bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipid Profile and Liver Histochemistry in Animal Models Exposed to Cigarette Smoke
Authors: Omotoso Gabriel Olaiya , Enaibe Bernard U , Akinola Oluwole Busayo , Kadir R Eniola , Akinlolu Adelaja A , Oyewopo Adeoye Oyetunji , Olawuyi Solomon Toluwase , Adebayo Joseph Oluwatope , Apalowo , Olanrewaju Samuel , Sofoluwe Adeyemi Victor
Published: February 2012

Cigarette smoke is known to be an important predisposing factor to many diseased conditions, such as cardiovascular diseases, liver disease, atherosclerosis and other metabolic disorders. The aim of this study was to examine the effects of exposure to smoke from burnt cotton wool and cigarette on plasma lipids, liver biochemistry and histology, in adult Wistar rats. The animals were divided into three groups of Control A: exposed to fresh atmospheric air; Group B: exposed to cotton wool smoke; and, Group C, exposed to cigarette smoke; and the experiment lasted for 35 days. The animals exposed to cigarette smoke and cotton wool smoke showed higher values of low density lipoprotein (LDL), and lower values of high density lipoprotein (HDL) compared to the control. The observation of the micro architecture and enzymes of the liver tissue revealed reduction in the number and size of liver cells, numerous fibrous tissues, elevated liver transaminases and reduction in endogenous anti-oxidants, with evidence of fatty degeneration, in animals exposed to cigarette smoke compared to those exposed to cotton wool smoke and fresh atmospheric air. Cigarette smoke caused accumulation of lipids in the liver cells, with evidence of on-going necrosis and fibrosis, which indicated the presence of non-alcoholic fatty liver disease.
Evaluation of Different Date Palm Varieties and Pheromone Traps Against Red Palm Weevil (Rhynchophorus ferrugineus) in Sindh
Authors: Shar Muhammad Usman , Rustamani Maqsood Anwar , Nizamani Shafi Muhammad , Buriro Abdul Sattar , Bhutto Liaquat Ali , Lodhi Abdul Mubeen
Published: February 2012

In a two-year study ten commercial date palm varieties were evaluated. The varieties showed varying response to Rhynchophorus ferrugineus Oliv; some varieties suffered heavy infestation while others indicated tolerance against R. ferrugineus. The most tolerant varieties with less infestation percentage against R. ferrugineus were Muzawati (8%) followed by Pathri (12%), Thothar (15%), Khar and Shakri (16%) respectively. The varieties which suffered high infestation rate were Karbalain, Dhedhi, Fasli, Aseel and Eidan Shah. To control the R. ferrugineus infestation pheromone trapping system was used. Significantly more R. ferrugineus (18-21) adults were captured during the 1st, 2nd, 3rd week of July and 2nd week of June. The studies conducted will be helpful in survey and control of R. ferrugineus infestation in Khairpur District of Sindh province.
Structure and Function of Cytochrome P450 Enzymes
Authors: Ortiz de Montellano Paul R.
Published: February 2012

This chapter summarizes the distribution and function of the human cytochrome P450 enzymes, including their relative abundance and polymorphisms, general spectroscopic properties, and structures. The universal catalytic cycle of cytochrome P450 enzymes, including the requisite electron‐donor partners, is also described.
Transcriptional Regulation of Cytochrome P450 Genes
Authors: Fraser Emily A. , Henderson Colin J. , Wolf C. Roland
Published: February 2012

The discovery and characterization of nuclear receptors, such as the aryl hydrocarbon receptor (AHR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR), and their involvement in the transcriptional regulation of cytochrome P450s have greatly increased our understanding of this process while providing a mechanistic basis for additional levels of control. This chapter details the role of AHR, CAR, and PXR in controlling cytochrome P450 expression, including cross talk between the receptors, the different classes of ligands bound by the receptors and the responses that they elicit, polymorphisms and splice variants of CAR and PXR, and species specificity in the context of CAR and PXR. Each of these factors and the interplay between them contribute to the growing layers of complexity that are being uncovered with regard to the transcriptional regulation of cytochrome P450 genes. The potential contributions of humanized transgenic models to this field are also discussed.
Carboxylesterases
Authors: Yan Bingfang
Published: February 2012

Carboxylesterases (CESs, E.C.3.1.1.1) constitute a large class of enzymes that hydrolyze chemicals containing such a functional group as a carboxylic acid ester, amide, and thioester. These enzymes are major pharmacokinetic determinants of ester/amide drugs and detoxify against organophosphorus and pyrethroid insecticides. In addition, these enzymes hydrolyze endogenous lipids and involve the assembling of lipoproteins. CESs exhibit overlapping substrate specificity; however, many drugs are hydrolyzed predominately by a single CES. Although there are exceptions, the relative sizes between the alcohol and acyl (acid) moieties of an ester contribute significantly to the isoform‐specific hydrolysis. CES activity is widely distributed in mammalian tissues, with the highest level in liver microsomes. High abundance of CESs in the liver is linked to certain cellular roles, notably in directing protein trafficking. CESs belong to the superfamily of α/β fold proteins and have similar crystal structure to other enzymes in this superfamily. CESs use a two‐step mechanism for catalysis. Hydrolysis of carboxylic acid esters leads to the formation of an alcohol and a carboxylic acid. Compounds with these moieties are substrates for conjugation enzymes or transporters. Likewise, hydrolysis may create or eliminate a substrate of other phase I enzymes, particularly cytochrome P450s. Like many other drug‐metabolizing enzymes, the expression of CESs is regulated by many factors including age, hormones, therapeutic agents, and environmental chemicals. Mammalian species express multiple forms of CESs. However, there are notable differences in substrate specificity, tissue distribution, and regulated expression.
Functional Genomics of the Human Glutathione Transferases
Authors: Board Philip G.
Published: February 2012

