bluuebunny/crossref_metadata_2025 huggingface dataset:
The Triffin Dilemma Again
Authors: Campanella Edoardo
Published: September 2010

Tiny changes in the American monetary policy can have dramatic effects on the rest of the world because of dollar’s double role of national and international currency. This is the Triffin dilemma. The paper shows how it works through three examples: price of commodities, dollarization, and the international financial position of the US. And it makes a proposal to solve these issues, creating a more stable monetary system. In particular, it suggests the creation of an international monetary system of block regional currencies. Globalization and regionalization should be the two forces leading towards the new monetary system. The US and Europe should consider to adopt the same currency through a system of fixed exchange rates (global currency). This currency should perform its duty of anchor of the system, reducing global imbalances and gyrations in price of commodities. Developing countries, by contrast, should create regional monetary unions (regional currencies), preserving the real exchange rate as shock absorber, but gaining in terms of time consistency and credibility.
Parameterization of ion-induced nucleation rates based on ambient observations
Authors: Nieminen T. , Paasonen P. , Manninen H. E. , Kerminen V.-M. , Kulmala M.
Published: September 2010

Abstract. Atmospheric ions participate in the formation of new atmospheric aerosol particles, yet their exact role in this process has remained unclear. Here we derive a new simple parameterization for ion-induced nucleation or, more precisely, for the formation rate of charged 2-nm particles. The parameterization is semi-empirical in the sense that it is based on comprehensive results of one-year-long atmospheric cluster and particle measurements in the size range ∼1–42 nm within the EUCAARI (European Integrated project on Aerosol Cloud Climate and Air Quality interactions) project. Data from 12 field sites across Europe measured with different types of air ion and cluster mobility spectrometers were used in our analysis, with more in-depth analysis made using data from four stations with concomitant sulphuric acid measurements. The parameterization was given in two slightly different forms: a more accurate one that requires information on sulfuric acid and nucleating organic vapor concentrations, and a simpler one in which this information is replaced with the global radiation intensity. In principle, these new parameterizations are applicable to all large-scale atmospheric models containing size-resolved aerosol microphysics.
Climate change between the mid and late Holocene in northern high latitudes – Part 1: Survey of temperature and precipitation proxy data
Authors: Sundqvist H. S. , Zhang Q. , Moberg A. , Holmgren K. , Körnich H. , Nilsson J. , Brattström G.
Published: September 2010

Abstract. We undertake a study in two parts, where the overall aim is to quantitatively compare results from climate proxy data with results from several climate model simulations from the Paleoclimate Modelling Intercomparison Project for the mid-Holocene period and the pre-industrial, conditions for the pan-arctic region, north of 60° N. In this first paper, we survey the available published local temperature and precipitation proxy records. We also discuss and quantifiy some uncertainties in the estimated difference in climate between the two periods as recorded in the available data. The spatial distribution of available published local proxies has a marked geographical bias towards land areas surrounding the North Atlantic sector, especially Fennoscandia. The majority of the reconstructions are terrestrial, and there is a large over-representation towards summer temperature records. The available reconstructions indicate that the northern high latitudes were warmer in both summer, winter and the in annual mean temperature at the mid-Holocene (6000 BP ± 500 yrs) compared to the pre-industrial period (1500 AD ± 500 yrs). For usage in the model-data comparisons (in Part 1), we estimate the calibration uncertainty and also the internal variability in the proxy records, to derive a combined minimum uncertainty in the reconstructed temperature change between the two periods. Often, the calibration uncertainty alone, at a certain site, exceeds the actual reconstructed climate change at the site level. In high-density regions, however, neighbouring records can be merged into a composite record to increase the signal-to-noise ratio. The challenge of producing reliable inferred climate reconstructions for the Holocene cannot be underestimated, considering the fact that the estimated temperature and precipitation fluctuations during this period are in magnitude similar to, or lower than, the uncertainties the reconstructions. We advocate a more widespread practice of archiving proxy records as most of the potentially available reconstructions are not published in digital form.
Strategies for validating and directions for employing SMOS data, in the Cal-Val project SWEX (3275) for wetlands
Authors: Marczewski W. , Slominski J. , Slominska E. , Usowicz B. , Usowicz J. , Romanov S. , Maryskevych O. , Nastula J. , Zawadzki J.
Published: September 2010

