bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of
ADME
Studies in Selecting Drug Candidates: Dependence of
ADME
Parameters on Physicochemical Properties
Authors: Hop Cornelis E. C. A.
Published: October 2012

Drug discovery is a time‐consuming and expensive endeavor fraught with many glaring failures in clinical trials. Optimization of drug absorption, distribution, metabolism, and excretion (ADME) parameters continues to play an important role to ensure that the exposure is sufficient to achieve proof of concept, and ultimately efficacy, safely in clinical trials to address unmet medical need. This chapter provides an overview of various
in vitro
and
in vivo
ADME studies commonly employed in drug discovery. Emphasis will be placed on the dependence of ADME parameters on physicochemical properties. The literature has been reviewed to highlight key relationships. However, literature reviews mainly focus on retrospective analyses. Therefore, examples are included to illustrate how these principles can be embedded in drug discovery and used in a prospective drug design fashion with an emphasis on finding the physicochemical “sweet spot” that balances various properties.
In silico
(ADME) models should be an integral part of design as well and the value of various models has been illustrated.
Effective Early Drug Development
Authors: Bekersky Ihor , Walzer Mark , Reid Susan , Tolbert Dwain
Published: October 2012

Drug development is a process that has no “short cuts” in spite of a detailed road map for developing safe and efficacious drugs. In this context, efficient drug development does not mean “quicker” or “less costly” but is a process that must maintain sight of safety and efficacy, produces information/data that is needed for “Go‐No Go” decisions using rational study designs and utilizes flexible study sequences‐not linear, ritualistic design. It is important to achieve the first goal: of an open IND, by use Exploratory Guidance as a tool to facilitate entry into humans when possible (IND‐enabling development). It should be kept in mind that phase 1/1a studies, whether in healthy subjects or patients, provides the learning phase of drug development, whereas, as development progresses to patients, the safe and effective use are confirmed and thus provide the basis for marketing approval.

All aspects of drug development are not addressed here. The present report primarily addresses early development (phase 1)as in many cases the “Go‐NoGo” decisions are defined. An overview of the drug development process , regulatory aspects, and the important IND‐enabling development, is presented. Considering that all development begins with evaluations of animal safety/toxicity, specifics germain to the transition from animals to humans are presented in some detail. The importance of clinical pharmacology, pharmacokinetics, and biopharmaceutics receive a more in depth treatment; collectively as these are the pivotal “learning” areas for successful confirmation as development moves to patients. In this context, decision making studies such as proof of concept and several phase 1 scenarios are presented as examples, drug metabolism and drug–drug interactions studies (in vitroandin vivo) are discussed in some detail.

As was stated earlier, an all‐encompassing review for drug development is not presented. However the text does provide a learning tool for those interested in the studies and decisions obtained to successful early drug development as a prelude to a more comprehensive development culminating with a safe and efficacious drug.
In SilicoModels of Drug Metabolism and Drug Interactions
Authors: Dimelow Richard J. , Metcalfe Paul D. , Thomas Simon
Published: October 2012

In silicomethods have multiple roles to play in drug discovery by reducing costs and increasing screening throughput compared toin vitroandin vivomethods, and by providing information to help guide chemical synthesis in producing compounds having desired properties. In terms of drug metabolism,in silicomethods can make predictions regarding the net rate of metabolism of a compound, the identity of enzyme isoforms that are likely to metabolise a compound, the concentration dependency of metabolism and the identity of expected metabolites. In terms of drug–drug interactions, models have been described for the inhibition of metabolism of one compound by another, and for the compound–dependent induction of drug–metabolising enzymes. Analogous models have been described for a number of properties of drug–transporting proteins. Physiologically‐based pharmacokinetic (PBPK) models can predict thein vivoconsequences of drug–drug interactions observed inin vitroassays or predicted byin silicomodels.

In this chapter we discuss several areas in whichin silicomodeling can contribute to the quantitative or qualitative understanding and prediction of drug metabolism and drug–drug interactions. We describe a number of the availablein silicoapproaches to these application areas and discuss, in some detail, a number of specific application areas in which these methods have been used. We describe the use of physiologically based modelling to obtain predictions of the extent of drug–drug interactions expectedin vivo. We finish with a discussion of some practical aspects of applyingin silicomethods in drug discovery.
Monoclonal Antibody Analyses of Microsomal Human Drug Metabolism and Multifunctional Cytochrome P450
Authors: Krausz Kristopher W. , Gelboin Harry V.
Published: October 2012

Monoclonal antibody (MAb)‐based methods are ideal reagents for cytochrome P450 (P450) research. The properties and molecular diversity of P450s make them extraordinarily suitable for investigation with MAbs. The P450s are present in multiple forms. Defining the role of each P450 isoform for drug metabolism in human liver microsomes (HLM)
in vitro
requires a method that is both highly specific and highly inhibitory to P450 activity and thus can identify and quantitate the contribution of single or several P450 isoforms that metabolize the drug. MAbs have been isolated that are inhibitory and specific to 13 human P450s. The MAbs may also be used to determine the role of each P450 isoform for a variety of nondrug metabolizing activities such as mutagenesis carcinogen S9 activation and binding to DNA and others described in the text.
Introduction: An Overview of the Role of Metabolism in Drug Toxicity
Authors: Nelson Sidney D.
Published: October 2012

