bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperbaric Oxygen Preconditioning Alleviates Myocardial Ischemic Injury in Rats
Authors: Han Cuihong , Lin Li , Zhang Weidong , Zhang Li , Lv Shijun , Sun Qiang , Tao Hengyi , Zhang John H. , Sun Xuejun
Published: August 2008

It has been shown that after ischemia-reperfusion, application of hyperbaric oxygen (HBO) reduces cardiac injury. In this study we tested the hypothesis that HBO preconditioning reduces injury to the ischemic myocardium. One hundred and eight adult male Sprague-Dawley rats (250–280 g) were randomly divided into four groups: normoxia + sham surgery (CS), normoxia + permanent occlusion of the left anterior descending (LAD) coronary artery (CMI), HBO preconditioning + sham surgery (HS), and HBO preconditioning + permanent LAD occlusion (HMI). Rats receiving HBO preconditioning were intermittently exposed to 100% O2 at 2.5 atmosphere absolute (ATA) for 60 min, twice daily for 2 days followed by 12 hrs of recovery in room air prior to the myocardial ischemic insult induced by LAD ligation. Rats in the normoxia group were time-matched with the HBO group and maintained under normoxic conditions prior to LAD occlusion. At 3 and 7 days after LAD occlusion, heart function parameters were measured by inserting a catheter into the left ventricle, infarct size was calculated using the method of TTC staining, myocardial capillary density was determined by immunohistochemical staining with a monoclonal anti-CD31/PECAM-1 antibody, and VEGF protein level was determined by Western blot analysis. At 3 days after LAD ligation, the infarct size of the HMI group was significantly smaller than that of the CMI group (26 ± 2.5% vs. 38 ± 3%, P < 0.05). The heart function parameters including left ventricular systolic pressure (LVSP), +dP/dtmax and −dP/dtmax were significantly improved in the HMI group compared to the CMI group at 3 and 7 days after LAD occlusion. Capillary density and VEGF protein levels were significantly increased in the ischemic myocardium pre-exposed to HBO. We conclude that HBO preconditioning alleviates myocardial ischemia in rat model.
Beneficial Effects of Ceftriaxone Against Pentylenetetrazole-Evoked Convulsions
Authors: Jelenkovic Ankica V. , Jovanovic Marina D. , Stanimirovic Danica D. , Bokonjic Dubravko D. , Ocic Gordana G. , Boskovic Bogdan S.
Published: August 2008

Although considered to be generally safe, a number of β-lactam antibiotics have been associated with epileptic seizures in humans. Furthermore, some β-lactam antibiotics, including ceftriaxone, are used to evoke convulsions under experimental conditions. Recently it was demonstrated that ceftriaxone increased expression of the glutamate transporter (GLT1) and its biochemical and functional activity in the brain of rodents. GLT1 regulates extracellular concentrations of glutamate, an excitatory amino acid involved in the pathogenesis of seizures and epilepsy. Because of its rapid transfer of glutamate into neurons and adjacent glial cells, GLT1 diminishes glutamate toxicity. We investigated whether ceftriaxone (200 mg/kg body wt) administered intraperitoneally (ip) for 6 days could modify the convulsant effects of pentylenetetrazole (PTZ, 100 mg/kg ip) in inbred male BALBcAnNCR and C57 black (BL)/6 mice aged 4 and 12 weeks. Ceftriaxone pretreatment provided significant protective effects against PTZ-evoked generalized clonic convulsions (GCCs), generalized clonic-tonic convulsions (GCTCs), and convulsion-induced mortality during a period of 30 mins after PTZ administration. The incidence of GCCs, GCTCs, and death was statistically significantly lower for BALBcAnNCR mice of both ages, particularly younger mice. The latency time for each of the three parameters was significantly greater, with the exception of GCCs in adult mice. Protective effects of ceftriaxone were also noticed in adult C57BL/6 mice but not in prepubertal C57BL/6 mice. This is the first demonstration of anticonvulsant effects of ceftriaxone or any other β-lactam antibiotic, which are not uniform across the mouse population. Our results provide new insight into the effects of ceftriaxone, which need further investigation.
Fructose-2,6-Bisphosphate Is Lower in Copper Deficient Rat Cerebellum Despite Higher Content of Phosphorylated AMP-Activated Protein Kinase
Authors: Gybina Anna A. , Prohaska Joseph R.
Published: August 2008

Limitation in copper (Cu) leads to pathophysiology in developing brain. Cu deficiency impairs brain mitochondria and results in high brain lactate suggesting augmented anaerobic glycolysis. AMP activated protein kinase (AMPK) is a cellular energy “master-switch” that is thought to augment glycolysis through phosphorylation and activation phosphofructokinase 2 (PFK2) resulting in increases of the glycolytic stimulator fructose-2,6-bisphosphate (F2,6BP). Previously, Cu deficiency has been shown to augment cerebellar AMPK activation. Cerebella of Cu-adequate (Cu+) and Cu-deficient (Cu−) rat pups were assessed to evaluate if AMPK activation in Cu− cerebella functioned to enhance PFK2 activation and increase F2,BP concentration. Higher levels of pAMPK were detected in Cu− cerebella. However, PFK2 activity, mRNA, and protein abundance were not affected by Cu deficiency. Surprisingly, F2,6BP levels were markedly lower in Cu− cerebella. Lower F2,6BP may be due to inhibition of PFK2 by citrate, as citrate concentration was significantly higher in Cu− cerebella. Data suggest AMPK activation in Cu− cerebellum does not augment glycolysis through a PFK2 mechanism. Furthermore, other metabolite data suggest that glycolysis may actually be blunted, since levels of glucose and glucose-6-phosphate were higher in Cu− cerebella than controls.
Luminal Antioxidants Enhance the Effects of Mesalamine in the Treatment of Chemically Induced Colitis in Rats
Authors: Ancha Hanumantha R. , Kurella Ravi R. , McKimmey Christine C. , Lightfoot Stanley , HartY Richard F.
Published: August 2008