Abstract. The paper tries interpreting how the method of SMOS observations realizes managing the problem of large scales and the target heterogeneity by means of employing the polarization angular signature. Land surface target on the Earth is naturally heterogeneous in its continuity of physical and biophysical properties. Soil moisture (SM) retrieval from SMOS data requires using the model CMEM to determine relations between the temperature brightness and water related properties and conditions, which are anchored to the ground by auxiliary data. SM retrieval must start from the conditions at least approaching physical reality. SMOS performs the data fusion in NRT (Nearly Real Time) in a very specific way, what is a new quality added to EO (Earth Observations). The paper demonstrates several effects of employing the SM retrievals from L1C data. Authors explain how they validate few selected test sites in Poland, and come to conclusions on choosing a strategy focused on validating single sites. Finally, they come to an understanding that SM retrieval is an advanced statistical method requiring good referencing to ground based physical conditions in large scales, worth confronting the shallow water content obtained from SMOS to that assessments of the total water content on continental scales, which available from effects of gravitational missions.
Linkage of cave-ice changes to weather patterns inside and outside the cave Eisriesenwelt (Tennengebirge, Austria)
Authors: Schöner W. , Weyss G. , Mursch-Radlgruber E.
Published: September 2010

Abstract. The behaviour of perennial ice masses in karst caves in relation to the outside climate is still not well understood, though a significant potential of the cave-ice for paleo-climate reconstructions could be expected. This study investigates the relationship between weather patterns inside and outside the cave Eisriesenwelt (Austrian Alps) and the ice-surface changes of the ice-covered part of the cave from extensive measurements. It is shown that under recent climate the cave ice mass balance is more sensitive to winter climate for the inner parts of the cave and sensitive to winter and summer climate for the entrance near parts of the cave. For recent climate conditions ice surface changes can be well described from cave atmosphere measurements, indicating a clear annual cycle with weak mass loss in winter due to sublimation, stable ice conditions in spring until summer (autumn for the remoter parts of the cave) and significant melt in late summer to autumn (for the entrance near parts of the cave). Interestingly, surface ice melt plays a minor role for ablation at the inner parts of the cave. Based on our measurements and other observations it is rather likely that sublimation was the major source for ice loss in Eisriesenwelt since the begin of the 20th century. Build-up of the ice in spring (as expected from theory) was not observed as a general feature of the ice dynamics. Generally, the ice body currently appears in a quite balanced state, though the influence of show-cave management on ice mass-balance could not be clearly quantified.
DNA
‐Binding Proteins From Starved Cells (
Dps
Proteins)
Authors: Stefanini Simonetta , Ceci Pierpaolo , Ardini Matteo , Ilari Andrea
Published: September 2010

In the recent past over 200 Dps (DNA‐binding proteins from starved cells) proteins have been identified in bacterial genomes. Dps proteins belong to the ferritin superfamily. They are expressed under conditions of oxidative and/or nutritional stress and are characterized by a highly conserved shell‐like structure of 12 identical subunits assembled with 23 symmetry. The internal cavity is designed to accommodate up to 500 iron/atoms per molecule in a soluble and bioavailable form. Dps proteins play an important role in the complex protection mechanism against oxidative damage. The presence of a highly conserved ferroxidase center, which uses hydrogen peroxide as physiological iron oxidant, confers to all Dps proteins the capacity to decrease the production of the hydroxyl‐radicals and, hence, to prevent the damage to DNA and other cellular components. Ferroxidase activity is of special importance in pathogenic bacteria since production of hydrogen peroxide in macrophages and neutrophiles represents one of the first host defense mechanisms. The capacity to bind DNA in a nonspecific manner and pack it into condensed structures, an attribute limited to some members of the family, represents the second distinctive mechanism used to advantage by Dps proteins for the survival of the organism.
Bases and Base Catalysis—Heterogeneous
Authors: Ono Yoshio
Published: September 2010

Although catalysis by solid bases has received much attention due to its importance in petroleum refining and petrochemical processes, relatively few studies have focused on catalysis by solid bases. Base catalysts, however, play a decisive role in a number of organic reactions essential for fine‐chemical synthesis. Solid‐base catalysis has many advantages over liquid bases in many respects from environmental aspects. This article offer general accounts of solid‐base catalysis and consists of three parts. The first part, gives the definition and concepts of solid bases and the methods for characterizing basic sites on solid surfaces. In the second part the typical solid‐base catalysts are surveyed. The solid bases include alkaline earth oxides, hydrotalcites and related materials, oxynitrides, zeolites, and modified zeolites alkaline metals and alkaline compounds such as KF/Al2O3and KNH2/Al2O3and amines anchored on mesoporous silica. The third part will show that a great variety of organic reactions is catalyzed by solid bases. The reactions described include the isomerization of alkenes and alkyns, aldol condensation, nitroaldol condensation, Knoevenagel condensation, Michael addition, substitution reactions, reactions of silicon compounds, and alkylation reactions.
Biphasic Catalysis—Homogeneous
Authors: Joó Ferenc
Published: September 2010

Homogeneous catalysis offers advantages over heterogeneous catalytic methods in that all catalyst molecules are available for the substrate, and the catalyst can be tailored to the desired chemical transformation by choosing (designing) the proper ligand environment. In most cases, however, industry uses heterogeneous catalysts because (in addition to their high activity and selectivity) catalyst–product separation poses no serious problems. A successful way of heterogenization of homogeneous catalysts is the separation of the reactants (products) and the catalyst into immiscible liquid phases (liquid multiphase catalysis).