The glutathione transferase (GST) super family of enzymes catalyze the conjugation of glutathione (GSH) to a wide range of exogenous and endogenous compounds. In addition to catalytic reactions, the GSTs also modulate several cell signaling kinases and ion channels such as Jun N‐terminal kinase and ryanodine receptors via protein /protein interactions. Pharmacogenetic studies have identified variations in drug response and susceptibility to cancer and other disorders associated with variant GST isoforms. In humans, the cytosolic GSTs have been subdivided into seven distinct classes termedAlpha, Mu, Pi, Theta, Sigma, Zeta, andOmegaand there are multiple genes in some classes. So far, 48 allelic variants that cause amino acid substitutions have been documented, and in many cases, the variant proteins have been functionally and structurally characterized. Some polymorphisms in promoter regions have been shown to affect the level of GST expressionin vitroandin vivo, and this area requires further investigation. Although the various members of the GST superfamily are characterized by striking differences in the reactions they catalyze and their substrate specificities, they share a similar structural fold. Representative structures of all the human GST classes have been determined by X‐ray crystallography.
ADMEProfiling in Drug Discovery and Development: An Overview
Authors: Bohnert Tonika , Prakash Chandra
Published: February 2012

The applications of parallel synthesis and combinatory chemistry to expedite lead finding and lead optimization processes have shifted the chemical libraries toward poorer biopharmaceutical, ADME (absorption, distribution, metabolism, and excretion), and pharmacokinetic (PK) properties. A drug candidate should have desirable biopharmaceutical properties such as good solubility and good permeability, as well as optimal and ADME/PK properties. The early knowledge of liability of biopharmaceutical, ADME/PK, and DDI properties is very valuable in drug candidate selection process. In the last one decade, multiplein silico, in vitro,andin vivoADME studies have been developed and implemented in the drug discovery and development process to alert chemists and drug metabolism scientists of the potential ADME, PK and DDI issues in the clinic. In this chapter, we attempt to discuss these various ADME profiling approaches in drug discovery and development process and the latest technologies of the selected assays.
Drug Metabolism in Drug Safety Evaluation
Authors: Baillie Thomas A.
Published: February 2012

Over the past two decades, drug metabolism has become an indispensible component of both research and development activities in the pharmaceutical industry, where it has played an increasingly important role in support of the safety assessment of new chemical entities (NCEs). In response to recent regulatory guidance on the safety evaluation of metabolites of candidate drugs in humans, novel approaches have been adopted to define the identities and levels of circulating metabolites in the plasma of both human subjects and the animal species employed in safety assessment programs. Considering the factors that need to be taken into account in assessing the safety of metabolites of NCEs, biotransformation products can be classified into two categories on the basis of their chemical reactivity: namely, “stable” and “chemically reactive.” In this chapter, the different experimental approaches employed to study these two groups are outlined, and the implications of the findings for lead optimization efforts in drug discovery, and for later phase clinical development programs, are discussed in the context of establishing the human safety of the NCE.
In VitroToxicity Screening in Early Drug Discovery: Importance of Metabolism and Reactive Metabolites
Authors: MKim James M.
Published: February 2012

In recent years, pharmaceutical companies have focused on understanding the potential liabilities associated with new chemical entities while they are optimizing standard drug like properties. When this tandem approach to drug development is applied, the result is the selection of a candidate for preclinical safety testing, which has a much higher probability of success. Bioavailability and metabolism are important determinants of drug like properties and toxicity. Absorption from the gut following the oral administration of a drug is important and is controlled by several factors. Metabolism in enterocytes and liver can profoundly affect both efficacy and toxicity. Data obtained fromin vitrosystems for determining gut absorption, metabolism, metabolic activation, activation or inhibition of molecular signaling pathways of toxicity, and biochemical function can be used to predictin vivoadverse events with a high degree of accuracy. The application ofin vitroscreening methods can also identify risk profiles that can help identify low incidence adverse events in humans that would result in the withdrawal of promising new drugs. By identifying and characterizing compound liabilities (hazard), it is possible to perform risk assessment analysis before moving a new drug candidate into preclinical safety testing, which will reduce late‐stage attrition.
The Application of Preclinical Toxicogenomics for Predicting and Understanding Drug‐Induced Toxicity and Metabolism
Authors: Fielden Mark , Karbowski Christine
Published: February 2012

The pharmaceutical industry is challenged by high rates of attrition during development because of preclinical and clinical toxicities that are not adequately predicted using current preclinical testing paradigms. Large‐scale gene expression profiling technologies, such as toxicogenomics, are being applied preclinically during drug discovery and lead optimization to diagnose and predict drug‐induced effects. When used together with classical pharmacokinetic parameters, toxicogenomics can provide an understanding of the pathways (phases I and II) of drug metabolism induced by drug treatment. This chapter focuses on the application of toxicogenomics in drug discovery for the prediction and mechanistic understanding of drug‐induced toxicity, as well as understanding mechanisms of drug metabolism for small‐molecule therapeutics.
Genetics of Drug Disposition
Authors: Bhathena Anahita , Katz David A.
Published: February 2012