Previous experiments in rats with chemically induced colitis have shown that the antioxidant N-acetylcysteine plus mesalamine (5-ASA) exerted a significantly greater therapeutic effect in promoting mucosal healing when compared to either agent alone. The aims of the present study were to compare the effects of three antioxidants plus mesalamine vs. 5-ASA alone in treatment of colitis induced by trinitrobenzene sulfonic acid (TNBS) in rats. Methods: Three days following induction of TNBS colitis, rats received 8 days of rectal therapy with 5-ASA, or 5-ASA plus vitamin C (ascorbic acid), 5-ASA plus phenyl butylnitrone (PBN) and 5-ASA plus vitamin E (α-tocopherol). Distal colonic tissues were examined for microscopic colitis and myeloperoxidase (MPO) activity. Results: Global assessments of microscopic colitis induced by TNBS indicated that 5-ASA alone significantly changed colonic injury by −31%. Combination therapy with ascorbic acid plus 5-ASA or α-tocopherol plus 5-ASA caused further significant change in TNBS colitis by −65 and −82%, respectively. Each of these values was significantly below scores observed with 5-ASA as monotherapy. Reduction in colitis with PBN plus 5-ASA was not different from 5-ASA alone. MPO activity was decreased significantly in response to monotherapy with 5-ASA and each of the antioxidants plus 5-ASA when compared to TNBS. α-Tocopherol plus 5-ASA, however, was the only treatment strategy that reduced significantly MPO activity below that recorded for 5-ASA alone. In conclusion, our results indicate that antioxidants other than N-acetylcysteine significantly enhance the therapeutic effectiveness of 5-ASA in the treatment of TNBS colitis. α-Tocopherol plus 5-ASA exerted profound anti-inflammatory and reparative effects upon colitis induced by TNBS.
B
12
‐Dependent Enzyme Reactions, Chemistry of
Authors: Buckel Wolfgang , Golding Bernard T.
Published: August 2008

The vitamin B
12
cofactor called coenzyme B
12
(adenosylcobalamin) assists enzymes called mutases and eliminases in the catalysis of molecular rearrangements. The mutases comprise reactions in which a substrate equilibrates with a product by migration of an amino group (as with β‐lysine 5,6‐aminomutase) or a carbon‐based group (e.g., COSCoA in methylmalonyl‐CoA mutase, which interconverts methylmalonyl‐CoA with succinyl‐CoA). The eliminases (e.g., propane‐1,2‐diol dehydratase) have either hydroxyl or amino as the migrating group, but they differ from the mutases by affording an intermediate that eliminates water or ammonia to give the observed product (e.g., propanal from propane‐1,2‐diol via propane‐1,1‐diol). Methylcobalamin is essentially an intermediary for synthetic reactions catalyzed by methyltransferases. These reactions depend on the “supernucleophilicity” of reduced vitamin B
12
(cob(I)alamin) and in humans provide for the synthesis of the amino acid methionine.
Cell Death: Biological Mechanisms and Small Molecule Inhibitors
Authors: Korkina Olga , Degterev Alexei
Published: August 2008

The process of regulated or programmed cell death (PCD) executed through genetically encoded intrinsic cellular machinery is widely accepted to represent one of the key cellular responses to extrinsic and intrinsic stimulation. Extensive analysis of PCD carried out during the last decade clearly established that proper execution of PCD is important for normal mammalian development and also for homeostasis of the adult organism. Deregulation of PCD has been linked to development of many severe human diseases like cancer, autoimmunity, stroke, and some neurodegenerative diseases. Although apoptosis, which is the first discovered form of PCD, has been and remains the mainstay of PCD research, better understanding of the process of apoptosis led to the surprising discovery that other forms of PCD also exist and play multiple important roles in health and disease. Small‐molecule inhibitors of apoptotic and nonapoptotic cell death have been successfully developed and proved very useful in defining the mechanisms and functional role of various PCD processes. Furthermore, some molecules have been developed extensively and represent emerging new therapies for human pathologies. In this article, we will discuss the major PCD‐related protein targets of chemical inhibitors and describe the major classes of small molecule inhibitors developed to this point.
Drug Discovery and Development: Computational Approaches
Authors: Li Honglin , Zheng Mingyue , Luo Xiaomin , Zhu Weiliang , Jiang Hualiang
Published: August 2008

Recently, computational approaches have been considerably appreciated in drug discovery and development. Their applications span almost all stages in the discovery and development pipeline, from target identification to lead discovery, from lead optimization to preclinical or clinical trials. In conjunction with medicinal chemistry, molecular and cell biology, and biophysical methods as well, computational approaches will continuously play important roles in drug discovery. Several new technologies and strategies of computational drug discovery associated with target identification, new chemical entity discovery, and lead optimization will be the focus of this review.
Peptide Synthesis: Coupling Methods
Authors: Benoiton N. Leo
Published: August 2008

