bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydrogenases: Theoretical Investigations Towards Bioinspired
H
2
Production and Activation
Authors: Bruschi Maurizio , Zampella Giuseppe , Greco Claudio , Bertini Luca , Fantucci Piercarlo , De Gioia Luca 
Published: September 2009

Abstract

Hydrogenases catalyze the reduction of protons, and have great biotechnological relevance in light of the key role played by H
2
in several industrial processes. Moreover, the industrial and social relevance of H
2
stems also from the observation that dihydrogen could be an efficient and cost‐attractive energy carrier for the future.

Hydrogenases invariably contain a transition metal ion (Fe and in some case Ni) in their active site, and therefore have attracted the attention of experimental and theoretical bioinorganic chemists, which have given fundamental contributions to the elucidation of structure‐activity relationships in this class of enzymes. In addition, the recent elucidation of the X‐ray structure of [NiFe]‐ and [FeFe]‐hydrogenases has prompted synthetic chemists to design and characterize bioinspired coordination compounds, with the aim of obtaining efficient catalysts for H
2
production/activation.

Here, we briefly review the contributions given by quantum chemistry to the characterization of key forms of the enzymes, the elucidation of reaction pathways and catalytic mechanisms, as well as the complementation of experimental data in the investigation of synthetic models. Emphasis is mainly given to underline the kind of insights that can be obtained using quantum chemical methods when investigating coordination compounds related to the hydrogenases active site, and to highlight some strengths and limitations of density functional theory, which currently is the most frequently used quantum chemical method to investigate metalloenzymes.
Computational Methods: Modeling of Reactivity in Zn‐Containing Enzymes
Authors: Mujika Jon I. , Mulholland Adrian J. , Harvey Jeremy N. 
Published: September 2009

AbstractComputation is increasingly well placed to offer insight into a range of structural and spectroscopic properties of Zn‐containing enzymes, as well as into their reactivity. The latter aspect is the focus of this article. Molecular dynamics simulations provide insight into substrate binding and active‐site relaxation around the metal and substrate. A significant challenge in such studies is the representation of the zinc center. Quantum mechanical methods, either on their own using small active‐site models, or for whole enzymes using hybrid techniques, provide insight into reaction paths and hence into transition states and intermediates. Examples of these applications are reviewed for carbonic anhydrase, carboxypeptidase A, thermolysin, type B β‐lactamase, and farnesyltransferase.
Combined Density Functional Theory (
DFT
) and Electrostatics Study of the Proton Pumping Mechanism in Cytochrome

C

Oxidase
Authors: Quenneville Jason , Popović Dragan M. , Stuchebrukhov Alexei A. 
Published: September 2009

Abstract

Cytochrome
c
oxidase is a redox‐driven proton pump which converts atmospheric oxygen to water and couples the oxygen reduction reaction to the creation of a membrane proton gradient. The structure of the enzyme has been solved; however, the mechanism of proton pumping is still poorly understood. Recent calculations from this group indicate that one of the histidine ligands of the enzyme's Cu
B
center, His291, may play the role of the pumping element. Here, we discuss results of calculations that combined first principles density functional theory (DFT) and continuum electrostatics to evaluate the energetics of the key energy generating step—the transfer of the chemical proton to the binuclear center of the enzyme, where the hydroxyl group is converted to water, and the concerted expulsion of the proton from d‐nitrogen of the His291 ligand of the Cu
B
center.
Nature of the Catecholate—
Fe
(
III
) Bond: High Affinity Binding and Substrate Activation in Bioinorganic Chemistry
Authors: Solomon Edward I. , Pau Monita Y. M. , Hocking Rosalie K. 
Published: September 2009