Drug disposition, a complex process culminating from the interplay of numerous drug–metabolizing enzymes, drug transport proteins, serum‐binding proteins, and transcription factors, is affected by multiple environmental and endogenous factors. Genetic variations in drug–metabolizing enzymes and drug transport proteins contribute toward variability in drug disposition. Our knowledge of these functional genetic variants and the tools to interrogate them are well developed. These tools have found use in drug development within the pharmaceutical industry, and for limited applications, making clinical treatment decisions. This chapter discusses the genetic variations in drug–metabolizing enzymes and transporters and their relevance for clinical pharmacokinetics.
Animal Models of Idiosyncratic, Drug‐Induced Liver Injury: Emphasis on the Inflammatory Stress Hypothesis
Authors: Zou Wei , Roth Robert A. , Ganey Patricia E.
Published: February 2012

Idiosyncratic, drug‐induced liver injury (IDILI) can result in permanent disability or death in patients, thus these reactions have obvious importance to human health. In addition, these reactions lead to withdrawals and restrictions in the use of efficacious drugs. Mechanisms by which IDILI occurs are unknown, and although many hypotheses have been proposed, there exists no conclusive support in people for any of them. Drugs that cause IDILI typically escape identification until they are in use in large numbers of people; accordingly, animal models to identify early in development which drugs have the propensity to cause IDILI and to study potential mechanisms would be useful. The inflammatory stress hypothesis proposes that an inflammatory episode can interact with drug exposure to render an individual susceptible to IDILI. This hypothesis has been the basis for the development of animal models in which rodents develop liver injury from exposure to drugs that cause IDILI in people. This chapter describes current hypotheses regarding IDILI and elaborates on the inflammatory stress hypothesis. Results of studies using the drug sulindac are emphasized.
Regulation of Drug Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer
Authors: Morgan Edward T. , Lee Choon‐Myung , Nyagode Beatrice A.
Published: February 2012

Under conditions of innate immune system activation (i.e., inflammation), the functions of specific cytochrome P450 enzymes, other drug metabolizing enzymes (DMEs), and drug transporters (DTs) are altered in the liver, small intestine, lung, kidney, and central nervous system (CNS). Many of these effects are primarily manifest at the transcriptional/RNA level, leading to corresponding changes in protein levels and function. This not only leads to altered drug and xenobiotic toxicity and action in diseased humans, but also has importance for disease therapy with biologic drugs that target inflammatory mediators or their receptors. Major roles for proinflammatory cytokines such as interleukin‐6 (IL‐6), IL‐1β, and tumor necrosis factor‐α(TNFα) are inferred from the abilities of these agents to affect DMEs and DTs in cultured cells andin vivo, but thein vivocontributions of cytokines to regulation of these proteins in different inflammatory disease states is still poorly understood.
Infusion Nanoelectrospray Ionization Mass Spectrometry
Authors: Henion Jack
Published: February 2012

This report reviews the introductory aspects of electrospray ionization coupled with mass spectrometry and highlights those aspects of electrospray that play an important role in its application to analyzing real‐world samples. Following a discussion of matrix effects, factors that affect analyte response and sensitivity, and the flow rate factors of the spray solvent, the relative benefits of on‐line HPLC or UPLC are contrasted with an infusion electrospray sample introduction approach, which, of course, precludes any aspects of chromatographic separation. The introduction of samples via infusion bypasses the need for a chromatographic system, including its pumps, autosampler, separation column, and the compromise of a mobile phase, which must accomplish the chromatographic separation while also allowing the electrospray ionization process to occur. Thus, infusion sample introduction is in principle much easier to accomplish. However, there are clear benefits to employing HPLC for the analysis of complex samples. So, how can infusion sample introduction be worthwhile?

It can be worthwhile because nanoelectrospray, or electrospray at 20–500 nL/min solvent flow rates, provides some unique benefits over the higher flow rate regime that has been customarily used. Thus, nanoelectrospray provides improved sensitivity, reduced matrix suppression, and normalized response from differing analytes and conserves precious samples if this is an issue. This review overviews these principles and provides several successful examples of published work where infusion nanoelectrospray experiments have merit.
Whole‐Body Autoradiography and Microautoradiography in Drug Discovery and Development
Authors: Solon Eric G.
Published: February 2012

This chapter describes the following three approaches used to study the tissue distribution of chemical and biological compounds in laboratory animals: (i) organ collection, homogenization/combustion, and liquid scintillation counting (LSC) analysis; (ii) whole‐body autoradiography (WBA), which includes quantitative whole‐body autoradiography (QWBA); and (iii) microautoradiography (MARG), which qualitatively resolves the localization of compounds to the cellular level in a histological preparation. LSC, WBA, QWBA, and MARG studies require the use of a radiolabeled chemical or biological test compound, which provides for the tracking and quantification of both the parent molecule and potential metabolites that might be formed. This chapter discusses the history, advantages, limitations, and examples of the application of each technique.
CYP450 Enzymes in Drug Discovery and Development: An Overview
Authors: Xu Lin , Das Biplab , Prakash Chandra
Published: February 2012