This article reviewsbiphasic catalysiswith homogeneously (molecularly) dispersed catalysts. Attention is focused on liquid–liquid biphasic systems, containing all the reactants and the catalyst(s) in dissolved state. Such biphasic systems are built up of two or more solvents with limited mutual solubility.Aqueous–organicandorganic–organic(including alsofluorous) biphasic systems have been studied for long; however, the use of biphasic reaction mixtures designed by usingfluorous solvents,ionic liquids, andsupercritical gasesin combination with each other or with appropriate aqueous or organic solvents has been rapidly developing recently. The properties of such systems together with the need of special ligand design or modifications are discussed, and their use is illustrated by describing typical reactions (hydrogenation, hydrogen transfer, hydroformylation, hydrocarboxylation, carbonylation, alkene metathesis, dimerization, polymerization, and other CC coupling reactions).
Mononuclear Ruthenium Catalysis
Authors: Woolley Graham , Rosenberg Edward
Published: September 2010

The various reactions catalyzed by mononuclear ruthenium complexes are reviewed through 2008. The reactions discussed are hydrogenation with dihydrogen of carbon–carbon multiple bonds and carbon–heteroatom bonds, hydrogenation via hydrogen transfer, oxidation of carbon–heteroatom bonds, oxidation of carbon–carbon bonds, oxidation of alkanes, nucleophilic addition to alkynes, reactions involving C–H activation, olefin metathesis, reactions involving allyl ruthenium intermediates, and a brief discussion of radical reactions involving mononuclear ruthenium complexes. The article attempts to emphasize the use of chiral auxiliaries for obtaining enantiospecific transformations and the impact of ligand structure on the mechanistic aspects of a particular transformation. The article is not intended to be comprehensive but tries to survey the range of organic transformations currently employing mononuclear ruthenium reactions. More than half of the references are from the past 10 years.
Extremophiles
Authors: Ozdemir Inci , Kelly Robert M.
Published: September 2010

Extremophiles are microorganisms with the ability to survive under extreme environmental conditions, including geothermal and arctic waters, glacial ices, deserts, saline lakes, and acidic, sulfurous hot springs. Adaptation of extremophiles to harsh conditions and unique stability of the enzymes (extremozymes) from these organisms have recently attracted a great deal of attention. Extremozymes have been replacing enzymes, which do not cope with harsh conditions, in many industries, such as pharmaceutical, food, chemical, laundry detergents, and bioremediation. Furthermore, there is an increasing demand of novel applications of these biocatalysts, working optimally over a range of extreme conditions, such as high temperature, high salinity, and high alkalinity. Developments in gene discovery and gene expression technologies hopefully will expand the exploitation of these biocatalysts. In this study, different types of extremophiles are introduced and the adaptations to extreme conditions for each condition are pointed. The biocatalysts from overlooked extremophiles and the applications of these biocatalysts are highlighted.
Metal Oxides
Authors: Bartley Jonathan K. , Hargreaves Justin S. J. , Hutchings Graham J. , Rico José L. , Taylor Stuart H. , Wells Richard P. K. , Willock David J.
Published: September 2010

This article details the preparation, catalytic activity, computer modeling, and design of heterogeneous oxide catalysts.
Reforming—Industrial
Authors: Moser Mark , Sadler Clayton C.
Published: September 2010

Catalytic reforming is one of the primary processes of refining. It is used widely today throughout the petroleum and petrochemical industries. The catalytic reforming unit is used for the production of the primary component of high‐octane motor fuels and also for the production of feedstocks for petrochemical processes. This article discusses the history of the technology, its various adaptations and current developments. The chemical reactions, their rates, thermodynamics, and reaction conditions are described. The properties of the feed and products are listed, as are process contaminants and their removal. Catalyst deactivation and the subsequent regeneration of the catalyst are discussed. Various methods of process modeling are listed. The composition and properties of the catalysts used are provided. Finally, a case study of an evaluation of process economics is given.
Understanding Enzyme Catalysis Using Computer Simulation
Authors: Parks Jerry M. , Imhof Petra , Smith Jeremy C.
Published: September 2010

Enzymes catalyze biochemical reactions with remarkable specificity and efficiency, usually under physiological conditions. Computer simulation is a powerful tool for understanding enzyme catalytic mechanisms, particularly in cases where standard experimental techniques may be of limited utility. Here, we present an overview of the application of computer simulation techniques to understand enzyme catalytic mechanisms. Examples using quantum chemical methods and quantum mechanical/molecular mechanical approaches are provided.
Virtual Screening
Authors: Muegge Ingo , Oloff Scott
Published: September 2010