The scientific knowledge of drug‐mediated toxicities and the role that drug metabolites play in those toxicities has increased dramatically over the last 50 years. Advances in systems biology approaches to better define the most important factors in drug‐metabolism‐based toxicities should identify new biomarkers that can provide early signals of potential drug toxicities and lead to improvements in drug safety.
Covalent Drug–Protein Adducts: An Exploration of Their Role in Drug‐Induced Liver and General Organ Toxicity
Authors: Evans David C.
Published: October 2012

Overcoming drug induced liver injury continues to represent a challenge for the pharmaceutical industry. Reducing metabolic drug bioactivation is a medicinal chemistry strategy that continues to represent the main platform to minimize this liability. Leveraging covalent binding studies to predict potential for liver toxicity has been widely investigated and appears to have some merit when performed in hepatocyte preparations and integrated with, for example, daily dose but clearly has limitations even when supplemented with data from additional assays that assess hepatotoxicity risk. Here we move beyond a discussion of acute liver toxicity as addressed by chemical synthetic strategies (focus on drug design) by exploring the underlying biochemical science and challenges that still exist regarding the predisposition of some people to idiosyncratic liver toxicity (focus on the individual). The hope is that the positive trajectory of the developing science in this area has the potential to deliver safer drugs to patients in need.
Drug–Drug Interactions 1: Inhibition
Authors: Subramanian Murali , Tracy Timothy S.
Published: October 2012

Predicting a potential drug–drug interaction of a new drug is not only judicious but also mandatory given the high incidences of avoidable deleterious drug–drug interactions that increase the exposure of the victim drug in the subject's bloodstream. Typically, a new chemical entity is tested for its potency to cause a clinically relevant drug–drug interaction. This is determined inin vitrostudies that determine the mechanism of inhibition and the affinity of the inhibitor to a particular enzyme. The affinity (IC50orKi) is subsequently translated into a clinical AUC change viain vitro in vivocorrelations. Translational models have explored roles of fraction metabolized, protein binding, physiological inhibitor concentration, intestinal contribution and the role of non‐P450s towards worsening or ameliorating inhibition. Particular ambiguity exists in terms of the relevant concentration of inhibitor to be used in these models. While predictions have greatly improved and AUC changes within 2‐fold can be made at least 70–90% of the time, the presence of false negatives provides room for caution. Further refinement of the model includes incorporation ofin vivodata to build models, and building sophisticated compartmental models to improve prediction.
Hybrid Mass Analyzers in Drug Metabolism Applications
Authors: Chacko Silvi A. , Ramanathan Ragu , Griffith Humphreys W. , Josephs Jonathan L.
Published: October 2012

Among the analytical techniques used in the biopharmaceutical industry, liquid chromatography mass spectrometry (LC‐MS) assays are highly sought out by the drug metabolism and pharmacokinetic (DMPK) scientists due to their sensitivity, selectivity, specificity, and speed. Some of the desired qualities of the individual mass analyzers (quadrupole mass filters, ion traps and time‐of‐flights) and ion manipulation techniques are combined into one instrument to configure hybrid mass spectrometers. Such hybrid mass spectrometers become even more selective and specific when either time‐of‐flight or Fourier transform based high resolution mass spectrometers (HRMS) are combined with either ion traps or quadrupole mass filters. HRMS‐based hybrid mass analyzers, including quadrupole‐ time‐of‐flights, linear ion trap‐orbitrap, and quadrupole‐orbitrap, have begun to become front line mass spectrometers across the biopharmaceutical industry, especially in the DMPK laboratories. The focus of this book chapter is hybrid mass spectrometers based strategies and procedures available for detection and characterization of xenobiotics at various stages of drug discovery and development.
Micellar Electrokinetic Chromatography
Authors: Khaledi Morteza G.
Published: October 2012

Micellar electrokinetic chromatography (MEKC) has extended the scope of applications of capillary electrophoresis (CE) to separation of uncharged molecules. MEKC offers a combination of unique features of capillary zone electrophoresis (CZE) and reversed phase liquid chromatography (RPLC) such as high efficiency, rapid analysis, small sample size, and small solvent consumption. Another unique advantage of MEKC is the flexibility and versatility of incorporating chemical selectivity in the separation process through careful adjustment of the pseudo‐stationary phase composition. This chapter provides an overview of electrokinetic chromatography covering topics such as fundamental parameters influencing retention, selectivity, and resolution, an overview of different classes of pseudo‐stationary phases, detection, microfluidic platforms for MEKC separations, use of MEKC as part of two‐dimensional separation methods, and applications.
Plasma Protein Binding Methods in Drug Discovery and Development: Bioanalysis
Authors: Cohen Lucinda H. , Nicoll‐Griffith Deborah A.
Published: October 2012