Peptide‐bond formation requires activation of a carboxyl group followed by aminolysis of the activated carbonyl. The reagents and methods employed for activation, the intermediates and activated forms generated and their aminolysis are described. Rationalization of the strategy employed to avoid isomerization during coupling is presented. Approaches for minimizing aggregation that interferes with coupling are also given.
Flavoenzymes, Chemistry of
Authors: van Berkel Willem J. H.
Published: August 2008

Flavoenzymes are omnipresent in nature and are involved in many cellular processes. Flavoenzymes typically contain the vitamin B2 derivatives FAD and FMN as a redox‐active prosthetic group. By varying the protein environment around the isoalloxazine ring of the flavin, evolution has created a great diversity of flavoprotein active sites and catalytic machineries. Most flavoenzymes perform one‐ or two‐electron redox reactions and belong to the following groups: Flavoprotein reductases primarily use NAD(P)H as electron donor and pass these electrons to a protein substrate or another electron acceptor. Flavoprotein dehydrogenases oxidize organic substrates and mainly use quinones and electron transfer proteins as electron acceptors. Flavoprotein disulfide oxidoreductases contain active‐site thiols. They use a dithiol substrate and NAD
+
to form a disulfide product and NADH or act in the other direction yielding NAD(P)
+
and a reduced (dithiol) product. Some flavoprotein (di)thiol oxidoreductases stabilize a reactive and reversibly oxidized cysteine in their active site. Flavoprotein oxidases catalyze the conversion of a substrate single bond to a double bond. The reduced flavin generated during this reaction is reoxidized by molecular oxygen to form hydrogen peroxide. Flavoprotein monooxygenases mainly use NAD(P)H as an electron donor and insert one atom of molecular oxygen into their substrates. By doing so, they act in different biological processes, ranging from lignin degradation and detoxification to the biosynthesis of polyketides and plant hormones.
Informatics for Glycans
Authors: Raman Rahul , Sasisekharan Ram
Published: August 2008

Databases and informatics tools are central to rapid acceleration in the progress of the genomics and proteomics fields. Glycomics, an emerging paradigm in the age of postgenomics, involves understanding the structure–function relationship of glycans in fundamental biological processes. In comparison with genomics and proteomics, the advancement of glycomics has faced unique challenges in the pursuit of developing tools, biological readouts, and an informatics platform to investigate glycan structure–function relationships. These challenges are because of the structural diversity and heterogeneity in glycans that develops from their complex nontemplate biosynthesis. This review focuses on areas of technologies for sequencing glycans and the importance of developing a bioinformatics platform to integrate the diverse data sets generated using the different technologies to allow a systems approach to glycan structure–function relationships. Although aspects of glycan analysis and integration of glycomics data sets have been covered in earlier reviews, this review brings these aspects together for both linear and branched glycans.
Mass Spectrometry: Applications in Phosphoproteomics
Authors: Giorgianni Francesco , Beranova‐Giorgianni Sarka
Published: August 2008

Proteins are biological macromolecules whose structure and functions are essential to every biological process within cells. Protein phosphorylation is one of the most important post‐translational modifications and it has a profound effect on protein function. Recently, concurrent advances in bioanalytical technologies and informatics enabled studies of proteins and phosphoproteins on a global scale. These large‐scale approaches represent an integral component of systems biology, which is an area of scientific inquiry that focuses on a biological system as a whole. State‐of‐the art mass spectrometry is a key technology for global‐scale protein and phosphoprotein analyses. Phosphorylated proteins from diverse biological systems can be probed with a combination of separation methods, tandem mass spectrometry, and bioinformatics, to reveal the identity of the phosphorylated protein and the exact localization of the site(s) of phosphorylation. Characterization of the phosphoproteomes in cells, tissues and biological fluids provides an excellent foundation on which to build new knowledge of living systems.
Membrane Proteins: Properties
Authors: Columbus Linda , Nakamoto Robert K. , Cafiso David S.
Published: August 2008

Membrane proteins constitute a significant fraction of the proteins that are encoded in the typical genome, and they are critical to many cellular processes, which include transport, cell signaling, and energy transduction. This importance is underscored by the fact that membrane proteins represent the major class of protein targets for pharmaceuticals that are currently in use. However, despite their importance, there are relatively few high‐resolution models for membrane proteins, and little is known about their molecular function. The lack of information on membrane proteins in part reflects the difficulties in efficient expression of this class of proteins and difficulties with structural approaches, such as high‐resolution nuclear magnetic resonance (NMR), that are not well suited to membrane proteins. In the field of structural biology, membrane proteins represent a significant challenge, and in recent years new structural and biochemical tools have been developed to characterize these systems. In this review, we discuss the functions and properties of membrane proteins, and we discuss the approaches and tools that yield new information on their structure and molecular function.
Metabolic Diseases: Biological Mechanisms
Authors: Arbeeny Cynthia M.
Published: August 2008