Virtual screening can be considered asin silicoanalog to high‐throughput screening. It is a knowledge‐driven approach toward finding new lead structures for drug discovery. There are a large variety of different virtual screening approaches and strategies available today. They include ligand‐based approaches such as compound similarity searching, pharmacophore searching, and applying predictive models derived using machine learning techniques as well as structure‐based approaches such as docking and scoring that use information about the protein target structures. Triaging hit sets using target‐independent filters such as drug‐likeness and diversity is an additional component of virtual screening. Using different virtual screening approaches in synergy has become more prevalent. Virtual screening applications have been combined with modern drug discovery technologies such as fragment‐based screening, combinatorial chemistry, and scaffold hopping methods to increase their effectiveness as lead identification tools.
Gene Therapy with PlasmidDNA
Authors: Bathula Surendar Reddy , Huang Leaf
Published: September 2010

Gene therapy is a promising therapeutic modality for the treatment of inherited as well as acquired genetic disorders. It can be defined as the use of nucleic acid transfer, either RNA or DNA, to treat or prevent a disease. Although initially most research on gene therapy has focused on the development of viral‐mediated approaches to deliver therapeutic genes to cells bothex vivoandin vivo, nonviral gene medicines have emerged as a potentially safe and effective gene therapy method for the treatment of a wide variety of acquired and inherited disorders. Compared to viral vectors, this delivery system has received great attention due to their several favorable properties, including low toxicity and immunogenicity, resistance to nuclease, and their efficiency is independent on size of the genetic cargo. One of the simplest approaches of delivery is direct gene transfer with naked plasmid DNA to the organs of interest.Plasmid DNAs (pDNAs), which carry recombinant genes of interest, are used for introducing genes to cells and organs. Various physical methods, for example, gene gun, electroporation, sonoporation, and laser irradiation increase the efficiency of the naked DNA incorporation. Synthetic gene delivery vectors such as cationic lipids and cationic polymers have the advantage of protecting the DNA against degradation by endogenous DNasein vivo, and can be targeted to a specific cellular site in some special cases. Varieties of lipid‐based systems have been designed, mostly containing cationic lipids of different structures. Vectors containing polymers, either synthetic or natural, have also been developed. Although significant progress has been made, nonviral vectors are still limited in their efficiency and by some cytotoxicity inherited in the bacterial pDNA, which hosts the gene of interest. Understanding mechanisms and means to overcome the cellular barriers for the DNA delivery will undoubtedly promote further development of pDNA‐mediated gene delivery. Great advancement has recently been made in the delivery of oligonucleotides, including siRNA, by nonviral vectors. This is because the nuclear membrane is not a delivery barrier for most of the oligonucleotides.
Tetracycline, Aminoglycoside, Macrolide, and Miscellaneous Antibiotics
Authors: Mitscher Lester A.
Published: September 2010

The identity, chemistry, biosynthesis, antimicrobial spectra, molecular mode of action, bacterial resistance mechanisms, side effects, and clinical uses of these important chemotherapeutic agents are discussed.
Recent Trends in Structure‐Based Drug Design and Energetics
Authors: Andricopulo Adriano D. , Guido Rafael V.C. , Trivella Daniela B.B. , Polikarpov Igor , Leitão Andrei , Montanari Carlos
Published: September 2010

The integration of cheminformatics tools, thermodynamic data, and structural information play a major role in the drug discovery process. Altogether, these methods can describe the molecular forces that govern the affinity and selectivity of bioactive molecules for their macromolecular targets. By being able to uncover the relationships between structure and energetics when using high‐resolution structural information and modern biophysical methods, one can fulfill the challenge of correctly interpreting drug–macromolecular interactions. These interactions are prone to be unveiled and scrutinized when structure‐based drug design is applied to a known three‐dimensional (3D) structure of a given protein. If fully integrated with structure‐based ligand design in an iterative way, computational methods can be of invaluable help to describe the ligand–target (cocomplex) formation. Structure‐based virtual screening can be used to rapid cherry‐pick the best candidates from a large pool of compounds in a chemical library after docking into the active sites of 3D protein structures. To pursue this, the quantification of favorable and unfavorable interactions requires knowledge of the thermodynamics of the interactions. Docking algorithms and molecular dynamics simulations can be used to predict binding energies for positioning ligands in target binding sites, but they only provide information regarded to the prediction of the change in the Gibbs free energy change, which hampers the thoroughly dissection of all other very important thermodynamic parameters—enthalpy, entropy, and heat capacity change. The major goal of this chapter is to show the integration of structure‐based drug design with the energetic. Microcalorimetric measurement of the drug–macromolecular interaction is an effective way to enhance the power, the medicinal chemists have on hand, to pursue a knowledge‐based approach toward the description of all of the noncovalent bond terms that take place in the cocomplex formation.
Use of Biological Fingerprints Versus Structure/Chemotypes to Describe Molecules
Authors: Mason Jonathan S.
Published: September 2010