This chapter provides an overview of both conventional and unconventional methods to determine plasma protein binding. Experiments using plasma protein binding advance our understanding of ADME properties to aid in drug candidate selection and development by determination of the unbound drug blood concentrations as well as (potentially) drug concentration at the site of action. Recent progress in automation as well as increased routine performance of the analytical instrumentation has enabled a greater number of compounds to be assayed earlier in discovery, and often with high enough quality to obviate the need for repeat studies during development. Significant effort has been invested to search for high throughput screening methods that reliably and accurately determine protein binding in early drug discovery. The development of 96‐well formats for equilibrium dialysis, ultrafiltration and ultracentrifugation, combined with liquid handling automation have transformed a formerly tedious, labor‐intensive assay into a process that can now be swiftly conducted. In addition, new approaches, referred to as emerging techniques, are also under investigation including chromatographic methods such as the human serum albumin column, spectroscopic methods including surface plasma resonance, solid phase microextraction, Transil™ membrane screening, and capillary electrophoresis methods. Several challenges still remain unsolved, particularly in cases of high protein binding with low exposure levels that fall below the normal limit of quantitation. This chapter describes the impact of high (>99%), undeterminable protein binding on compound developability as well as possible solutions including plasma dilution techniques.
DDI
Risk Assessment and Evaluation in Pharmaceutical Development: Interfacing Drug Metabolism and Clinical Pharmacology
Authors: Venkatakrishnan Karthik
Published: October 2012

Scientifically guided risk assessment and clinical pharmacologic evaluation of pharmacokinetic (PK) drug–drug interactions (DDI) are key components of contemporary drug development and play an integral role in the overall benefit/risk evaluation of new molecular entities (NMEs). DDI risk assessment and clinical evaluation should consider the potential for the NME to alter the PK of coadministered drugs (NME as the precipitant) and also the potential for coadministered drugs to alter NME PK (NME as the object). Risk assessment begins with
in vitro
and mechanistic studies of the NME's potential to alter drug disposition via inhibition or induction of drug‐metabolizing enzymes and transport proteins, and additionally, studies that elucidate the clearance mechanisms of the NME itself. This is followed by a mechanistic and quantitative translation of
in vitro
parameters to estimate clinical PK consequences of a potential DDI (i.e., expected increase in object drug exposure). When the risk for DDI cannot be definitively dismissed as low based on translational assessment from the results of
in vitro
studies, controlled clinical DDI studies are designed to evaluate the clinical pharmacologic correlates of the
in vitro
data. Finally, the results of clinical DDI studies will need to be interpreted in the context of knowledge of the therapeutic index of the object drug, gained from exposure–response understanding for both safety and efficacy endpoints. This chapter provides a technical overview and strategic perspectives on each of these aspects of DDI risk assessment and clinical evaluation, with the use of examples that illustrate applications in drug development and the translation of scientific knowledge to prescribing guidance, in the context of currently available regulatory guidance and published scientific opinion.
Assessing the Hepatic Disposition and Toxicity of Xenobiotics Using Primary Hepatocytes
Authors: Sahi Jasminder , Smith Cornelia , Easterwood LaHoma , Grepper Susan , LeCluyse Edward
Published: October 2012

Over the past decade or more, primary hepatocytes have become a standardin vitrotool to evaluate hepatic drug uptake and metabolism, cytochrome P450 (P450) induction, and drug interactions affecting hepatic metabolism and transport. For studies involving short incubation periods, suspensions of isolated hepatocytes have proved very useful for the study of drug uptake mediated via SLC transporters, metabolism mediated by phase I and phase II drug‐metabolizing enzymes and hepatotoxicity, because the incubation medium and cells can be easily separated for analysis of drug metabolites, after which the hepatocytes can be fractionated or extracted. Whole hepatocytes are advantageous for many metabolism‐related experiments because these cells do not require the addition of exogenous cofactors and metabolic enzymes such as is the case for microsomes and recombinant enzymes. Moreover, membrane transporters, which could be rate limiting for uptake of certain compounds, are functional in suspension hepatocytes. When longer‐term incubations are required, for example, for hepatotoxicity or enzyme regulation studies, the cells need to be maintained in primary culture for several days or weeks, hepatocytes can be cultured in 3D configurations or in sandwich culture, which prolongs the longevity of hepatocyte cultures while retaining essential absorption, distribution, metabolism, excretion (ADME)‐related functions. The large number of hepatocytes produced in a single preparation allows for greater data acquisition compared toin situsystems such as isolated perfused liver orin vivoexperiments. Improved isolation and cryopreservation strategies, including pooling and freezing of hepatocytes from multiple donors, have provided a reproducible and constant source of cells, allowing for screening studies using the same hepatocyte preparation(s) over extended periods of time. The enzyme and transporter kinetics and response to treatment with drug candidates/toxins are similar in both fresh and cryopreserved hepatocytes and reflect the enzyme specificity and potency observedin vivoin a species‐specific manner. Overall, the versatility and biological fidelity of primary hepatocytes makes them an excellent tool for preclinical development andin vitro/in vivoextrapolations for drug metabolism and pharmacokinetics (DMPK).
Uniformly Interconnected Silver‐Nanowire Networks for Transparent Film Heaters
Authors: Kim TaeYoung , Kim Yeon Won , Lee Ho Seok , Kim Hyeongkeun , Yang Woo Seok , Suh Kwang S.
Published: October 2012

