities as the xyln/xylo mixture in hydrolyzing the natural substrates oat spelt xylan and wheat arabinoxylan. Compared to the xyln/ara mixture, the xyln–ara chimera released the same amounts of xylose from oat spelt xylan and ∼30% more from wheat arabinoxylan at pH 6. Our results demonstrate the feasibility and advantages of generating bifunctional enzymes for the improvement of xylan bioconversion. Biotechnol. Bioeng. 2009; 102: 684–692. © 2008 Wiley Periodicals, Inc.
An ACP Structural Switch: Conformational Differences between the Apo and Holo Forms of the Actinorhodin Polyketide Synthase Acyl Carrier Protein
Authors: Evans Simon E. , Williams Christopher , Arthur Christopher J. , Burston Steven G. , Simpson Thomas J. , Crosby John , Crump Matthew P.
Published: September 2008

The actinorhodin (act) synthase acyl carrier protein (ACP) from Streptomyces coelicolor plays a central role in polyketide biosynthesis. Polyketide intermediates are bound to the free sulfhydryl group of a phosphopantetheine arm that is covalently linked to a conserved serine residue in the holo form of the ACP. The solution NMR structures of both the apo and holo forms of the ACP are reported, which represents the first high resolution comparison of these two forms of an ACP. Ensembles of twenty apo and holo structures were calculated and yielded atomic root mean square deviations of well‐ordered backbone atoms to the average coordinates of 0.37 and 0.42 Å, respectively. Three restraints defining the protein to the phosphopantetheine interface were identified. Comparison of the apo and holo forms revealed previously undetected conformational changes. Helix III moved towards helix II (contraction of the ACP), and Leu43 on helix II subtly switched from being solvent exposed to forming intramolecular interactions with the newly added phosphopantetheine side chain. Tryptophan fluorescence and S. coelicolor fatty acid synthase (FAS) holo‐synthase (ACPS) assays indicated that apo‐ACP has a twofold higher affinity (Kd of 1.1 μM) than holo‐ACP (Kd of 2.1 μM) for ACPS. Site‐directed mutagenesis of Leu43 and Asp62 revealed that both mutations affect binding, but have differential affects on modification by ACPS. Leu43 mutations in particular strongly modulate binding affinity for ACPS. Comparison of apo‐ and holo‐ACP structures with known models of the Bacillus subtilis FAS ACP–holo‐acyl carrier protein synthase (ACPS) complex suggests that conformational modulation of helix II and III between apo‐ and holo‐ACP could play a role in dissociation of the ACP–ACPS complex.
Computational techniques applied to the study of the oxidation kinetics of iron and molybdenum cyanocomplexes by peroxynitrous acid
Authors: Herrero H. , Rodado G. M. , Mucientes A. E.
Published: September 2008

The oxidation kinetics of iron and molybdenum cyanocomplexes by peroxynitrous acid were studied by computational techniques. The rate constants of ONOOH decomposition and substrate oxidation were calculated by fitting the experimental data to the solution of the ordinary differential equations mechanism. There is a linear relationship between the rate constants which is solved by varying the initial concentration of one of the reactive species. The rate constants of the steps involved in ONOOH decomposition were also determined following the same procedure and considering a linear relationship between the rate constants. The results are consistent with the values previously found using the conventional method of integration, and they validate the prior steady state assumption. Copyright © 2008 John Wiley & Sons, Ltd.
Highly Phosphorylated Core Oligosaccaride Structures from Cold‐Adapted Psychromonas arctica
Authors: Corsaro Maria M. , Pieretti Giuseppina , Lindner Buko , Lanzetta Rosa , Parrilli Ermenegilda , Tutino Maria L. , Parrilli Michelangelo
Published: September 2008

Many cold habitats contain plenty of microorganisms that represent the most abundant cold‐adapted life forms on earth. These organisms have developed a wide range of adaptations that involve the cell wall of the microorganism. In particular, bacteria enhance the synthesis of unsaturated fatty acids of membrane lipids to maintain the membrane fluidity, but very little is known about the adaptational changes in the structure of the lipopolysaccharides (LPSs), the main constituent of the outer leaflet of the outer membrane of Gram‐negative bacteria. The aim of this study was to investigate the chemical structure of these LPSs for insight into the temperature‐adaptation mechanism. For this objective, the cold‐adapted Psychromonas arctica bacterium, which lives in the arctic sea‐water near Spitzbergen (Svalbard islands, Arctic) was cultivated at 4 °C. The lipooligosaccharides (LOSs) were isolated and analysed by means of chemical analysis and electrospray ionisation high‐resolution Fourier transform mass spectrometry. The LOS was then degraded either by mild hydrazinolysis (O‐deacylation) or with hot 4 M KOH (N‐deacylation). Both products were investigated in detail by using 1H and 13C NMR spectroscopy and mass spectrometry. The core consists of a mixture of species that differ because of the presence of nonstoichiometric D‐fructose and/or D‐galacturonic acid units.
Stereoselective Synthesis of L‐Guluronic Acid Alginates
Authors: Dinkelaar Jasper , van den Bos Leendert J. , Hogendorf Wouter F. J. , Lodder Gerrit , Overkleeft Herman S. , Codée Jeroen D. C. , van der Marel Gijsbert A.
Published: September 2008

The glycosylation properties of gulopyranosides have been mapped out, and it is shown that gulose has an intrinsic preference for the formation of 1,2‐cis‐glycosidic bonds. It is postulated that this glycosylation behaviour originates from nucleophilic attack at the oxacarbenium ion, which adopts the most favourable 3H4 conformation. Building on the stereoselectivity of gulose, a guluronic acid alginate trisaccharide was assembled for the first time by using gulopyranosyl building blocks.
A Potent Integrin Antagonist from a Small Library of Cyclic RGD Pentapeptide Mimics Including Benzyl‐Substituted Azabicycloalkane Amino Acids
Authors: Arosio Daniela , Belvisi Laura , Colombo Lino , Colombo Matteo , Invernizzi Donatella , Manzoni Leonardo , Potenza Donatella , Serra Massimo , Castorina Massimo , Pisano Claudio , Scolastico Carlo
Published: September 2008

A small library of cyclic RGD pentapeptide mimics, including benzyl‐substituted azabicycloalkane amino acids, was synthesized with the aim of developing active and selective integrin antagonists. In vitro binding assays established one particular compound with affinity for both the αvβ3and the αvβ5integrins. The synthesis in solution and the in vitro screening of these RGD derivatives, as well as the determination of the conformational properties of the integrin ligands by spectroscopic and computational methods are described.