Cytochrome P450 enzymes play an important role in the metabolism of foreign molecules (drugs and environmental chemicals) and endogenous compounds. This large enzyme family facilitates to eliminate xenobiotics from the body and catalyzes the catabolism of endogenous compounds for their physiological functions. In this chapter, we describe the most recent advances in our knowledge and application of P450 enzymes in drug discovery and development with particular emphasis on their involvement in the metabolism of drugs. In addition, we have also summarized the basic catalytic activity of this enzyme family, commonly observed biotransformation in drugs, the species and ethnic variation in the expression of P450 enzymes, and the tools used to extrapolate metabolism and toxicity in animals to humans.
Predicting Human Biotransformation Pathways
Authors: Anderson Shelby , Luffer‐Atlas Debra , Pat Knadler Mary
Published: February 2012

Knowledge of the human biotransformation pathways is critical for safe and effective dosing of a new molecular entity (NME). Predicting human biotransformation pathways begins in the early discovery phase wherein silicoandin vitrotools are utilized. As development progresses, additional studies are conducted bothin vitroandin vivo, first in animals and then in humans.In vivostudies start with determination of a metabolic profile followed by administration of a radiolabeled dose of an NME to determine the extent of metabolism and the identity of the metabolites.
Laboratory Maintenance of Agrobacterium
Authors: Morton Elise R. , Fuqua Clay
Published: February 2012

Agrobacterium species are plant‐associated relatives of the rhizobia. Several species cause plant diseases such as crown gall and hairy root, although there are also avirulent species. A. tumefaciens is the most intensively studied species and causes crown gall, a neoplastic disease that occurs on a variety of plants. Virulence is specified by large plasmids, and in the case of A. tumefaciens this is called the Ti (tumor‐inducing) plasmid. During pathogenesis, virulent agrobacteria copy a segment of the Ti plasmid and transfer it to the plant, where it subsequently integrates into the plant genome and expresses genes that result in the disease symptoms. A. tumefaciens has been used extensively as a plant genetic engineering tool, and is also a model microorganism that has been well studied for host‐microbe associations, horizontal gene transfer, cell‐cell communication, and biofilm formation. This unit describes standard protocols for laboratory cultivation of A. tumefaciens. Curr. Protoc. Microbiol. 24:3D.1.1‐3D.1.16. © 2012 by John Wiley & Sons, Inc.
Laboratory Maintenance of Helicobacter Species
Authors: Blanchard Thomas G. , Nedrud John G.
Published: February 2012

Helicobacter species are Gram‐negative bacteria that colonize the gastric or intestinal mucosa of many mammalian and avian hosts and induce histologic inflammation. The association of H. pylori with gastritis, peptic ulcer disease, and gastric cancers makes it a significant human pathogen. Animal models for these diseases are being used to explore the pathogenesis of H. pylori infection and in vaccine development. Both bacterial and host factors contribute to Helicobacter pathogenesis; therefore, the microbiology is very important. This unit describes how to culture the most commonly used gastric Helicobacter species, H. pylori, H. mustelae, and H. felis. Curr. Protoc. Microbiol. 24:8B.1.1‐8B.1.19. © 2012 by John Wiley & Sons, Inc.
Cell Culture Assay for Transient Replication of Human and Animal Papillomaviruses
Authors: Wilson Van G.
Published: February 2012

This unit contains protocols for evaluation of replication functionality of papillomavirus genomes or subgenomic fragments. Replication is measured after transient cotransfection of the genome (or subgenomic fragment) with expression vectors encoding the viral E1 and E2 proteins. Input DNA is methylated at the adenine of GATC sequences by propagation in E. coli. DNA that replicates in mammalian cells will lose the adenine methylation and become DpnI‐resistant, while residual methylated input DNA will remain DpnI‐sensitive. After transfection, DNA extraction, and DpnI digestion, replicated DNA can be detected by Southern blotting as a full‐length plasmid, since it is resistant to digestion. This assay can be used to map the genomic location of a functional origin or to evaluate replication activity of mutations in either the origin DNA sequences or the E1 or E2 proteins. Curr. Protoc. Microbiol. 24:14B.1.1‐14B.1.18. © 2012 by John Wiley & Sons, Inc.
Human Cytomegalovirus: Bacterial Artificial Chromosome (BAC) Cloning and Genetic Manipulation
Authors: Paredes Anne M. , Yu Dong
Published: February 2012

The understanding of human cytomegalovirus (HCMV) biology was long hindered by the inability to perform efficient viral genetic analysis. This hurdle was recently overcome when the genomes of multiple HCMV strains were cloned as infectious bacterial artificial chromosomes (BACs). The BAC system takes advantage of the single‐copy F plasmid of E. coli that can stably carry large pieces of foreign DNA. In this system, a recombinant HCMV virus carrying a modified F plasmid is first generated in eukaryotic cells. Recombinant viral genomes are then isolated and recovered in E. coli as BAC clones. BAC‐captured viral genomes can be manipulated using prokaryotic genetics, and recombinant virus can be reconstituted from BAC transfection in eukaryotic cells. The BAC reverse genetic system provides a reliable and efficient method to introduce genetic alterations into the viral genome in E.coli and subsequently analyze their effects on virus biology in eukaryotic cells. Curr. Protoc. Microbiol. 24:14E.1.1‐14E.1.33. © 2012 by John Wiley & Sons, Inc.
Tin Oxide with Controlled Morphology and Crystallinity by Atomic Layer Deposition onto Graphene Nanosheets for Enhanced Lithium Storage
Authors: Li Xifei , Meng Xiangbo , Liu Jian , Geng Dongsheng , Zhang Yong , Banis Mohammad Norouzi , Li Yongliang , Yang Jinli , Li Ruying , Sun Xueliang , Cai Mei , Verbrugge Mark W.
Published: February 2012