Molecules are usually described by their chemical structure and by fingerprints derived from this. These range from 2D structure based, that only represent the underlying structure that gives rise to the properties recognized by a biological target to 3D pharmacophores or molecular interaction fields, that much better represent how the protein binding sites would “see” a molecule. However, all of these have many limitations, including conformation for the 3D structure‐based approaches. More recently, experimental profiling data have been generated that enables a molecule to be described by a fingerprint of binding affinity to a diverse set of biological targets (pharmacological and “antitargets” such as CYP450 metabolic enzymes). These results show that small changes in structure can cause large changes in broad biological profile, and that a structure‐based analysis/clustering of compounds, such as different hits, leads, or clinical candidates, often does not provide a differentiation that is relevant in biological space. The data show that “selective” versus “nonselective” compounds, and the type of off‐target effects are not evident from a “chemotype” approach. The concept of “biological fingerprints” as a better way to describe compounds of biological interest is described in this chapter, focusing on the power of these descriptors versus structure‐based descriptors to differentiate compounds and enable the selection of the best lead compounds.
Process Development of Protein Therapeutics
Authors: Thomas James N. , Guhan S. Sam , Pettit Dean K.
Published: September 2010

The application of recombinant DNA technology to the production of protein therapeutics has undergone considerable progress since first introduced 30 years ago. Considerable scientific effort has been devoted to developing robust processes that produce large amounts of complex proteins with the desired product quality attributes. An overview of the contributions from the four major disciplines working in concert to deliver these processes and methods will be covered. This chapter will discuss some of the tools, methods, and approaches used to produce, purify, formulate, and analyze the drugs of modern biotechnology. Future trends in each of the disciplines will also be presented.
Multiple Sclerosis
Authors: Huryn Donna M.
Published: September 2010

Multiple sclerosis
(
MS
) is a severe, debilitating disease that affects more than a million individuals worldwide. Unfortunately, most aspects of this disease are poorly understood, thereby making drug discovery efforts particularly challenging. Historically, therapeutics for MS have relied on broad immunosuppression, and therefore these agents cause significant limiting side effects. Many of these older drugs were developed first as cancer therapeutics, and their ability to prevent the proliferation of immune cells was exploited in treating MS patients. Other current frontline therapies include immunosuppressants and immunomodulators that originally found use in inflammatory or other automimmune disorders. Current efforts are focusing on a more subtle approach at immunomodulation that target specific aspects of the immune response or putative MS autoantigens. This chapter provides an overview of currently approved therapies, including small‐molecule and protein‐based therapeutics as well as a more detailed review of promising new approaches, particularly those with a medicinal chemistry component.
Hsp
90 Inhibitors
Authors: Blagg Brian S. J. , Hadden M. Kyle
Published: September 2010

The Hsp90 molecular chaperones represent a promising target for the development of anticancer and neuroprotective agents as they are responsible for the conformational maturation of numerous signaling proteins and the refolding of aggregated proteins, respectively. In this chapter, a summary of recent developments toward the treatment of these diseases by small‐molecule modulators of Hsp90 is provided.
Histone Deacetylase Inhibitors: A Brief Overview Of Their Role And Medicinal Chemistry
Authors: Angibaud P. , Van Emelen K. , Arts J.
Published: September 2010

Histone deacetylase
s (
HDAC
s) comprise a family of proteins that impact critical cellular processes through regulation of chromatin remodeling and gene transcription. HDACs have emerged as attractive targets for the development of new anticancer agents and a number of structurally diverse inhibitors of HDAC from natural or synthetic origin have been described in the literature. This chapter focuses on those having reached clinical phases. For each, synthesis pathway,
in vitro
properties and short clinical profiles are presented. Recent developments in medicinal chemistry of HDAC inhibition are also reported.
Polymer Light‐Emitting Diodes
Authors: Weder Christoph , Kostka James
Published: September 2010

Electroluminescent devices based on polymeric materials have been a primary subject of research interest because of their potential for display and solid‐state lighting applications. These types of devices, termed polymer light‐emitting diodes, or PLEDs, offer the efficiency and lifetime benefits associated with solid‐state semiconductor technology, in addition to cost effective solution processing. Due to these inherent advantages, the field has grown rapidly over the past two decades, beyond the point of commercial exploitation. This article summarizes the exciting progress of the technology, addressing a broad range of topics including operating principles, device architecture, materials selection, and application requirements.
Smart Polymers–Biotechnological and Biomedical Applications
Authors: Galaev I. Yu.
Published: September 2010

Stimuli‐responsive or “smart” polymers undergo reversible phase separation from aqueous solutions triggered by small changes in the environment. The polymers are used in bioseparation (affinity precipitation, aqueous two‐phase polymer systems, smart chromatographic matrices responding to temperature), for production of smart surfaces for the mild detachment of cultivated mammalian cells, as a “chemical valve” regulating porosity of the system, as drug‐delivery systems, and for the development of microactuators and bioanalytical systems.
PolyHIPEs — Porous Polymers from High Internal Phase Emulsions
Authors: Silverstein Michael S. , Cameron Neil R.
Published: September 2010