Abstract

Catecholate‐Fe(III) (high‐spin) bonds are important in many areas of bioinorganic chemistry. These exhibit low‐energy, intense ligand‐to‐metal charge transfer (LMCT) transitions reflecting highly covalent bonds. This high covalency can make a major contribution to function. In this review, we develop the method of metal L‐edge X‐ray absorption spectroscopy (XAS) as a probe of differential orbital covalency (DOC), the amount of ligand character in the different d orbitals of a metal site in a highly covalent environment. We then apply this method to experimentally determine the covalency of the ligand‐metal bonds related to the siderophores and computationally evaluate this contribution to their high stability constants. We then use variable‐temperature, variable‐field, magnetic circular dichroism (VTVH MCD) spectroscopy to assign the LMCT transitions of the catecholate‐, substrate‐bound Fe
III
site of the intradiol dioxygenases. A reaction coordinate is presented where this charge transfer can overcome the spin‐forbidden nature of the reaction of the bound catecholate (singlet) with dioxygen (triplet).
Calcium and Neurotransmitter Release
Authors: Delaney Kerry R , Stanley Elise E 
Published: September 2009

Abstract

Information is coded in the brain as patterns of electrical impulses that are transmitted along nerve processes. These impulses are passed from one neuron to the next primarily at chemical synapses where the electrical event is converted to the release of a neurotransmitter substance that activates the next neuron in the pathway. Neurotransmitter release is triggered by the opening of ‘voltage‐sensitive’ calcium channels, the admission of a small pulse of Ca
2+
ions and the binding of these ions to the neurotransmitter secretion apparatus culminating in the fusion and discharge of a transmitter‐filled secretory vesicle. Increasing evidence suggests that most synapses an individual release site is gated by ion influx through one or more nearby calcium channels. In this section, we explore the physiology of this impulse‐to‐secretion gating mechanism.

Key Concepts

Information is transmitted between one neuron and the next at
synapses
where the nerve fibre terminal of the upstream (presynaptic) neuron contacts the surface membrane of the downstream (postsynaptic) one.

Most synapses transmit by secreting a chemical neurotransmitter across the narrow space between pre‐ and postsynaptic surface membranes.

Transmitter secretion is triggered by an electrical impulse that travels down the presynaptic nerve fibre to the terminal.

Neurotransmitter is stored in tiny membrane ‘packets’ called synaptic vesicles which can be triggered to secrete by fusing with the presynaptic membrane at the ‘transmitter release site’.

The synaptic vesicles are ‘docked’ at the release site ready for secretion.

Influx of calcium ions through selective voltage‐sensitive ion channels (calcium channels) plays a key role to link the action potential to the triggering of secretory vesicle discharge.

Calcium channels are positioned very close to the secretory vesicles so that when they open the spurt of entering calcium ions, called a ‘calcium domain’, can rapidly and effectively access the triggering sites for synaptic vesicle fusion.
Multiple Sclerosis
Authors: Preiningerova Jana , Bomprezzi Roberto , Vollmer Timothy L , Waxman Stephen G 
Published: September 2009

Abstract

Multiple sclerosis (MS) is the leading cause of neurological disability in young women in the USA and Europe and the second leading cause of such disability in young men. Major advances have been made in the past two decades in understanding the pathogenesis and immunobiology of MS resulting in major advances in the treatment of the disease over the past 15 years. These advances are the consequence of advanced neuroimaging, molecular biology and immunological techniques. However, the disease remains generally incurable. Further advances will depend on developing more selective immunotherapeutic strategies, particularly involving B cells and regulatory T cells as well as developing therapeutic strategies to prevent neurodegeneration and to induce repair in the central nervous system (CNS) of patients with MS.

Key Concepts:

MS is the leading cause of neurological disability in young women in North America and Europe.

Although there is good evidence that MS results from both genetic and environmental factors, the exact nature of those factors remains uncertain.

Although often classified as a disease of myelin, recent research clearly demonstrates the immune attack on the CNS destroys neurons, axons and oligodendroglia; therefore MS is more properly considered an inflammatory disease of the CNS.