As one of the most promising negative electrode materials in lithium‐ion batteries (LIBs), SnO2 experiences intense investigation due to its high specific capacity and energy density, relative to conventional graphite anodes. In this study, for the first time, atomic layer deposition (ALD) is used to deposit SnO2, containing both amorphous and crystalline phases, onto graphene nanosheets (GNS) as anodes for LIBs. The resultant SnO2‐graphene nanocomposites exhibit a sandwich structure, and, when cycled against a lithium counter electrode, demonstrate a promising electrochemical performance. It is demonstrated that the introduction of GNS into the nanocomposites is beneficial for the anodes by increasing their electrical conductivity and releasing strain energy: thus, the nanocomposite electrode materials maintain a high electrical conductivity and flexibility. It is found that the amorphous SnO2‐GNS is more effective than the crystalline SnO2‐GNS in overcoming electrochemical and mechanical degradation; this observation is consistent with the intrinsically isotropic nature of the amorphous SnO2, which can mitigate the large volume changes associated with charge/discharge processes. It is observed that after 150 charge/discharge cycles, 793 mA h g−1 is achieved. Moreover, a higher coulombic efficiency is obtained for the amorphous SnO2‐GNS composite anode. This study provides an approach to fabricate novel anode materials and clarifies the influence of SnO2 phases on the electrochemical performance of LIBs.
WDR62 missense mutation in a consanguineous family with primary microcephaly
Authors: Bacino Carlos A. , Arriola Luis A. , Wiszniewska Joanna , Bonnen Penelope E.
Published: February 2012

We report on a consanguineous couple with two affected sons who presented with primary microcephaly and moderate to severe intellectual disabilities. A SNP array uncovered two overlapping regions of copy‐neutral absence of heterozygosity (AOH) in both sibs. This led to sequencing of WDR62, a gene that codes for a spindle pole protein recently identified as a cause of primary microcephaly. A homozygous missense mutation in WDR62, p.E400K, was found in both boys and segregated with the condition in this family. WDR62 is one of seven genes responsible for autosomal recessive primary microcephaly (MCPH), and appears to be one of the most frequently involved in MCPH following ASPM. Studies of ASPM and WDR62 should perhaps be pursued in all cases of primary microcephaly with or without gross brain malformations. © 2012 Wiley Periodicals, Inc.
Familial 16q24.3 microdeletion involving ANKRD11 causes a KBG‐like syndrome
Authors: Sacharow Stephanie , Li Deling , Fan Yao Shan , Tekin Mustafa
Published: February 2012

Haploinsufficiency of ANKRD11 encoding ankyrin repeat domain‐containing protein 11 was recently reported as the cause of a syndrome due to microdeletion, characterized by intellectual disability with minor facial anomalies and short stature. Most recently, intragenic mutations of ANKRD11 were found in a cohort of patients with KBG syndrome. KBG is an autosomal dominant intellectual disability syndrome characterized by short stature, characteristic facial appearance, macrodontia, and skeletal anomalies. It remains unknown if deletion of the entire ANKRD11 causes KBG syndrome. We present a mother and child with a heterozygous 365 Kb deletion at 16q24.3 containing ANKRD11, ZNF778, and SPG7 genes. The child presented with developmental delay, facial anomalies, hand anomalies, and a congenital heart defect. The mother has short stature, facial anomalies, macrodontia, hand anomalies, and learning disability. Both individuals had many findings reported in KBG syndrome and the family met the suggested diagnostic criteria. However, typical macrodontia with fused incisors, costovertebral anomalies, and delayed bone age were not present. We conclude that microdeletions involving ANKRD11 result in a phenotype similar to that of KBG syndrome. © 2012 Wiley Periodicals, Inc.
The ever‐expanding spectrum of congenital muscular dystrophies
Authors: Mercuri Eugenio , Muntoni Francesco
Published: February 2012

Congenital muscular dystrophies are a highly heterogeneous group of conditions. In the last few years the identification of several new genes encoding for both glycosyltransferases and structural proteins has expanded the spectrum of the known forms. New classifications based on combined clinical, genetic and pathological data include all the recently discovered genes and allow an easier identification of the different forms and insight on pathogenetic mechanisms. The aim of this review is to discuss the most recent advances in this field, providing a conceptual framework to help the understanding of the responsible mechanisms and, when available, an update on the therapeutic perspectives.ANN NEUROL 2012;72:9–17
Nonisothermal cure kinetics and diffusion effect of liquid‐crystalline epoxy sulfonyl bis(1,4‐phenylene)bis[4‐(2,3‐epoxypropyloxy)benzoate] resin with aromatic diamine
Authors: Gao Jungang , Huo Li , Du Yonggang
Published: February 2012