The fabrication and design principles for using silver‐nanowire (AgNW) networks as transparent electrodes for flexible film heaters are described. For best practice, AgNWs are synthesized with a small diameter and network structures of the AgNW films are optimized, demonstrating a favorably low surface resistivity in transparent layouts with a high figure‐of‐merit value. To explore their potential in transparent electrodes, a transparent film heater is constructed based on uniformly interconnected AgNW networks, which yields an effective and rapid heating of the film at low input voltages. In addition, the AgNW‐based film heater is capable of accommodating a large amount of compressive or tensile strains in a completely reversible fashion, thereby yielding an excellent mechanical flexibility. The AgNW networks demonstrated here possess attractive features for both conventional and emerging applications of transparent flexible electrodes.
Comparative assessment of the sensitivity of localized surface plasmon resonance transducers and interference‐based Fabry‐Pérot transducers
Authors: Kedem O. , Vaskevich A. , Rubinstein I.
Published: October 2012

Localized surface plasmon resonance (LSPR) transducers have been widely investigated for use in sensing applications. An alternative approach based on interference from thin films (Fabry‐Pérot interferometers) has been previously advanced, offering a rather high sensitivity. Both methods involve easily produced substrates and simple optical setups. Here, the sensitivity offered by typical transducers of the two kinds in a usual sensing scenario is compared quantitatively, using experimental and simulated data, and their respective advantages are discussed. To facilitate the comparison a simple sensitivity parameter is proposed. It is concluded that LSPR transducers offer superior sensitivity for analytes and recognition interfaces of small dimensions (up to several nanometers), especially in a wet environment, while the interference transducers become advantageous for thicker layers in dry conditions. For LSPR transducers, significantly higher sensitivity is obtained by using reflection, rather than transmission, measurements.
Synthesis of highly selective spherical caffeine imprinted polymers via ultrasound‐assisted precipitation polymerization
Authors: Phutthawong Nathaporn , Pattarawarapan Mookda
Published: October 2012

A facile and efficient method for synthesis of molecularly imprinted polymers via ultrasound‐assisted precipitation polymerization was developed. Caffeine was applied as a model template in the imprinting using methacrylic acid and ethylene glycol dimethacrylate as a functional monomer and a crosslinker, respectively. Polymerization under sonochemical conditions proceeded rapidly (within 3 h at 60°C) to afford polymer microspheres with narrow size distributions in excellent yields while maintaining the binding specificity toward the template. It was found that the imprinted polymer prepared at low initial temperature (40°C) exhibited the best caffeine binding performance in terms of specificity and selectivity. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Resistivity Tomography in the Park of Pratolino at Vaglia (Florence, Italy)
Authors: Cozzolino Marilena , Di Giovanni Elisa , Mauriello Paolo , Vanni Desideri Andrea , Patella Domenico
Published: October 2012

Within this article are the results of a geoelectrical survey performed in the park of Pratolino at Vaglia (Florence, Italy), using the multiple dipole–dipole profile technique. The purpose was to outline the location of the main body of the ancient Villa Medici di Pratolino, of which only a separate building, now known as Villa Demidoff, is visible in its full splendour. The three‐dimensional probability‐based electrical resistivity tomography inversion (PERTI) approach has been adopted. The three‐dimensional resistivity tomography inversion provides evidence at the expected depth of burial of a regular pattern of resistivity relative maxima, mostly distributed along the sides of a mesh closely resembling the structural plan of a building. The almost perfect superposition of the high resistivity source image over an official historical plan of the ancient Villa Medici has allowed the regular mesh of the resistivity maxima to be ascribed to remains of walls. As the Pratolino case‐history is one of the first applications of the PERTI algorithm to real field datasets, its performance has been tested using the well‐known ERTLab commercial software as a benchmark. The comparison has shown a very good agreement between the two inversions and also confirmed the much higher computing speed and greater versatility of the PERTI algorithm, as outlined in a previous paper where only synthetic models were tested. Copyright © 2012 John Wiley & Sons, Ltd.
New small proteinase inhibitors from Capsicum annuum seeds: Characterization, stability, spectroscopic analysis and a cDNA cloning
Authors: F. Ribeiro Suzanna F. , S. Fernandes Kátia V. , Santos Izabela S. , Taveira Gabriel B. , Carvalho André O. , Lopes José Luiz S. , Beltramini Leila M. , Rodrigues Rosana , Vasconcelos Ilka M. , Da Cunha Maura , Souza‐Filho Gonçalo A. , Gomes Valdirene M.
Published: October 2012

Recent results from our laboratory have previously shown the purification of a small serine proteinase inhibitor (PI), named CaTI1, from Capsicum annuum seeds. This work demonstrated the characterization of CaTI now named CaTI1, and the identification of two other small serine PIs, named CaTI2 and CaTI3, also present in these seeds. CaTI1 presented molecular mass of 6 kDa and pI value of ∼9.0. CaTI1 inhibited both trypsin and chymotrypsin with inhibition constants (Ki and Ki′) of 14 and 2.8 nM for trypsin and 4.3 and 0.58 nM for chymotrypsin, respectively. Circular dichroism analysis suggested the predominance of both disordered and β‐strands regions in the secondary structure. CaTI1 presented striking physico‐chemical stability. In an attempt to get the entire sequence of CaTI1 we found another PI called CaTI2. The discussion of this finding is in the main text. A degenerate primer was designed based on the sequence of trypsin inhibitor CaTI1 in an attempt to achieve the cloning of this PI. Surprisingly, the alignment of the predicted peptide derived from the cDNA with the protein database showed similarity with other C. annuun PIs, and thus it was called CaTI3. © 2012 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 132–140, 2013.
Using electrophoretic mobility shift assays to measure equilibrium dissociation constants: GAL4‐p53 binding DNA as a model system
Authors: Heffler Michael A. , Walters Ryan D. , Kugel‡ Jennifer F.
Published: October 2012