Although classically considered an autoimmune disease driven by autoaggressive T cells, clinical data suggests B lymphocytes also play a key role in the pathogenesis of MS.

Mechanisms of immune attack on the CNS may vary from patient to patient but in general include both cellular and humoral mechanisms.

Brain magnetic resonance imaging (MRI) has fundamentally changed our understanding of disease activity in MS patients. It is now known that much of the damage to the CNS is not apparent clinically in the early phase of the disease, but contributes to the long‐term disability of the disease.

Recently, major advances have been made in developing therapies that can slow the progression of MS. However, no cure has yet been found.

Neurodegeneration appears to be a consequence of the immune attack on the CNS and may result in continued progression of disability even if the immune attack on the CNS is inhibited.

Recently it has become clear that the brain in MS patients is constantly attempting to repair the damage done by the immune attack both through remyelination and cortical remodelling. In fact, these processes appear to explain the clinical appearance of stability in MS patients at a time when the MRI demonstrates ongoing inflammation and damage.

Advances in our understanding of the pathogenesis and treatment of MS has significant implications for other inflammatory diseases of the nervous system.
Proteoglycans
Authors: Schwartz Nancy B 
Published: September 2009

Abstract

Proteoglycans are complex extracellular macromolecules consisting of a multidomain core protein to which are attached one or more glycosaminoglycan (GAG) chains. They are structurally very diverse, due to variations in length and sequence of the core proteins as well as abundance, distribution and composition of the GAG chains. Core proteins are often arranged in modules which have structural and functional significance, and the same module may be found in more than one core protein type. A single core protein type may have different GAG substituents and differing roles in different tissues. Proteoglycans have diverse, but often vital functions in a variety of tissue context. Genetic studies of proteoglycan core proteins and their modifying enzymes have elucidated numerous heritable diseases and syndromes. Much of our understanding of the structure, function, evolution, gene regulation and mutations causing heritable disorders of proteoglycans, in general, derives from the model proteoglycan, aggrecan.

Key Concepts

Glycosaminoglycans are linked to proteoglycan core proteins via a limited number of
O
‐ or
N
‐glycosyl bonds.

Synthesis of GAG chains proceeds by the sequential action of glycosyltransferases that catalyse transfer of a glycosyl unit from a nucleotide sugar to a protein or nonreducing end of a sugar acceptor.

Proteoglycans are abundant components of the extracellular matrix and associated with the cell surface.

Although there are only six major classes of proteoglycan types, there is great diversity in structure, size and composition.

Important functions have been attributed to both the protein backbone and glycosaminoglycan substituents.

Proteoglycans modulate numerous molecular interactions, for example, cell–cell signalling.

Heritable proteoglycan disorders cause a wide range of phenotypes with examples from all clinical specialities.
Enzyme Kinetics: Steady State
Authors: Cleland W Wallace 
Published: September 2009

Abstract

The kinetics of enzyme‐catalysed reactions can be analysed in terms of steady state models if the substrate concentrations are more than an order of magnitude higher than the enzyme level. Such analysis yields Michaelis constants, maximum velocities and useful information on reaction mechanisms. Thus when there are two or more substrates, the number of terms in the denominator of the rate equation tells the type of mechanism. A sequential mechanism has a constant term plus ones in the concentration of each substrate and one including both concentrations. A ping pong mechanism has no constant term in the denominator. An ordered sequential mechanism where the binding of the first substrate is at equilibrium lacks a denominator term in the concentration of the second substrate. Other types of steady state studies include the use of inhibitors, determination of pH profiles and the effect of isotopic substitutions on the rates.

Key Concepts:

As long as substrate concentrations are more than an order of magnitude greater than the enzyme level, the reaction will be in a steady state.

Steady state rate equations are simple ratios of a numerator that is a function of substrate concentrations and a maximum velocity divided by a denominator that represents the distribution of the enzyme among all possible forms that are present in the steady state.