Obesity, type 2 diabetes (T2D), lipid disorders, and hypertension are chronic and disabling diseases that afflict hundreds of millions of individuals worldwide. In this article, they are collectively referred to as “cardiometabolic diseases,” because they have “common ground:” They increase the risk of cardiovascular disease (CVD) morbidity and mortality. Considerable research has been performed to understand the etiology of cardiometabolic diseases and to translate this research into effective treatment paradigms. However, it has been challenging to understand the initiation and progression of cardiometabolic diseases. This difficulty is attributed to the complexities involved in metabolic regulation, a resultant “snowballing” effect, and a downward spiral as disease progresses. The first line of therapy for treating obesity, T2D, and/or dyslipidemia is lifestyle intervention, which can impact significantly on disease and decrease CV risk, but is usually not effective because of lack of patient compliance. Patients are then given a plethora of drugs to treat the individual risk factors. However, new therapies are critically needed, because most patients require multiple drugs, some drugs may treat one CVD risk factor and exacerbate another, and most patients do not meet treatment goals. A “magic bullet” that treats the underlying causes that contribute to cardiometabolic risk has been a longstanding goal but remains elusive. Ongoing research to uncover novel targets holds promise for future therapeutics that might treat multiple facets of cardiometabolic diseases. This introductory review focuses on the epidemiology and etiology of cardiometabolic diseases, current therapies, and future treatment strategies.
Natural Products: An Overview
Authors: Clardy Jon , Fischbach Michael A.
Published: August 2008

Natural products, the remarkable collection of small molecules made by living organisms in an idiosyncratic manner, have made important contributions to organic chemistry, biology, and medicine. Although natural products contain a mother lode of molecular diversity, all of their structures reflect an evolutionary history and a biosynthetic production from a limited set of starting materials and reactions. The structures of natural products differ quantifiably from the small molecules usually found in the screening libraries used in high‐throughput assays. Deeper structural analysis often reveals that natural products bind important biological targets with an exquisite degree of shape and charge complementarity. In addition, natural products often employ a variety of stratagems to disguise reactive functional groups until they are needed. Biosynthetic pathways for natural products resemble those used to construct more common biomolecules; the main themes are reactions that couple monomers into larger molecules and the lavish use of redox chemistry not just to create skeletons but also to cross‐link them and decorate them with oxygen‐based functionality. Although the historic contributions of natural products to chemistry, biology, and medicine are clear, their current use, especially in drug discovery, seems less clear. However, efforts to explore new areas of biological diversity, mine genomes, and study the natural roles of natural products are rejuvenating natural products research and illuminating its future.
NMR: Applications in Chemical Biology
Authors: Nielsen Gerd , Stadler Max , Jonker Henry , Betz Marco , Schwalbe Harald
Published: August 2008

Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful method to determine the structure of biomacromolecules and their complexes in solution. It allows determination of the dynamics of proteins, RNA, DNA, and their complexes at atomic resolution. Therefore, NMR spectroscopy can monitor the often transient weak interactions in the interactome of proteins and the interaction between proteins and small‐molecule ligands. In addition, intrinsically unstructured proteins can be investigated, and first reports of structure determination of membrane proteins in the immobilized state (solid state) are developing. This review will introduce the fundamental NMR observables as well as the methods to investigate structure and dynamics, and it will discuss several examples where NMR spectroscopy has provided valuable information in the context of Chemical Biology.
Proteins: Computational Analysis
Authors: Gromiha M. Michael , Selvaraj S.
Published: August 2008

Proteins are biological macromolecules synthesized with genetically determined sequences of amino acids by the formation of peptide bonds through the removal of water molecules. The chemical nature of amino acids is important for the folding and stability of protein structures. In this article, we give an overview of the computational analysis of protein structure and function from the viewpoint of chemical biology. The biological insights obtained from the analysis of known protein structures and their applications to protein structure prediction and folding rates are outlined. The computational analysis needed for understanding the functions and stability of proteins and for predicting the functionally important residues is described. The methods developed for understanding the factors that influence the stability of proteins and predicting protein stability during mutation are explored. Furthermore, the current status of computational protein design and the approaches to understanding the recognition mechanism of protein complexes are discussed.
Transient State Enzyme Kinetics
Authors: Johnson Kenneth A.
Published: August 2008

Transient‐state kinetic analysis defines the elementary steps along the pathway of an enzyme‐catalyzed reaction. The methods rely on rapidly mixing a substrate with a sufficient concentration of enzyme to allow a direct observation of intermediates and products formed at the active site during a single enzyme cycle. Stopped‐flow methods afford observation of reactions by monitoring changes in optical signals (i.e., absorbance, fluorescence, and light scattering) as a function of time after mixing. Analysis of the substrate concentration dependence of the rates and the amplitudes of observable species can define the sequence of events that occur after substrate binding. Rapid‐chemical quench‐flow methods require two sequential mixing events: one to start the reaction and a second to stop the reaction by the addition of a quenching agent. One then quantifies the amount of product formed, often by chromatography, to resolve radiolabeled substrate from the product. Because one can observe the conversion of substrate to product directly on a known concentration scale, rapid quench experiments can be interpreted directly. In the final analysis, the most rigorous interpretation relies on global analysis fitting both stopped‐flow and rapid quench‐flow data simultaneously to establish a reaction pathway and the rates of interconversion of kinetically significant intermediates. Accordingly, transient‐state kinetic methods allow a definition of a reaction sequence by direct measurement of each step to establish the kinetic and thermodynamic basis for enzyme specificity and efficiency.
Pharmaceutical Industry: Biocatalysts and Chemocatalysts
Authors: Ager David J. , May Oliver
Published: August 2008