An undergraduate biochemistry laboratory experiment is described that will teach students the practical and theoretical considerations for measuring the equilibrium dissociation constant (KD) for a protein/DNA interaction using electrophoretic mobility shift assays (EMSAs). An EMSA monitors the migration of DNA through a native gel; the DNA migrates more slowly when bound to a protein. To determine a KD the amount of unbound and protein‐bound DNA in the gel is measured as the protein concentration increases. By performing this experiment, students will be introduced to making affinity measurements and gain experience in performing quantitative EMSAs. The experiment describes measuring the KD for the interaction between the chimeric protein GAL4‐p53 and its DNA recognition site; however, the techniques are adaptable to other DNA binding proteins. In addition, the basic experiment described can be easily expanded to include additional inquiry‐driven experimentation. © 2012 by The International Union of Biochemistry and Molecular Biology
Proteopedia: 3D visualization and annotation of transcription factor–DNA readout modes
Authors: Machado Ana Carolina Dantas , Saleebyan Skyler B. , Holmes Bailey T. , Karelina Maria , Tam Julia , Kim Sharon Y. , Kim Keziah H. , Dror Iris , Hodis Eran , Martz Eric , Compeau Patricia A. , Rohs Remo
Published: October 2012

3D visualization assists in identifying diverse mechanisms of protein‐DNA recognition that can be observed for transcription factors and other DNA binding proteins. We used Proteopedia to illustrate transcription factor‐DNA readout modes with a focus on DNA shape, which can be a function of either nucleotide sequence (Hox proteins) or base pairing geometry (p53). © 2012 by The International Union of Biochemistry and Molecular Biology
Synthesis and Photophysical Characterisation of a Fluorescent Nucleoside Analogue that Signals the Presence of an Abasic Site in RNA
Authors: Tanpure Arun A. , Srivatsan Seergazhi G.
Published: October 2012

The synthesis and site‐specific incorporation of an environment‐sensitive fluorescent nucleoside analogue (2), based on a 5‐(benzofuran‐2‐yl)pyrimidine core, into DNA oligonucleotides (ONs), and its photophysical properties within these ONs are described. Interestingly and unlike 2‐aminopurine (a widely used nucleoside analogue probe), when incorporated into an ON and hybridised with a complementary ON, the emissive nucleoside 2 displays significantly higher emission intensity than the free nucleoside. Furthermore, photophysical characterisation shows that the fluorescence properties of the nucleoside analogue within ONs are significantly influenced by flanking bases, especially by guanosine. By utilising the responsiveness of the nucleoside to changes in base environment, a DNA ON reporter labelled with the emissive nucleoside 2 was constructed; this signalled the presence of an abasic site in a model depurinated sarcin/ricin RNA motif of a eukaryotic 28S rRNA.
Extended Model for Theoretical Determination of Mass Transfer Coefficients in Multiphase Flows – Part 1
Authors: John Saskia , Dujardin Viviane , Kück Ulf Daniel , Mießner Ulrich , Räbiger Norbert
Published: October 2012

Die Auslegung von Reaktoren mit Mehrphasensystemen und die Steuerung überlagerter chemischer Reaktionen stellen auch heute noch Herausforderungen dar. Neuere, erweiterte Erkenntnisse zur Charakterisierung der Meso‐Ebene in Mehrphasenströmungen weisen vielversprechende Optionen in Hinblick auf eine theoretische Abschätzung von Stoffübergangskoeffizienten auf. Bestehende Modellansätze sind bisher nur für enge Anwendungsbereiche der Mehrphasenströmung gültig. Welche Möglichkeiten sich durch eine, auf den neuen Erkenntnissen basierende Zusammenführung der Modelle für die zukünftige Modellierung und die Berechnung des Stofftransportes ergeben, wird in dem vorliegenden Artikel aufgezeigt.
A new two‐step single slope A/D converter for using in CMOS image sensors
Authors: Teymouri Masood
Published: October 2012

This paper presents a high‐speed, high‐resolution column parallel analog‐to‐digital converter (ADC) with global digital error correction. Proposed A/D converter is suitable for using in high‐frame‐rate complementary metal–oxide–semiconductor (CMOS) image sensors. This new method has more advantages than conventional ramp ADC from viewpoint of speed and resolution. A prototype 11‐bit ADC is designed in 0.25‐µm CMOS technology. Moreover, an overall signal‐to‐noise ratio of 63.8 dB can be achieved at 0.5Msample/s. The power dissipation of all 320 column‐parallel ADCs with the peripheral circuits consume 76 mW at 2.5‐V supplies. Copyright © 2012 John Wiley & Sons, Ltd.
Keeping pace with climate change: what is wrong with the evolutionary potential of upper thermal limits?
Authors: Santos Mauro , Castañeda Luis E. , Rezende Enrico L.
Published: October 2012