The curing kinetics of the liquid‐crystalline epoxy resin sulfonyl bis(1,4‐phenylene)bis[4‐(2,3‐epoxypropyloxy)benzoate] with 4,4′‐diaminodiphenylsulfone was investigated by nonisothermal differential scanning calorimetry. The relationship between the apparent activation energy (Ea) and the conversion was determined, and the effects of the molecular structure and the order of liquid crystallinity on Ea are discussed in detail. Some parameters were evaluated with the autocatalytic kinetic model of the Šesták–Berggren (S–B) equation. The results show that there were some deviations of these simulation curves from the experimental curves at high heating rates and in the late stage of the curing reaction. The diffusion effect in the nonisothermal curing reaction is discussed, and a diffusion factor was proposed and introduced into the S–B equation. Then, a modified S–B equation was created, as follows:
${{d\alpha } \over {dt}} = K\alpha ^m (1 - \alpha )^n \times {1 \over {1 + \exp \left[ {C\left( {\alpha - \alpha _c } \right)} \right]}}$, where α is the conversion, t is the time, m and n are reaction orders, K is rate constant, C is the diffusion coefficient, and αc is the critical conversion. The theoretical simulation curves agreed very well with the experimental data as determined with the modified S–B equation, which may be more useful for describing and predicting the nonisothermal curing reaction kinetics of epoxy resin. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Effect of oxidation progress of tributylborane on the grafting of polyolefins
Authors: Liu Shujuan , Zheng Zhen , Li Minrui , Wang Xinling
Published: February 2012

Effect of the oxidation progress of tributylborane on the grafting reaction of PMMA onto high‐density polyethylene (HDPE) and isotropic polypropylene (iPP) surface with tributylborane as initiator was studied in detail. The oxidation of tributylborane was triggered by the slow diffused oxygen or exposed contact to oxygen, so that the oxidation progress of tributylborane would be different. The grafted polyolefin surfaces were characterized by attenuated total reflection infrared (ATR‐IR) spectroscopy, X‐ray photoelectron spectroscopic (XPS), scanning electron microscope (SEM) and so on. The results of ATR‐IR spectroscopy and XPS analysis suggested that PMMA could be grafted onto polyolefin surfaces successfully through these two ways, but the grafting degrees were varied due to the different oxidation progresses of tributylborane. The surface morphologies of the polyolefin indicated the different grafting degrees as a result of different oxidation progress of tributylborane. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Vegetable oil‐based highly branched polyester modified epoxy based low VOC high solid industrial paint
Authors: Konwar Uday , Karak Niranjan , Jana Tirthankar
Published: February 2012

Mesua ferrea L. seed oil based highly branched polyester modified epoxy resin has been utilized as a binder system for a low volatile organic compound (VOC) containing high solid paint formulation. The highly branched low molecular weight polyester resin acts as the reactive diluent of the epoxy resin which satisfies to reduce VOC emission and produces high solid paint system. The prepared Mesua ferrea L. seed oil based highly branched polyester modified epoxy paint (test paint) was assessed against commercially available epoxy paint (standard paint) for protective coating application. Different physical and performance properties of the paint viz. nonvolatile content, specific gravity, viscosity, drying time, scratch hardness, gloss, impact resistance, and chemical properties such as corrosion resistance, salt spray resistance, UV resistance were measured as per the standard methods. The surface morphology and the thermal stability of the paints were also studied by scanning electron microscope (SEM) and thermogravimetric analysis (TGA). The shear thinning behavior was observed for both the paints as indicated by rheological study. The results indicate that the test paint is comparable with the standard paint. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Preparation of highly exfoliated and transparent polycarbonate/clay nanocomposites by melt blending of polycarbonate and poly(methyl methacrylate)/clay nanocomposites
Authors: Dhibar Saptarshi , Kar Prativa , Khatua B. B.
Published: February 2012

In this report, we introduce an industrially feasible method that involves melt blending of polycarbonate (PC) and in situ suspension polymerized exfoliated PMMA/clay (Na+MMT) nanocomposites to prepare highly exfoliated PC/clay nanocomposites. The rational behind this is that PC is well known to form miscible blend with low molecular weight PMMA. Thus, low molecular weight PMMA/clay exfoliated nanocomposites were prepared by suspension polymerization using pre‐exfoliated clay (Na+MMT) in water media during the polymerization. The (80/20 w/w) PC/PMMA blends without and with Na+MMT showed single glass transition temperature (Tg), indicating complete miscibility of the polymers in the blend. The surface morphologies of the composites were studied by scanning electron microscopy (SEM). Wide‐angle X‐ray diffraction and transmission electron microscope (TEM) studies of the nanocomposites revealed delamination of the clay silicate layers in the PC matrix. The properties of the (80/20 w/w) PC/PMMA‐Na+MMT nanocomposites were significantly higher than that of the pure PC. Moreover, retention of the optical transparency of PC in the nanocomposites could be due to the presence of unmodified clay (Na+MMT), which did not contain any organic modifier (quaternary ammonium salt) that could decompose during melt mixing of PC at high temperature (≈ 280°C). © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo
Authors: Burleigh Annika , Chanalaris Anastasios , Gardiner Matthew D. , Driscoll Clare , Boruc Olga , Saklatvala Jeremy , Vincent Tonia L.
Published: February 2012

Objective

Mechanical joint loading is critical for the development of osteoarthritis (OA). Although once regarded as a disease of cartilage attrition, OA is now known to be controlled by the expression and activity of key proteases, such as ADAMTS‐5, that drive matrix degradation. This study was undertaken to investigate the link between protease expression and mechanical joint loading in vivo.