A large variety of porous polymers, generally known as polyHIPEs, have been synthesized using high internal phase emulsions (HIPEs) as templates for the porous structure. HIPEs are formed by mixing two immiscible liquids in the presence of an emulsifier, usually a surfactant, such that the internal phase content is more than 74 %. PolyHIPE are synthesized through the polymerization of monomers in the external phase. The internal phase can be evacuated through holes that develop in the polymer walls, yielding a porous polymer. Hydrophobic polymers can be synthesized within water‐in‐oil emulsions and hydrophilic polymers can be synthesized within oil‐in‐water emulsions. The types of materials synthesized include copolymers, interpenetrating polymer networks, biodegradable materials, organic‐inorganic hybrids that can be pyrolyzed to porous inorganics, nanocomposites, and hydrophobic‐hydrophilic bicontinuous polymers. The large number of methods available to functionalize polyHIPEs have enhanced their utility for such applications as chemical synthesis, chromatography, ion exchange, separation, sensing, tissue engineering, and controlled drug delivery, to name but a few. This article describes HIPE formation and stability, polyHIPE synthesis and functionalization, polyHIPE morphology, polyHIPE properties, a variety of different polyHIPE‐based materials, and polyHIPE applications.
Chemical Synapses
Authors: Thiele Sherri , Nash Joanne
Published: September 2010

Chemical synapses are among the most elaborate junctions existing between two cells, enabling communication between neurons through chemical neurotransmission within milliseconds. This fast rate of transmission is achieved through three subsynaptic compartments; the presynaptic bouton, the synaptic cleft and the postsynaptic junction. The presynaptic bouton packages neurotransmitters into synaptic vesicles then releases them into the synaptic cleft. Release of synaptic vesicles occurs through several distinct stages, coordinated by a group of specialised proteins. The postsynaptic density (PSD) has evolved into a complex neurotransmitter reception apparatus, which enables the postsynaptic terminal to modulate the downstream response to neurotransmitters. Following activation of receptors on the postsynaptic membrane, neurotransmitters are taken back up into the presynaptic bouton and repackaged into synaptic vesicles (SVs). The synaptic cleft contains proteins that ensure that active zone and PSD remain in proximity. These proteins are also required during synaptogenesis to ensure that the synapse forms properly.

Key Concepts:

There are three major structural components that define the synapse: the presynaptic bouton (also known as presynaptic terminal), postsynaptic junction (also known as postsynaptic terminal) and the synaptic cleft.

The presynaptic bouton is responsible for packaging neurotransmitters into synaptic vesicles, then releasing their contents into the synaptic cleft in response to calcium influx.

Synaptic vesicles are released at a specialised site within the presynaptic bouton known as the active zone.

Synaptic vesicles are released by a process known as exocytosis through several distinct steps involving specialised proteins that form a highly interactive and dynamic protein complex at the site of synaptic vesicle release.

Interpretation of the presynaptic message takes place at the postsynaptic membrane through transmembrane proteins called receptors.

The postsynaptic density is situated adjacent to the postsynaptic membrane within the postsynaptic terminal, juxtaposed to the presynaptic active zone.

The postsynaptic density is composed of receptors, scaffolding and adhesion proteins, kinases and phosphatases, as well as cytoskeletal elements, which are linked together to form macromolecular complexes.

The postsynaptic density of excitatory synapses is thicker (more pronounced) than the postsynaptic density of inhibitory synapses.

The synaptic cleft is a narrow space, approximately 20–30 nm wide situated between the presynaptic and the postsynaptic plasma membranes.

The synaptic cleft is composed of proteinaceous and carbohydrate‐rich cell adhesion molecules.
Immune Defence: Microbial Interference
Authors: Merino S , Tomás JM
Published: September 2010

The immune system controls the host–microbe interactions, the outcome of which can range from symbiotic coexistence with commensally microbiota, to mild asymptomatic infections, to highly virulent infectious diseases. This control is achieved by two defence mechanisms: the innate immune defence, which consists in a nonspecific mechanism, and the adaptive immunity defence, acquired over time following infections or vaccination. Despite the sophisticated immune system, extracellular and intracellular pathogens have developed numerous, and often ingenious strategies, to evade, interfere or eradicate the effectiveness of host immune defences. Although the strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms shared between these microbial pathogens. The success of each pathogen depends on the coordinated activities of its virulence factors to overcome host barriers to colonisation and its ability to mount an effective anti‐immune response within the infected host, which can ultimately result in acute disease or chronic infection.

Key Concepts:

Immunoglobulin proteases cleave antibodies rendering them nonfunctional and leading to deficiencies in the immune system.

Complement regulators prevent complement activation and cell destruction.

Interference with major histocompatibility complexes overcomes T‐cell recognition.

Microbial interference with cytokines modulates intracellular signalling critical to the regulation, proliferation and differentiation of lymphocytes, which drive inflammation.