The potential of populations to evolve in response to ongoing climate change is partly conditioned by the presence of heritable genetic variation in relevant physiological traits. Recent research suggests thatDrosophila melanogasterexhibits negligible heritability, hence little evolutionary potential in heat tolerance when measured under slow heating rates that presumably mimic conditions in nature. Here, we study the effects of directional selection for increased heat tolerance usingDrosophilaas a model system. We combine a physiological model to simulate thermal tolerance assays with multilocus models for quantitative traits. Our simulations show that, whereas the evolutionary response of the genetically determined upper thermal limit (CTmax) is independent of methodological context, the response in knockdown temperatures varies with measurement protocol and is substantially (up to 50%) lower than forCTmax. Realized heritabilities of knockdown temperature may grossly underestimate the true heritability ofCTmax. For instance, assuming that the true heritability ofCTmax in the base population ish2 = 0.25, realized heritabilities of knockdown temperature are around 0.08–0.16 depending on heating rate. These effects are higher in slow heating assays, suggesting that flawed methodology might explain the apparently limited evolutionary potential of cosmopolitanD.melanogaster.
Avoiding minorities: Social invisibility
Authors: Pérez Juan A. , Passini Stefano
Published: October 2012

Three experiments examined how self‐consciousness has an impact on the visual exploration of a social field. The main hypothesis was that merely a photograph of people can trigger a dynamic process of social visual interaction such that minority images are avoided when people are in a state of self‐reflective consciousness. In all three experiments, pairs of pictures—one with characters of social minorities and one with characters of social majorities—were shown to the participants. By means of eye‐tracking technology, the results of Experiment 1 (n = 20) confirmed the hypothesis that in the reflective consciousness condition, people look more at the majority than minority characters. The results of Experiment 2 (n = 89) confirmed the hypothesis that reflective consciousness also induces avoiding reciprocal visual interaction with minorities. Finally, by manipulating the visual interaction (direct vs. non‐direct) with the photos of minority and majority characters, the results of Experiment 3 (n = 56) confirmed the hypothesis that direct visual interaction with minority characters is perceived as being longer and more aversive. The overall conclusion is that self‐reflective consciousness leads people to avoid visual interaction with social minorities, consigning them to social invisibility. Copyright © 2012 John Wiley & Sons, Ltd.
SILAC‐based proteomic analysis to investigate the impact of amyloid precursor protein expression in neuronal‐like B103 cells
Authors: Chaput Dale , Kirouac Lisa Hornbeck , Bell‐Temin Harris , Stevens Stanley M. , Padmanabhan Jaya
Published: October 2012

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. Amyloid plaque formation through aggregation of the amyloid beta peptide derived from amyloid precursor protein (APP) is considered one of the hallmark processes leading to AD pathology; however, the precise role of APP in plaque formation and AD pathogenesis is yet to be determined. Using stable isotope labeling by amino acids in cell culture (SILAC) and MS, protein expression profiles of APP null, rat neuronal‐like B103 cells were compared to B103–695 cells that express the APP isoform, APP‐695. A total of 2979 unique protein groups were identified among three biological replicates and significant protein expression changes were identified in a total of 102 nonredundant proteins. Some of the top biological functions associated with the differentially expressed proteins identified include cellular assembly, organization and morphology, cell cycle, lipid metabolism, protein folding, and PTMs. We report several novel biological pathways influenced by APP‐695 expression in neuronal‐like cells and provide additional framework for investigating altered molecular mechanisms associated with APP expression and processing and contribution to AD pathology.
Neurobehavioral, cellular, and molecular consequences of single and multiple mild blast exposure
Authors: Kamnaksh Alaa , Kwon Sook‐Kyung , Kovesdi Erzsebet , Ahmed Farid , Barry Erin S. , Grunberg Neil E. , Long Joseph , Agoston Denes
Published: October 2012

Mild traumatic brain injury, caused by the exposure to single or repeated blast overpressure, is a principal concern due to its pathological complexity and neurobehavioral similarities with posttraumatic stress disorder. In this study, we exposed rats to a single or multiple (five total; administered on consecutive days) mild blasts, assessed their behavior at 1 and 16 days postinjury) and performed histological and protein analyses of brains and plasma at an early (2 h) and a late (22 days) termination time point. One day postinjury, multiple‐injured (MI) rats showed the least general locomotion and the most depression‐ and anxiety‐related behaviors among the experimental groups; there were no such differences at 16 days. However, at the later time point, both injured groups displayed elevated levels of select protein biomarkers. Histology showed significantly increased numbers of TUNEL+ (terminal‐deoxy‐transferase‐mediated dUTP nick‐end labeling)‐positive cells in the dorsal and ventral hippocampus (DHC and VHC) of both injured groups as early as 2 h after injury. At 22 days, the increase was limited to the VHC of MI animals. Our findings suggest that the exposure to mild blast overpressure triggers early hippocampal cell death as well as neuronal, glial, and vascular damage that likely contribute to significant, albeit transient increases in depression‐ and anxiety‐related behaviors. However, the severity of the observed pathological changes in MI rats failed to support the hypothesized cumulative effect of repeated injury. We infer that at this blast frequency, a potential conditioning phenomenon counteracts with and reduces the extent of subsequent damage in MI rats.
REV1 and DNA polymerase zeta in DNA interstrand crosslink repair
Authors: Sharma Shilpy , Canman Christine E.
Published: October 2012