Catalytic reactions provide the opportunity to perform more environmentally friendly reactions. As the pharmaceutical industry produces a large amount of waste for a relatively small amount of drug product manufactured, the use of catalytic reactions is becoming more important. Catalysts can be biological or chemical in nature and can be used to effect a wide variety of transformations.
Flavin‐Mediated Hydroxylation Reactions
Authors: Entsch Barrie , Ballou David P.
Published: August 2008

Flavins react with oxygen and can form stable flavin peroxides in an aprotic solvent or buried in a protein. It is this hydroperoxide or peroxide that is the oxygenating agent in flavoproteins. This property is used in nature to carry out aromatic hydroxylations, halogenations, Baeyer‐Villiger oxygenations, hydroxylation of xenobiotics and some metabolites, as well as light emission from luciferase. Several groups of enzymes seem to have evolved hydroxylating properties independently of each other. One group consists of the two‐component flavin‐dependent hydroxylases that use many of the same principles as the single component hydroxylases, although they also have some special requirements. After a brief introduction to the reactivity of flavins with oxygen, we examinep‐hydroxybenzoate hydroxylase as the paradigm for the chemistry and protein functions exhibited by these enzymes. We then discuss unique features of each group of enzymes and the exciting prospects for future research.
Allergy and Asthma: Small Molecule Approaches
Authors: Walsh Garry M.
Published: August 2008

Current therapies for asthma and allergy are aimed at controlling disease symptoms. For most asthmatics, inhaled anti‐inflammatory therapy is effective, but a subset of patients remains symptomatic despite optimal treatment creating a clear unmet medical need. Although considered a less‐serious condition than asthma, allergic diseases are common and considerably impact on the quality of life of affected individuals. Innovative disease‐modifying therapeutics are needed for both allergy and asthma. Biopharmaceutical approaches may identify small molecules that target key cells and mediators that drive the inflammatory responses that underlie the pathogenesis of allergy and asthma.
Thrombin
Authors: Cera Enrico Di
Published: August 2008

Thrombin is a Na
+
‐activated, allosteric serine protease that plays opposing functional roles in blood coagulation. Binding of Na
+
is the major driving force behind the procoagulant, prothrombotic, and signaling functions of the enzyme, but is dispensable for cleavage of the anticoagulant protein C. The anticoagulant function of thrombin is under the allosteric control of the cofactor thrombomodulin. Thrombin exists in three forms, E*, E, and E:Na
+
, which interconvert under the influence of ligand binding to distinct domains. Transitions among these forms control key functional aspects of the enzyme.
Group
II
Introns
Authors: Roitzsch Michael
Published: August 2008

The self‐splicing group II introns are among the largest naturally occurring ribozymes and have been found primarily in organellar genomes of plants, fungi, bacteria, proteobacteria, and blue algae. More recently, a group II intron was found in a primitive metazoan. More than 200 different group II introns have been identified to date. All group II introns have a conserved secondary structure composed of six stem‐loop structures termed domains D1–D6, which are arranged around a central wheel and provide distinct contributions to intron function. Group II introns catalyze their own excision from pre‐RNA by two consecutive transesterifications and concomitant splicing of the flanking exons. The reaction requires Mg
2+
ions, which are directly involved in catalysis and are also needed for proper folding of the intron. Intriguingly, group II introns share several mechanistic and structural features with the eukaryotic spliceosome, which suggests an evolutionary relationship.
In vivo
, group II intron splicing is generally assisted by proteins. With the help of proteins, some group II introns can also reverse the splicing reaction and integrate themselves into target genomes; this process resembles transposition of non‐LTR retrotransposons and can be exploited for biotechnological applications.
Modified Nucleosides in
RNA
Authors: Abeydeera N. Dinuka , Chow Christine S.
Published: August 2008

Natural and unnatural modified nucleosides play important roles in chemistry and biology. Over 100 different functional group modifications occur on natural nucleosides, which range from sugar methylations to base isomerization reactions. Unnatural modifications are also broad in their range of possible structures and applications. Both types of modifications have been incorporated site specifically into RNAs to understand their biological roles or to be used as biophysical, structure, and mechanistic probes. More recently, modified RNAs have been applied as therapeutic agents. This article summarizes the approaches toward generation of modified nucleosides and their incorporation into RNA using chemical, biochemical, or combined (semisynthesis) approaches. Some examples of applications with modified RNAs will also be discussed.
A new, nonphosgene route to poly(bisphenol a carbonate) by melt‐phase interchange reactions of alkylene diphenyl dicarbonates with bisphenol A
Authors: Sweileh Bassam A. , A‐Hiari Yusuf M. , Aiedeh Khaled M.
Published: August 2008

