bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural Products: An Overview
Authors: Clardy Jon , Fischbach Michael A. 
Published: August 2008

Abstract
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

AbstractNuclear 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

AbstractProteins 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

AbstractTransient‐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

AbstractCatalytic 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

AbstractFlavins 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

Abstract
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

Abstract

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

Abstract

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

Abstract
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

AbstractThis 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

AbstractBACKGROUND: 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

AbstractBACKGROUND: 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

AbstractArtificial 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

AbstractIn 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

AbstractWhen 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

AbstractDiffuse 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

AbstractConcept, 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

AbstractTerminal 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)