Steady state kinetic studies enable one to distinguish kinetic mechanisms and can also give information on rate limiting steps and in favorable cases, chemical mechanism.
Mammalian Embryo:HoxGenes
Authors: Alexander Tara B , Krumlauf Robb 
Published: September 2009

AbstractHoxgenes are evolutionarily conserved transcription factors that play important roles in establishing the basic body plan of animals. Mammals have 39Hoxgenes clustered into four chromosomal complexes. This gene family regulates the regional character and patterning of diverse structures along the anterior–posterior (A/P) axis of the embryo. Nested patterns ofHoxgene expression generate a Hox combinatorial protein code that orchestrates the morphogenesis of structures in the nervous system, axial skeleton, limbs, intestine and many other tissues. In light of their key role in regulating morphogenesis across animal species, modulation ofHoxexpression or function over the course of evolution is believed to have been important in generating diversity.Key concepts:Axial patterning is the process that generates different regional characteristics during the development of a tissue, such as the nervous system or skeleton.Hoxgenes encode a family of transcription factors that regulate the identity of structures along the anterior–posterior axis of embryos.Colinearity is the correlation between the order ofHoxgenes along a chromosome and their expression along the axis of an embryo.The collection of Hox proteins expressed in a region provides a combinatorial code for specifying diversity.Posterior prevalence is a model for explaining why some Hox proteins dominate over others when they are coexpressed.Selector genes control the identity of a tissue.Homeotic transformation is the conversion of one structure into another due to loss or gain of selector gene activity.Segmentation subdivides a developing tissue, such as the hindbrain or skeleton, into repeating units that ultimately generate different structures along an axis.Subfunctionalization is the partitioning of function and regulation between duplicated genes compared with the ancestral gene.Changes inHoxexpression or function may be important for generating differences in structures during evolution of vertebrates.Cooption refers to the redeployment or coupling of a common molecular pathway to multiple patterning processes.
Mammalian Embryo: Branching Morphogenesis
Authors: Davies Jamie A 
Published: September 2009

AbstractBranched structures are common in mammals and exist mainly to solve problems of transport. Branched architectures allow a surface area to be packed into a small volume, minimize the distance of cells from transport systems and from the entrance of a system to its end. For development and evolution, branched structures offer the advantage of being scaleable: tree‐shaped systems can grow and add branches without altering their basic nature. Branching morphogenesis takes place by four methods: fusion, clefting, sprouting and intussusception. All are controlled by paracrine factors and take place through changes in the behaviours of cytoskeleton‐adhesion systems.Key concepts:The internal anatomy of mammals involves many branched structures.Branched architectures optimize transport in compact organisms.Branched architectures can be scaleable, which has evolutionary and developmental implications.Branching can be by fusion, clefting, sprouting and intussusception.The largest branches tend to be stereotypical and under precise genetic control, but the finest ones are pseudo‐fractal and quite variable.Branching depends on ramogenic signals from surrounding cells.Branching structures have endogenous mechanisms to ensure appropriate spacing; at least some rely on repulsive autocrine cues.
Follicular Dendritic Cells (
B
Lymphocyte Stimulating)
Authors: El Shikh Mohey Eldin M , El Sayed Rania M , Tew John G , Burton Gregory F 
Published: September 2009

Abstract

Follicular dendritic cells (FDCs) are unique immune system cells that contribute to the maintenance of humoral (i.e. antibody) immune responses. These cells are located in the follicles of secondary lymphoid tissues (e.g. lymph nodes and spleen), where they trap and retain antigens in the form of highly immunogenic immune complexes (ICs). FDC‐ICs are composed of antigen plus specific antibody and/or complement proteins. These trapped antigens, combined with other soluble and membrane‐bound signals contributed by FDCs, are essential to the development and maintenance of the germinal centre reaction and IgG and IgE responses respectively. FDCs also appear to contribute to initial IgM responses. In addition to their positive effects on humoral immunity, FDCs may promote diseases including HIV/AIDS (
human immunodeficiency virus
/acquired immunodeficiency syndrome), prion diseases and follicular lymphomas. A better understanding of FDCs should permit better regulation of antibody responses and may also allow the amelioration of some disease states.