Intracellular resistance allows microorganisms to circumvent humoral defence mechanisms and spread within the host.

Immunosuppresion reduces T or B lymphocytes’ defence.
Complement: Classical and Lectin Pathways
Authors: Arlaud Gérard J , Thielens Nicole M
Published: September 2010

The classical and
lectin
pathways of complement are major recognition systems of innate immunity that are found in mammals and other animal species. By means of several multimolecular proteases –
C1
, the
mannan‐binding lectin
(MBL)–
MBL‐associated serine protease 2
(MBL–MASP‐2) and the
ficolin–
MASP‐2 complexes – each comprising a recognition protein and a protease component, they detect pathogens and other targets and thereby trigger proteolytic reactions. Both pathways converge to the formation of
C3 convertase
, a complex protease that cleaves
C3
, the central component of the complement system. Proteolytic cleavage of
C3
generates a series of fragments and elicits various effector mechanisms, including inflammation and phagocytosis. These mechanisms contribute to the elimination of pathogenic microorganisms and altered host cells from blood and tissues and modulate the adaptive immune response.

Key Concepts:

C1q, MBL and ficolins are pattern‐recognition molecules able to sense conserved motifs on pathogens and altered self‐cells.

C1q is a major sensor of apoptotic cells and regulator of immune tolerance.

Proteolytic cleavage of C3 is pivotal for amplification of the complement response and labelling of the target particles.

Target recognition, proteolysis and complex formation generate conformational changes that underlie complement functioning.

Complement activation and activity are tightly regulated to avoid noxious side effects on normal host cells and tissues.
Amino Acid Biosynthesis
Authors: Deferrari Giacomo , Mannucci Irene , Garibotto Giacomo
Published: September 2010

Amino acids are classically considered as the building blocks for the synthesis of proteins. Besides this, some of them play a major role in other functions, such as regulation of protein turnover and signal transduction, transport of nitrogen and carbon across the organs, or neurotransmission. The unique characteristics of amino acids are the presence of a free amino group in the α‐carbon and a free carboxyl group. The amino acids differ from each other with respect to their side‐chains. The amino acids are classified into subgroups according to their similarity in carbon skeleton, substituent groups or a common metabolic pathway. The biosynthesis of amino acids involves several biochemical pathways in which amino acids are assembled from other precursors. The biosynthesis of amino acids is distinct from that involving lipids or carbohydrates because it includes the use of nitrogen.

Key Concepts:

Amino acids are classically considered as the building blocks from which proteins are synthesised. Besides this, some of them play a major role in the regulation of protein turnover and signal transduction, transport of nitrogen and carbon across the organs, and neurotransmission.

The biosynthesis of amino acids involves several biochemical pathways in which amino acids are assembled from other precursors. The biosynthesis of amino acids is distinct from that involving lipids or carbohydrates because it includes the use of nitrogen.

The fixation of nitrogen is a process that converts atmospheric nitrogen to a form that can be used biologically.

The pathways for the synthesis of essential amino acids are present only in microorganisms and plants.

Nine of 12 nonessential amino acids are synthesised from amphibolic intermediates, whereas three amino acids (tyrosine, cysteine and hydroxylysine) derive from essential amino acids. Amino acid transaminases, glutamate dehydrogenase and glutamine synthetase play a central role in the synthesis of nonessential amino acids.

The major pathway by which ammonia is incorporated into amino acids is through the reductive amination of α‐ketoglutarate to glutamate. Ammonia is highly toxic for animals. Glutamine is a nontoxic carrier of ammonia.

In the human adult as much as 200–250 g of proteins are degraded daily, and their constituent amino acids are in large part reutilised in protein synthesis.

Amino acid deficiency states can result if any of the essential amino acid is present in inadequate amounts or omitted from the diet.

Alanine, glutamate and glutamine are crucial links between energy and protein metabolism. Moreover, glutamine and alanine biosynthesis in the peripheral tissues (muscle) provides a means for the transport of carbon to the liver for gluconeogenesis and nitrogen for ureagenesis.

There are several nonprotein functions of amino acids, such as the biosynthesis of purines and pyrimidines, which involve more nonessential than essential amino acids.
Major Histocompatibility Complex (
MHC
): Mouse
Authors: Stuart Patrick M
Published: September 2010

The major histocompatibility complex (MHC) of the mouse, which is called the
H2
complex, is located on chromosome 17. It contains genes critical to the functioning of the immune system, the products of which are intimately involved in the initiation of immune responses. The proteins made by these genes display a significant amount of polymorphism, or sequence variability. Few genes possess this degree of polymorphism, but it is critical to the immune response and to the survival of a species. The chief characteristic of MHC molecules is their ability to bind small peptides. These bound peptides along with specific areas of the MHC molecule are the structures that interact with the T‐cell receptor (TCR) leading to activation of a T‐cell immune response, which in turn can active other cells of immune system. Thus they determine which TCR's are functional which in turn indicates which peptides a T cell will respond to.