This article describes a new, nonphosgene method for the synthesis of poly(bisphenol A carbonate) (PC). The method involves three steps: the reaction of an aliphatic diol with phenyl chloroformate to form an alkylene diphenyl dicarbonate, the reaction of the alkylene diphenyl dicarbonate with bisphenol A to produce an aromatic–aliphatic polycarbonate, and the thermal treatment of the polycarbonate at 180–210°C under a stream of nitrogen with Ti(OBu)4 to give PC and a cyclic alkylene carbonate. The method furnished low to moderate molecular masses of PC upon the complete elimination of the aliphatic moieties. The approach may be considered a new method, based on polycarbonate thermochemical degradation, for the synthesis of cyclic aliphatic carbonates. The obtained polymers were characterized by intrinsic viscosity and IR, 1H‐NMR, and 13C‐NMR spectroscopy. The thermal treatment step was conducted in a glass reaction tube at 180–210°C under a stream of nitrogen, and the reaction was completed by heating to 250°C. In the thermal treatment step, semisolid effluents composed of cyclic alkylene carbonates were formed and subsequently eliminated from the reaction mixture. Heating to 250°C under nitrogen or under a dynamic vacuum furnished the pure aromatic PC residue. This intrachange reaction provides a flexible method for the synthesis of polycarbonates with alkylene diols containing two or three methylene groups, from which the pure PC homopolymer can be prepared. The potential of this approach was demonstrated by the successful synthesis of PC homopolymer from five different polycarbonates with a bisphenol A unit linked to 1,2‐propylene, 1,3‐propylene, 2‐methyl‐1,3‐propylene, 2,2‐dimethyl‐1,3‐propylene, and 1,3‐butylene as the alkane chains. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Artesunate: developmental toxicity and toxicokinetics in monkeys
Authors: Clark Robert L. , Arima Akihiro , Makori Norbert , Nakata Yasuto , Bernard Frederic , Gristwood William , Harrell Andrew , White Tacey E.K. , Wier Patrick J.
Published: August 2008

BACKGROUND: The developmental toxicity, toxicokinetics, and hematological effects of the antimalarial drug, artesunate, were previously studied in rats and rabbits and have now been studied in cynomolgus monkeys. METHODS: Groups of up to 15 pregnant females were dosed on Gestation Days (GD) 20–50 or for 3–7‐day intervals. RESULTS: At 30 mg/kg/day, 6 embryos died between GD30 and GD40. Histologic examination of 3 live embryos (GD26–GD36) revealed a marked reduction in embryonic erythroblasts and cardiomyopathy. At 12 mg/kg/day, 6 embryos died between GD30 and GD45. Four surviving fetuses examined on GD100 had no malformations, but long bone lengths were slightly decreased. At the developmental no‐adverse‐effect‐level (4 mg/kg/day), maternal plasma AUC was 3.68 ng.h/mL for artesunate and 6.93 ng.h/ml for its active metabolite, dihydroartemisinin (DHA). No developmental toxicity occurred with administration of 12 mg/kg/day for 3 or 7 days, GD29–31 or GD27–33 (maternal plasma AUC of 9.84 ng.h/mL artesunate and 16.4 ng.h/mL DHA). Exposures at embryotoxic doses were substantially lower than human therapeutic exposures. However, differences in monkey and human Vss for artesunate (0.5 L/kg vs. 0.18 L/kg) confound relying solely on AUC for assessing human risk. Decreases in reticulocyte count occur at therapeutic doses in humans. Changes to reticulocyte counts at embryotoxic doses in monkeys (≥12 mg/kg/day) were variable and generally minor. CONCLUSIONS: Artesunate was embryolethal at ≥12 mg/kg/day when dosed for at least 12 days at the beginning of organogenesis, but not when dosed for 3 or 7 days, indicating that developmental toxicity of artesunate is dependent upon duration of dosing in cynomologus monkeys. Birth Defects Res (Part B) 83:418–434, 2008. © 2008 Wiley‐Liss, Inc.
Developmental toxicity of artesunate in the rat: comparison to other artemisinins, comparison of embryotoxicity and kinetics by oral and intravenous routes, and relationship to maternal reticulocyte count
Authors: Clark Robert L. , Lerman Steven A. , Cox Estella M. , Gristwood William E. , White Tacey E.K.
Published: August 2008

BACKGROUND: The antimalarial, artesunate, is teratogenic and embryolethal in rats, with peak sensitivity on Days 10 and 11 postcoitum (pc). METHODS: We compared the developmental toxicity of structurally related artemisinins, dihdyroartemisinin (DHA), artemether (ARTM), and arteether (ARTE) to that of artesunate after oral administration to rats on Day 10 pc. In separate studies, embryolethality was characterized after single intravenous (IV) administration of artesunate on Day 11 pc, and toxicokinetic parameters following oral and IV administration were compared. Lastly, to determine whether maternal hematologic effects occurred at doses that affect embryonic erythroblasts, artesunate was orally administered on Day 11 pc at a dose that caused 100% embryolethality. RESULTS: All artemisinins caused the same pattern of embryolethality and fetal cardiovascular and skeletal abnormalities as previously shown for artesunate. In the IV study, marked postimplantation loss occurred at 1.5 and 3 mg/kg artesunate, but not at 0.75 mg/kg. Among the toxicokinetic parameters evaluated, only the DHA AUC0‐t was similar at embryolethal oral and IV doses of artesunate. An embryolethal dose of artesunate caused a 15% decrease in maternal reticulocyte counts and no other hematologic effects. CONCLUSIONS: Several structurally related artemisinins cause similar developmental toxicity, suggesting an artemisinin class effect. Equally embryotoxic oral and IV treatments of one artemisinin compound (artesunate) produced similar systemic exposure to the artesunate metabolite, DHA, suggesting that DHA may be the proximate developmental toxicant. Embryolethal doses of artesunate only caused minor changes in maternal reticulocyte counts indicating that adult hematology parameters are not as sensitive as embryonic erythroblasts. Birth Defects Res (Part B) 83:397–406, 2008. © 2008 Wiley‐Liss, Inc.
Synthetic Receptors for the Differentiation of Phosphorylated Peptides with Nanomolar Affinities
Authors: Grauer Andreas , Riechers Alexander , Ritter Stefan , König Burkhard
Published: August 2008