Methods

We performed a microarray analysis of genes expressed in the whole joint following surgical induction of murine OA (by cutting the medial meniscotibial ligament). Gene expression changes were validated by reverse transcriptase–polymerase chain reaction in whole joints and microdissected tissues of the joint, including the articular cartilage, meniscus, and epiphysis. Following surgery, mouse joints were immobilized, either by prolonged anesthesia or by sciatic neurectomy.

Results

Many genes were regulated in the whole joint within 6 hours of surgical induction of OA in the mouse. These included Arg1, Ccl2, Il6, Tsg6, Mmp3, Il1b, Adamts5, Adamts4, and Adamts1. All of these were significantly regulated in the articular cartilage. When joints were immobilized by prolonged anesthesia, regulation of the vast majority of genes was abrogated. When joints were immobilized by sciatic neurectomy, regulation of selected genes was abrogated, and OA was prevented up to 12 weeks postsurgery.

Conclusion

These findings indicate that gene expression in the mouse joint following the induction of OA is rapid and highly mechanosensitive. Regulated genes include the known pathogenic protease ADAMTS‐5. Targeting the mechanosensing mechanisms of joint tissue may offer new strategies for disease modification.
New Formulation of Dynamic Output Feedback Robust Model Predictive Control with Guaranteed Quadratic Boundedness
Authors: Ding Baocang
Published: February 2012

The dynamic output feedback robust model predictive controller for a system with both polytopic uncertainty and bounded disturbance is addressed in this paper. This controller utilizes a main optimization problem to find the control law and a simple auxiliary optimization problem to refresh the bounds on the true state. The main optimization problem, which is not necessarily solved at each sampling instant, achieves the near‐optimal solution. The auxiliary optimization, which is solved at each sampling instant, is followed with a simple criterion which determines whether or not to solve the main optimization problem at the next sampling time. By applying the proposed method, the augmented state of the closed‐loop system is guaranteed to converge to the neighborhood of the equilibrium point.
Operator‐Based Robust Right Coprime Factorization and a Nonlinear Control Scheme for Nonlinear Plant with Unknown Perturbations
Authors: Bu Ni , Deng Mingcong
Published: February 2012

This paper is concerned with operator‐based robust right coprime factorization for nonlinear plants with unknown perturbations. Firstly, the right factorization for by nonlinear plant with unknown perturbations is realized using isomorphism and some sufficient conditions are proposed to guarantee the robust stability of the obtained nonlinear feedback control system as well as the plant output asymptotically tracking to the reference input. Secondly, a quantitative control scheme is designed to satisfy the sufficient conditions. Finally, the effectiveness of the proposal is demonstrated by the simulation results.
Computer tomographic evaluation of talar edge configuration for osteochondral graft transplantation
Authors: Wiewiorski Martin , Hoechel Sebastian , Wishart Katarina , Leumann André , Müller‐Gerbl Magdalena , Valderrabano Victor , Nowakowski Andrej Maria
Published: February 2012

To successfully surgically reconstruct osteochondral lesions of the talus, the exact three‐dimensional (3D) configuration of the upper articular surface of the talus has to be respected. We assessed the talar geometry by measuring the coronal and sagittal talar edge radius and the frontal talar profile in multiplanar reconstructions of computer tomographic (CT) studies of 79 patients (83 feet) with a healthy ankle joint. An image visualization software designated for coordinate measurement was used to perform the measurement. In the coronal plane, the mean lateral talar edge radius was 4.0 mm and the medial 4.5 mm. In the sagittal planes the mean lateral talar edge radius was 20.3 mm, the radius of the sulcus 20.7 mm and the medial talar edge radius 20.4 mm. The talus showed a concave shape in coronal cuts. These results show a significant difference between medial and lateral talar edge configuration in coronal planes. The measurements of the lateral and medial sagittal radius and the mid‐sagittal radius in the sulcus tali show no statistically significant difference. The depth of the talar sulcus shows no correlation to age or sex. Different sizes of custom‐made tissue‐engineered grafts according to the location of the osteochondral lesion at the talus are needed for exact surgical reconstruction of the anatomy. Osteochondral lesions are three dimensional; therefore, a 3D preoperative planning tool by CT scan or MRI is mandatory. Clin. Anat. 25:773–780, 2012. © 2012 Wiley Periodicals, Inc.
Stat3 is involved in the motility, metastasis and prognosis in lingual squamous cell carcinoma
Authors: Zhao Yan , Zhang Jiali , Xia Haibin , Zhang Bi , Jiang Tao , Wang Jiawei , Chen Xinmin , Wang Yining
Published: February 2012