DNA interstrand crosslinks (ICLs) are covalent linkages between two strands of DNA, and their presence interferes with essential metabolic processes such as transcription and replication. These lesions are extremely toxic, and their repair is essential for genome stability and cell survival. In this review, we will discuss how the removal of ICLs requires interplay between multiple genome maintenance pathways and can occur in the absence of replication (replication‐independent ICL repair) or during S phase (replication‐coupled ICL repair), the latter being the predominant pathway used in mammalian cells. It is now well recognized that translesion DNA synthesis (TLS), especially through the activities of REV1 and DNA polymerase zeta (Polζ), is necessary for both ICL repair pathways operating throughout the cell cycle. Recent studies suggest that the convergence of two replication forks upon an ICL initiates a cascade of events including unhooking of the lesion through the actions of structure‐specific endonucleases, thereby creating a DNA double‐stranded break (DSB). TLS across the unhooked lesion is necessary for restoring the sister chromatid before homologous recombination repair. Biochemical and genetic studies implicate REV1 and Polζ as being essential for performing lesion bypass across the unhooked crosslink, and this step appears to be important for subsequent events to repair the intermediate DSB. The potential role of Fanconi anemia pathway in the regulation of REV1 and Polζ‐dependent TLS and the involvement of additional polymerases, including DNA polymerases kappa, nu, and theta, in the repair of ICLs is also discussed in this review. Environ. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc.
DNA polymerase delta in dna replication and genome maintenance
Authors: Prindle Marc J. , Loeb Lawrence A.
Published: October 2012

The eukaryotic genome is in a constant state of modification and repair. Faithful transmission of the genomic information from parent to daughter cells depends upon an extensive system of surveillance, signaling, and DNA repair, as well as accurate synthesis of DNA during replication. Often, replicative synthesis occurs over regions of DNA that have not yet been repaired, presenting further challenges to genomic stability. DNA polymerase δ (pol δ) occupies a central role in all of these processes: catalyzing the accurate replication of a majority of the genome, participating in several DNA repair synthetic pathways, and contributing structurally to the accurate bypass of problematic lesions during translesion synthesis. The concerted actions of pol δ on the lagging strand, pol ϵ on the leading strand, associated replicative factors, and the mismatch repair (MMR) proteins results in a mutation rate of less than one misincorporation per genome per replication cycle. This low mutation rate provides a high level of protection against genetic defects during development and may prevent the initiation of malignancies in somatic cells. This review explores the role of pol δ in replication fidelity and genome maintenance. Environ. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc.
Complex spatial feedbacks of tephra redistribution, ice melt and surface roughness modulate ablation on tephra covered glaciers
Authors: Nield Joanna M. , Chiverrell Richard C. , Darby Stephen E. , Leyland Julian , Vircavs Larisa H. , Jacobs Benjamin
Published: October 2012

Tephra fallout from the 2011 Grímsvötn eruption onto Svínafellsjökull, Iceland, created an ice‐ash landscape of a type that is rarely studied but is nevertheless common in glacio‐volcanic regions. We used terrestrial laser scanning (TLS) to measure ice surface topography and absorption at high spatial resolution, confirming ablation rates either reduce or increase under thick (insulating) and thin (reduced albedo) ash deposits, respectively. Fourier transform analysis of the TLS data identified that a three‐fold increase in aerodynamic roughness was attributable to an increase in larger (> 0·2 m) surface features. Moreover, TLS measurements revealed the importance of ash redistribution by meltwater in generating differential melting which modifies roughness and ash patchiness, such that the net effect of these spatial ash–ice feedbacks was to reduce ablation rates by up to 59%. The modulating effects of these previously undocumented feedbacks on ablation rates are, therefore, significant and must be correctly parameterized if ash‐covered glacier mass balances are to be predicted correctly. Copyright © 2012 John Wiley & Sons, Ltd.
Toxicity of sediments potentially contaminated by coal mining and natural gas extraction to unionid mussels and commonly tested benthic invertebrates
Authors: Wang Ning , Ingersoll Christopher G. , Kunz James L. , Brumbaugh William G. , Kane Cindy M. , Evans R. Brian , Alexander Steven , Walker Craig , Bakaletz Steve
Published: October 2012