Artificial ditopic receptors for the differentiation of phosphorylated peptides varying in i+3 amino acid side chains were synthesized, and their binding affinities and selectivities were determined. The synthetic receptors show the highest binding affinities to phosphorylated peptides under physiological conditions (HEPES, pH 7.5, 154 mM NaCl) reported thus far for artificial systems. The tight and selective binding was achieved by high cooperativity of the two binding moieties in the receptor molecules. All receptors interact with phosphorylated serine by bis(ZnII–cyclen) complex coordination and a second binding site recognizing a carboxylate or imidazole amino acid side chain functionality.
Region‐specific alterations in astroglial TWIK‐related acid‐sensitive K+‐1 channel immunoreactivity in the rat hippocampal complex following pilocarpine‐induced status epilepticus
Authors: Kim Ji‐Eun , Kwak Sung‐Eun , Choi Soo‐Young , Kang Tae‐Cheon
Published: August 2008

In the present study, we performed an analysis of tandem of P domains in a weak inwardly rectifying K+ channel (TWIK)‐related acid‐sensitive K+ (TASK)‐1 channel immunoreactivity in the rat hippocampal complex following pilocarpine‐induced status epilepticus (SE). In control animals, TASK‐1 immunoreactivity was strongly detected in astrocytes in the hippocampal complex. One day after SE, TASK‐1 immunoreactivity in astrocytes was markedly reduced only in the molecular layer of the dentate gyrus. One week after SE, loss of astrocytes was observed in the molecular layer of the dentate gyrus. At this time point, TASK‐1 immunoreactive cells were detected mainly in the subgranular region. These cells had bipolar, elongated cell bodies with fusiform‐shaped nuclei and showed vimentin immunoreactivity. Four weeks after SE (when spontaneous seizure developed), typical reactive astrogliosis was observed in the dentate gyrus and the CA1 region. Almost no astrocytes in the molecular layer showed TASK‐1 immunoreactivity, whereas astrocytes in the CA1 region showed strong TASK‐1 immunoreactivity. These findings indicate that, after SE, TASK‐1 immunoreactivity was differentially altered in astrocytes located in different regions of the hippocampal complex, and these changes were caused by astroglial degeneration/regeneration. Therefore, alteration in TASK‐1 immunoreactivity may contribute to acquisition of the properties of the epileptic hippocampal complex. J. Comp. Neurol. 510:463–474, 2008. © 2008 Wiley‐Liss, Inc.
Numerical analysis of the rectangular domain decomposition method
Authors: Jun Younbae , Mai Tsun‐Zee
Published: August 2008

When solving parabolic partial differential equations using finite difference non‐overlapping domain decomposition methods, one often uses the stripwise decomposition of spatial domain and it can be extended to the rectangular decomposition without further analysis. In this paper, we analyze the rectangular decomposition when the modified implicit prediction (MIP) algorithm is used. We show that the performance of the rectangular decomposition and the stripwise decomposition is different. We compare spectral radius, maximum error, efficiency, and total operations of the rectangular and the stripwise decompositions. We investigate the accuracy of the interface of the rectangular decomposition and the effects of the correction phase of the rectangular decomposition. Numerical experiments have been done in both two and three spatial dimensions and show that the rectangular decomposition is not better than the stripwise decomposition. Copyright © 2008 John Wiley & Sons, Ltd.
Near infrared optical tomography using NIRFAST: Algorithm for numerical model and image reconstruction
Authors: Dehghani Hamid , Eames Matthew E. , Yalavarthy Phaneendra K. , Davis Scott C. , Srinivasan Subhadra , Carpenter Colin M. , Pogue Brian W. , Paulsen Keith D.
Published: August 2008

Diffuse optical tomography, also known as near infrared tomography, has been under investigation, for non‐invasive functional imaging of tissue, specifically for the detection and characterization of breast cancer or other soft tissue lesions. Much work has been carried out for accurate modeling and image reconstruction from clinical data. NIRFAST, a modeling and image reconstruction package has been developed, which is capable of single wavelength and multi‐wavelength optical or functional imaging from measured data. The theory behind the modeling techniques as well as the image reconstruction algorithms is presented here, and 2D and 3D examples are presented to demonstrate its capabilities. The results show that 3D modeling can be combined with measured data from multiple wavelengths to reconstruct chromophore concentrations within the tissue. Additionally it is possible to recover scattering spectra, resulting from the dominant Mie‐type scatter present in tissue. Overall, this paper gives a comprehensive over view of the modeling techniques used in diffuse optical tomographic imaging, in the context of NIRFAST software package. Copyright © 2008 John Wiley & Sons, Ltd.
Charge‐injection photogate pixel fabricated in CMOS silicon‐on‐insulator technology
Authors: Durini Daniel , Brockherde Werner , Hosticka Bedrich J.
Published: August 2008