Key Concepts

Antigens are trapped and retained for months on the surfaces of follicular dendritic cells (FDCs) in secondary lymphoid tissues (e.g. spleen and lymph nodes).

FDC‐trapped antigens maintain memory IgG and IgE immune responses.

FDC‐ICs are highly immunogenic and minute quantities are sufficient to generate significant antibody responses.

FDCs provide both antigen and other signals that are central to the induction and maintenance of specific antibody responses.

FDCs can play roles in both health and disease (e.g. HIV/AIDS, prion diseases and follicular lymphomas).
Evolution of Vertebrate Limb Development
Authors: Tanaka Mikiko 
Published: September 2009

AbstractThe origin and diversification of fins and limbs have long been a focus of interest to both palaeontologists and developmental biologists. Studies conducted in recent decades have resulted in enormous progress in the understanding of the genetic and developmental bases of the evolution of paired appendages in vertebrates. These discoveries in the areas of genetics and developmental biology have shed light on the mechanisms underlying the evolution of this key morphological innovation in vertebrates. In this article, I discuss recent advances in these fields and how they can provide a mechanistic explanation for the origin and evolution of paired appendages.Key ConceptsAccording to the fossil record, single pair of fin‐like structures emerged in the bodies of certain ancestral jawless vertebrates, and two pairs of fins are unique to jawed vertebrates.There are two separate phases/waves ofHoxdgene expression in tetrapod limbs. The first wave precedes the formation of the proximal parts of the limb, whereas the second wave corresponds to the most distal part of the limb (digits).The earliest known amphibian fossils,AcanthostegaandIchthyostega, seem to have had more than five digits in their limbs. It has been proposed that regulatory changes inHoxand/orShhexpression modified the digit number during evolution.Regulatory modifications of specific gene expression appear to account for the evolution of paired appendages, such as the increasing length of bat wings, the loss of limbs in pythons, and pelvic reduction in sticklebacks.
AIDS
: Clinical Manifestations
Authors: Boesecke Christoph , Dore Gregory J , Cooper David A 
Published: September 2009

Abstract

In the course of time
human immunodeficiency virus
(HIV) notably affects the host's immune system. As a result, HIV‐infected people can experience a wide range of clinical manifestations, especially if the infection is not being treated duly with combination antiretroviral therapy (cART). At such an advanced stage of the disease, patients eventually face severe illnesses. Of these, more than 20 conditions, including opportunistic infections and malignancies, have been classified as AIDS (acquired immune deficiency syndrome)‐defining illnesses to date. Recently, clinical research has also focused on serious non‐AIDS‐related events (SNAEs). This term refers to an increasing rate of illnesses such as cardiovascular, liver and renal diseases as well as neoplasms occurring in long‐term‐treated patients on the basis of longer life expectancy. However, there are still significant differences in access to and availability of antiretroviral therapy throughout the world which leads to contrasting patterns in the spectrum of AIDS‐defining illnesses in resource‐limited settings and developed countries.

Key concepts:

AIDS‐defining illnesses mainly occur at a very advanced stage of the HIV infection.

More than 20 conditions are currently listed as AIDS‐defining illnesses.

The spectrum of AIDS‐defining illnesses varies in developed and resource‐limited settings.

Pneumocystis jiroveci

pneumonia is the most common AIDS‐related illness in industrialized countries.

Tuberculosis is the most common AIDS‐related illness in developing countries.

Antiretroviral therapy has had a significant impact on the spectrum of AIDS‐defining illnesses.

Owing to the now longer life expectancy serious non‐AIDS‐related illnesses have become more important in clinical management.