Sediment toxicity tests were conducted to assess potential effects of contaminants associated with coal mining or natural gas extraction activities in the upper Tennessee River basin and eastern Cumberland River basin in the United States. Test species included two unionid mussels (rainbow mussel, Villosa iris, and wavy-rayed lampmussel, Lampsilis fasciola, 28-d exposures), and the commonly tested amphipod, Hyalella azteca (28-d exposure) and midge, Chironomus dilutus (10-d exposure). Sediments were collected from seven test sites with mussel communities classified as impacted and in proximity to coal mining or gas extraction activities, and from five reference sites with mussel communities classified as not impacted and no or limited coal mining or gas extraction activities. Additional samples were collected from six test sites potentially with high concentrations of polycyclic aromatic hydrocarbons (PAHs) and from a test site contaminated by a coal ash spill. Mean survival, length, or biomass of one or more test species was reduced in 10 of 14 test samples (71%) from impacted areas relative to the response of organisms in the five reference samples. A higher proportion of samples was classified as toxic to mussels (63% for rainbow mussels, 50% for wavy-rayed lampmussels) compared with amphipods (38%) or midge (38%). Concentrations of total recoverable metals and total PAHs in sediments did not exceed effects-based probable effect concentrations (PECs). However, the survival, length, or biomasses of the mussels were reduced significantly with increasing PEC quotients for metals and for total PAHs, or with increasing sum equilibrium-partitioning sediment benchmark toxic units for PAHs. The growth of the rainbow mussel also significantly decreased with increasing concentrations of a major anion (chloride) and major cations (calcium and magnesium) in sediment pore water. Results of the present study indicated that (1) the findings from laboratory tests were generally consistent with the field observations of impacts on mussel populations; (2) total recoverable metals, PAHs, or major ions, or all three in sediments might have contributed to the sediment toxicity; (3) the mussels were more sensitive to the contaminants in sediments than the commonly tested amphipod and midge; and (4) a sediment toxicity benchmark of 1.0 based on PECs may not be protective of mussels. Environ. Toxicol. Chem. 2013;32:207–221. © 2012 SETAC
Individual variation in body burden, lipid status, and reproductive investment is related to maternal transfer of a brominated diphenyl ether (BDE-99) to eggs in the zebra finch
Authors: Eng Margaret L. , Elliott John E. , Letcher Robert J. , Williams Tony D.
Published: October 2012

Avian eggs are exposed to hydrophobic contaminants through maternal transfer. How maternal transfer of contaminants within a species is influenced by individual variation in characteristics such as body burden, yolk precursor levels, or reproductive investment is not understood. The authors investigated sources of variation in the maternal transfer of 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99) in zebra finches (Taeniopygia guttata). The authors dosed adult female zebra finches with levels of BDE-99 relevant to exposure in wild birds (0, 33.7 or 173.8 ng/g body wt/d) for three weeks prior to pairing. Maternal BDE-99 and very-low-density lipoprotein (VLDL) in plasma were measured during egg formation and at clutch completion, and BDE-99 was measured in the corresponding egg. The lipid-normalized egg-to-maternal tissue BDE-99 relationship decreased with increasing maternal burden. Individual variation in maternal VLDL was related to BDE-99 transfer to the eggs when BDE-99 was at background levels in control birds, but not when BDE-99 was elevated in dosed birds. The decrease in maternal plasma BDE-99 over the laying period was only significant (p < 0.05) in the high-dose birds. Finally, the decrease in BDE-99 in maternal plasma during egg-laying was significantly positively correlated with clutch mass in the high-dose group. These results suggest that the relationship between maternal and egg contaminant levels can be highly variable. This has significant implications for using eggs as indicators of adult or environmental concentrations. Environ. Toxicol. Chem. 2013;32:345–352. © 2012 SETAC
Wireless MIMO switching: network‐coded MMSE relaying and user group selection
Authors: Wang Fanggang
Published: October 2012

A wireless relay that forms a one‐to‐one mapping from the inputs (uplinks) to the outputs (downlinks) is called a multiple‐input multiple‐output (MIMO) switch. The MIMO switch carries outprecode‐and‐forward, where all users send their signals in the uplink, and then, the MIMO switch precodes the received vector signal for broadcasting in the downlink. Ideally, each user employs a receive filter to recover its desired signal from one other user with no or little interference from other users. We first propose a joint design of the precoder and the receive filters to achieve the minimum‐mean‐ square‐error (MMSE), where network coding technique is incorporated, assuming that full channel state information is available at the relay. When the number of relay antennas is smaller than the number of source users, that is, the users that need to transmit signals, we investigate user group selection algorithms for the proposed MMSE relaying schemes. Our results indicate that the proposed MMSE relaying scheme outperforms the existing zero‐forcing/MMSE schemes. In addition, the results validate the efficiency of the proposed user group selection algorithms. Copyright © 2012 John Wiley & Sons, Ltd.
Recent Progress in the Synthesis and Structural Clarification of Thermotropic Cubic Phases
Authors: Kutsumizu Shoichi
Published: October 2012

This review article focuses on recent advances and challenges in the field of thermotropic cubic phases of the bicontinuous type (Cubbi) formed by low molecular mass molecules. In the Cubbi phases, the constituent molecules self‐organize into 3D network structures, although local molecular diffusional motions are preserved to some extent. This review illustrates which types of molecules form such structures, and summarizes the latest developments in structural characterization. Moreover, their phase behaviors, and analogies and differences in comparison with other related systems such as lyotropic liquid crystals and block copolymers are discussed. Finally, potential applications utilizing the dynamically ordered 3D network structures are presented.