Key Concepts:

The historical background and the genetics of MHC development are described.

The expression and function of MHC class I genes is described.

The function of CD8+ T cells requires expression of MHC class I genes.

Peptide loading is required for MHC class I expression.

MHC class I polymorphism is important for species resistance to infectious disease.

The expression and function of MHC class II genes is described.

MHC class II expression is required for generation and function of CD4 T cells.

Nonclassical class I molecules are important in generating responses to commonly expressed molecules expressed by pathogenic organisms.

The function of other genes found within the H2 complex is described.
Inflammation: Chronic
Authors: Kumar Rakesh K , Wakefield Denis
Published: September 2010

Chronic inflammation may result from failure to eliminate an irritant that causes acute inflammation, from an autoimmune response to a self‐antigen, or may be caused by an innately chronic irritant of low intensity that persists. It is a biologically distinct pattern of response that is characterised by simultaneous inflammation and repair. Recruitment and activation of macrophages is typical of chronic inflammation, and is often accompanied by recruitment of cell types participating in an immunological response, notably T lymphocytes. Significant destruction of tissue may occur. Repair, which involves induction of granulation tissue, may lead to subsequent scarring. The chronic inflammatory response is regulated by the coordinated action of various cytokines and growth factors. Many common and clinically important disease states result from chronic inflammation, and this process also contributes to other diseases which are not primarily identified as inflammatory.

Key Concepts:

Chronic inflammation is a key process underlying many common and important diseases, as well as other disease states which are not obviously inflammatory.

Compared to acute inflammation, chronic inflammation is a biologically distinct pattern of response, characterised by simultaneous inflammation and repair.

Macrophages and their derivatives are key participants in a chronic inflammatory response.

The immune response contributes to the pathogenesis of many chronic inflammatory diseases.

Chronic inflammation is regulated by a complex interaction between cytokines that promote inflammatory cell recruitment/activation and growth factors that promote healing.
Bacterial Capsules and Evasion of Immune Responses
Authors: Merino S , Tomás JM
Published: September 2010

The bacterial surface contains various structures that are capable of activating the host defences and consequently inducing host immune responses. Bacterial capsules are one of the most external structures on the bacterial surface, which may completely surround all the antigenic molecules or may be coexpressed with other bacterial antigens. They are involved in a wide range of biological processes, such as prevention of desiccation, adherence and resistance to nonspecific and specific host immunity.

Gram‐negative and Gram‐positive capsular polysaccharides contribute to the bacterial resistance of host immune responses by different mechanisms. Usually, capsular polysaccharides that mask the underlying cell surface structures activate weakly or not at all the immune system, whereas bacterial capsules coexpressed with other bacterial antigens activate the immune system but mask opsonines and prevent complement attack complex formation, as well as phagocytosis.

Key Concepts:

Bacterial capsules completely surround bacterial cell and enhance the ability of bacteria to cause disease.

Polysaccharides are polymeric carbohydrate structures, formed of one or more sugar residues repeating units joined together by glycosidic bonds.

Antigenic variation modifies microorganism's surface structures and allows them to overcome the immune response.
Bacterial
DNA
Polymerase I
Authors: Allen William J , Li Ying , Waksman Gabriel
Published: September 2010

Bacterial
deoxyribonucleic acid (DNA) polymerase I
is a family of enzymes involved in bacterial DNA synthesis and lesion repair. These enzymes have a multidomain structure, consisting of a single polypeptide chain that encompasses a distinct polymerase domain, a proofreading 3′–5′
exonuclease
and/or a 5′–3′
exonuclease
activity. Members of the
polymerase I
family have been investigated extensively, both because of their vital role in replicating and maintaining bacterial chromosomes, and because of their importance as tools in molecular biology, in particular for the polymerase chain reaction (PCR) and DNA sequencing. Studies on the

Escherichia coli

DNA polymerase I
in particular have yielded significant insights into the mechanism of DNA polymerisation which is shared by almost all other nucleotide polymerases.

Key Concepts:

Bacterial DNA polymerase I enzymes are multidomain proteins with separate polymerisation, proofreading and 5′–3′ exonuclease functions.

They perform a vital function in bacteria by carrying out DNA repair and some aspects of chromosomal replication.

Polymerases incorporate one nucleotide at a time to the 3′ end of the primer DNA strand in a template‐directed manner.

Members of the DNA polymerase I family are able to replicate DNA with far greater accuracy than base pairing alone can account for.

The polymerisation reaction is a multistep process during which the enzyme switches between substrate binding and nucleotide incorporation conformations.

The 5′–3′ exonuclease allows the polymerase to degrade RNA primers and to assist with DNA repair.

Thermostable family I DNA polymerases are used extensively in polymerase chain reaction to amplify DNA and for DNA sequencing.