Concept, theoretical analysis, and experimental results obtained from a charge‐injection photogate (CI‐PG) pixel detector fabricated in CMOS silicon‐on‐insulator (SOI) technology are presented. The charge collected in the photodetector during a certain charge collection (integration) time is injected into the substrate for readout. This readout principle presents a huge internal photocurrent amplification (∼104) taking place in the photodetector, obtained through the ‘time‐compression’ approach. Here, the readout circuitry is fabricated on highly doped, 200 nm thick, SOI film, while the photogate detector is fabricated on higher resistivity handle‐wafer. The latter, together with the 30 V biasing possibilities, enhances the quantum efficiency of the pixel, especially for irradiations with wavelengths in the near‐infra‐red part of the spectra. Copyright © 2008 John Wiley & Sons, Ltd.
Bis(acetylido) Complexes of Ruthenium(II) Bearing Monodentate Phosphane Ligands
Authors: Field Leslie D. , Magill Alison M. , Dalgarno Scott J. , Jensen Paul
Published: August 2008

Terminal acetylenes react with cis‐RuMe2(PMe3)4 to form the bis(acetylido) complexes cis/trans‐Ru(C≡CR)2(PMe3)4 in good yield. The structures of trans‐2 (R = Ph), cis‐3 (R = p‐C6H4‐OMe), trans‐4 (R = p‐C6H4‐Me), cis‐6 (R = Me), trans‐7 (R = SiMe3) and cis‐8 (R = H) were determined by X‐ray crystallography. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Combined Experimental and Density Functional Theory Studies on the Crystal Structures and Magnetic Properties of Mg(Mg1–xMnx)2Sb2 (x ≈ 0.25) and BaMn2Sb2
Authors: Xia Sheng‐Qing , Myers Chad , Bobev Svilen
Published: August 2008

Reported are the synthesis and structural characterization of two ternary transition metal intermetallic compounds, Mg(Mg1–xMnx)2Sb2 (where x is approximately 0.25) and BaMn2Sb2·Mg(Mg2.50(3)Mn0.5)2Sb2 crystallizes in the trigonal space group P$\bar {3}$m1 (no. 164) and belongs to the CaAl2Si2‐type, while BaMn2Sb2 is isostructural with the body‐centred tetragonal ThCr2Si2‐type (I4/mmm, no. 139). Both structures have been refined from single‐crystal X‐ray diffraction data and their magnetic properties determined with the aid of a SQUID‐magnetometry. The experimental results have been corroborated by electronic‐structure calculations using the linear muffin‐tin orbital (LMTO) method. Spin‐polarized density‐functional theory calculations confirm the antiferromagntically ordered magnetic structures. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
A Simple Two‐Step Sequence for the Synthesis of Novel 4‐Aryl‐4,5‐dihydro‐6H‐[1,3]dioxolo[4,5‐h]pyrrolo[1,2‐a][1]benzazepin‐6‐ones from 6‐Amino‐3,4‐methylenedioxyacetophenone
Authors: Abonia Rodrigo , Cuervo Paola , Insuasty Braulio , Quiroga Jairo , Nogueras Manuel , Cobo Justo
Published: August 2008

Herein is provided an efficient and two‐step short procedure for the synthesis of novel 6H‐[1,3]dioxolobenzo[4,5‐h]pyrrolo[1,2‐a][1]benzazepin‐6‐one derivatives promoted by commercial phosphoric acid. In a parallel approach some pyrrolyl chalcones were isolated that proved to behave as intermediates for the title compounds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Protonation of Diarylacetylenes in Superacid HSO3F and Their Oxidation in the HSO3F/PbO2 System: One‐Pot Synthesis of Polysubstituted Naphthalenes
Authors: Vasilyev Aleksander V. , Shchukin Andrey O. , Walspurger Stéphane , Sommer Jean
Published: August 2008

In the superacid HSO3F, diarylacetylenes bearing one electron‐withdrawing group (NO2, CN, COMe, CO2Me) in each arene ring form stable ions, protonated at these groups. Oxidation of such diarylacetylenes in the HSO3F/PbO2 system at –75 to –50 °C over 2–2.5 h, followed by quenching of the reaction mixture with hydrochloric (or hydrobromic) acid at –60 to 25 °C, resulted in the formation of (E,E)‐1,4‐dichloro (or dibromo)‐1,2,3,4‐tetraarylbuta‐1,3‐dienes. These butadienes spontaneously undergo electrocyclic transformation into polysubstituted naphthalenes at room temperature. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Altruism or psychological escape: Why does empathy promote prosocial behavior?
Authors: Stocks Eric L. , Lishner David A. , Decker Stephanie K.
Published: August 2008

Why does empathy promote prosocial behavior? Previous research suggests that empathically aroused individuals help those in need, even when physical escape from the need situation is easy, and this evidence has been used to support the claim that empathy evokes an altruistic motive. However, existing research has not addressed the possibility that empathically aroused participants help because ease of physical escape fails to provide adequate psychological escape from awareness of the victim's suffering and the aversive empathic arousal such awareness produces. The two experiments reported here examined this issue by directly manipulating empathic arousal and the perceived ease of psychological escape among potential helpers. In both experiments, higher rates of helping were observed among empathically aroused participants, even under conditions of easy psychological escape. The findings of both experiments suggest that empathy evokes an altruistic motive to reduce the victim's suffering rather than an egoistic aversive‐arousal reduction motive. In addition, the results of Experiment 1 suggest that concern for psychological escape from the suffering of others may constitute an important independent prosocial motive in need of future study. Copyright © 2008 John Wiley & Sons, Ltd.