The signal transducers and activators of transcription 3 (Stat3) has been detected in many types of cancer and plays an important role in tumour‐cell survival, proliferation, self‐renewal and invasion. To address the possibility that Stat3 may be involved in the metastasis and prognosis in lingual squamous cell carcinoma, we examined whether Stat3 expression associates with metastasis or survival rate in human clinical samples. We found that there was a significant correlation between Stat3 expression and lymph node metastasis (P = 0.009), stages (P = 0.029), recurrence (P = 0.0032) and death (P = 0.0356). The specific knockdown of Stat3 by RNA interference strongly inhibited the motile and invasion activity of tumour cells. Our results suggest that Stat3 is involved in the motility, metastasis and progression in human lingual squamous cell carcinoma, and thus, it may be a therapeutic target for human lingual squamous cell carcinoma. Copyright © 2012 John Wiley & Sons, Ltd.
Redox‐Active Nickel in Carbon Nanotubes and Its Direct Determination
Authors: Ambrosi Adriano , Pumera Martin
Published: February 2012

The presence of residual metal‐catalyst impurities in carbon nanotubes is responsible for their toxicity. It is important to differentiate between the total amount of impurities and the redox‐active (bioavailable) amount of such impurities because only the bioavailable impurities exhibit toxic effects. Herein, we report a simple and specific method for quantifying the amount of redox‐active Ni present in various commercial samples of CNTs. It is based on the electrochemical oxidation of Ni(OH)2 that is formed in alkaline solutions when Ni impurities are opened to the surrounding environment. Metallic Ni impurities play an extremely active role in toxicological assays as well as in undesired catalytic processes, and thus a method to rapidly quantify the amount of redox‐active Ni is of great importance.
Polycyclic Cage Structures as Lipophilic Scaffolds for Neuroactive Drugs
Authors: Joubert Jacques , Geldenhuys Werner J. , Van der Schyf Cornelis J. , Oliver Douglas W. , Kruger Hendrik Gert , Govender Thavendran , Malan Sarel F.
Published: February 2012

Polycyclic cage scaffolds have been successfully used in the development of numerous lead compounds demonstrating activity in the central nervous system (CNS). Several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, and stroke, as well as drug abuse, can be modulated with polycyclic cage derivatives. These cage moieties, including adamantane and pentacycloundecane derivatives, improve the pharmacokinetic and pharmacodynamic properties of conjugated parent drugs and serve as an important scaffold in the design of therapeutically active agents for the treatment of neurological disorders. In this Minireview, we focus on the recent developments in the field of polycyclic cage compounds, as well as the relationship between the lipophilic character of these cage‐derived drugs and the ability of such compounds to target and reach the CNS and improve the pharmacodynamic properties of compounds conjugated to it.
A Two‐Step Strategy for Structure–Activity Relationship Studies of N‐Methylated Aβ42 C‐Terminal Fragments as Aβ42 Toxicity Inhibitors
Authors: Li Huiyuan , Zemel Reeve , Lopes Dahabada H. J. , Monien Bernhard H. , Bitan Gal
Published: February 2012

Neurotoxic Aβ42 oligomers are believed to be the main cause of Alzheimer’s disease. Previously, we found that the C‐terminal fragments (CTFs), Aβ(30–42) and Aβ(31–42) were the most potent inhibitors of Aβ42 oligomerization and toxicity in a series of Aβ(x–42) peptides (x=28–39). Therefore, we chose these peptides as leads for further development. These CTFs are short (12–13 amino acids) hydrophobic peptides with limited aqueous solubility. Our first attempt to attach hydrophilic groups to the N terminus resulted in toxic peptides. Therefore, we next incorporated N‐methyl amino acids, which are known to increase the solubility of such peptides by disrupting the β‐sheet formation. Focusing on Aβ(31–42), we used a two‐step N‐methyl amino acid substitution strategy to study the structural factors controlling inhibition of Aβ42‐induced toxicity. First, each residue was substituted by N‐Me‐alanine (N‐Me‐A). In the next step, in positions where substitution produced a significant effect, we restored the original side chain. This strategy allowed exploring the role of both side chain structure and N‐Me substitution in inhibitory activity. We found that the introduction of an N‐Me amino acid was an effective way to increase both the aqueous solubility and the inhibitory activity of Aβ(31–42). In particular, N‐Me amino acid substitution at position 9 or 11 increased the inhibitory activity relative to the parent peptide. The data suggest that inhibition of Aβ42 toxicity by short peptides is highly structure‐specific, providing a basis for the design of new peptidomimetic inhibitors with improved activity, physicochemical properties, and metabolic stability.
A Theoretical Investigation Into the 1,3‐Dipolar Cycloaddition of Azidotrimethylsilane Onto Nanographene
Authors: Yuan Yanli , Chen Peiyu , Ren Xingye , Wang Hongming
Published: February 2012

The mechanism of the 1,3‐dipolar cycloaddition reaction of azidotrimethylsilane (ATS) onto nanographene (NG) is thoroughly investigated at the B3LYP/6‐31G(d,p) level. Calculations reveal that the reaction occurs through a two‐step reaction mechanism. The first step is the chemical adsorption and the second one is the decomposition of the thereby formed nitride upon thermal activation, giving rise to an N‐bridged product ultimately. The latter is the rate‐determining step. Two possible pathways are compared to show that the [3+2] channel is favored over the [3+4] channel. The former is a symmetric synchronous process, whereas the latter follows an asymmetric concerted way, which can be rationalized by means of the frontier molecular orbital (FMO) theory. The reactivity of NG is discussed in detail, revealing that it is the electron density at the functionalization site which dominates the reactivity rather than the energetic effect. As a result, the edge area is calculated to be much more reactive than the centre.