bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemoprevention of Aerodigestive Tract Cancers
Authors: Kim Edward S. , Hong Waun Ki , Khuri Fadlo Raja
Published: July 2002

▪ Abstract  Epithelial cancers are a major worldwide health problem. Since the mid-1970s, advances in multidisciplinary cancer therapeutics have only slightly improved the mortality rate from epithelial malignancies. Chemoprevention is the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent progression to invasive cancer. Chemopreventive medicine is based on translating basic biologic research into clinical chemical interventions, thus attempting to impede carcinogenesis. Its principles build on the concepts of field cancerization (diffuse epithelial injury that results from carcinogen exposure) and multistep carcinogenesis (a stepwise accumulation of cellular and genetic alterations that progress to cancer). Chemoprevention targets the carcinogenic process at earlier and potentially more reversible stages, focusing on the inhibition of one or many steps in the progression towards cancer. Strategies of chemoprevention include primary prevention in groups at high risk, reversal of premalignant lesions, and prevention of second primary tumors.
The Mechanisms of Action of PPARs
Authors: Berger Joel , Moller David E.
Published: July 2002

▪ Abstract  The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.
REGULATION OF PECTINOLYSIS IN ERWINIA CHRYSANTHEMI
Authors: Hugouvieux-Cotte-Pattat Nicole , Condemine Guy , Nasser William , Reverchon Sylvie
Published: July 2002

Erwinia chrysanthemi is an enterobacterium that causes various plant diseases. Its pathogenicity results from the secretion of pectinolytic enzymes responsible for the disorganization of the plant cell wall. The E. chrysanthemi strain 3937 produces two pectin methylesterases, at least seven pectate lyases, a polygalacturonase, and a pectin lyase. The extracellular degradation of the pectin leads to the formation of oligogalacturonides that are catabolized through an intracellular pathway. The pectinase genes are expressed from independent cistrons, and their transcription is favored by environmental conditions such as presence of pectin and plant extracts, stationary growth phase, low temperature, oxygen or iron limitation, and so on. Moreover, transcription of the pectin lyase gene responds to DNA-damaging agents. The differential expressions of individual pectinase genes presumably reflect their role during plant infection. The regulation of pel genes requires several regulatory systems, including the KdgR repressor, which mediates the induction of all the pectinolysis genes in the presence of pectin catabolites. KdgR also controls the genes necessary for pectinase secretion and other pectin-inducible genes not yet characterized. PecS, a cytoplasmic protein homologous to other transcriptional regulators, can bind in vitro to the regulatory regions of pectinase and cellulase genes. The PecT protein, a member of the LysR family of transcriptional regulators, represses the expression of some pectinase genes and also affects other metabolic pathways of the bacteria. Other proteins involved in global regulations, such as CRP or HNS, can bind to the regulatory regions of the pectinase genes and affect their transcription.
RNA VIRUS MUTATIONS AND FITNESS FOR SURVIVAL
Authors: Domingo E. , Holland J. J.
Published: July 2002

▪ Abstract  RNA viruses exploit all known mechanisms of genetic variation to ensure their survival. Distinctive features of RNA virus replication include high mutation rates, high yields, and short replication times. As a consequence, RNA viruses replicate as complex and dynamic mutant swarms, called viral quasispecies. Mutation rates at defined genomic sites are affected by the nucleotide sequence context on the template molecule as well as by environmental factors. In vitro hypermutation reactions offer a means to explore the functional sequence space of nucleic acids and proteins. The evolution of a viral quasispecies is extremely dependent on the population size of the virus that is involved in the infections. Repeated bottleneck events lead to average fitness losses, with viruses that harbor unusual, deleterious mutations. In contrast, large population passages result in rapid fitness gains, much larger than those so far scored for cellular organisms. Fitness gains in one environment often lead to fitness losses in an alternative environment. An important challenge in RNA virus evolution research is the assignment of phenotypic traits to specific mutations. Different constellations of mutations may be associated with a similar biological behavior. In addition, recent evidence suggests the existence of critical thresholds for the expression of phenotypic traits. Epidemiological as well as functional and structural studies suggest that RNA viruses can tolerate restricted types and numbers of mutations during any specific time point during their evolution. Viruses occupy only a tiny portion of their potential sequence space. Such limited tolerance to mutations may open new avenues for combating viral infections.
SOMETHING FROM ALMOST NOTHING: Carbon Dioxide Fixation in Chemoautotrophs
Authors: Shively Jessup M. , van Keulen Geertje , Meijer Wim G.
Published: July 2002

▪ Abstract  The last decade has seen significant advances in our understanding of the physiology, ecology, and molecular biology of chemoautotrophic bacteria. Many ecosystems are dependent on CO2 fixation by either free-living or symbiotic chemoautotrophs. CO2 fixation in the chemoautotroph occurs via the Calvin-Benson-Bassham cycle. The cycle is characterized by three unique enzymatic activities: ribulose bisphosphate carboxylase/oxygenase, phosphoribulokinase, and sedoheptulose bisphosphatase. Ribulose bisphosphate carboxylase/oxygenase is commonly found in the cytoplasm, but a number of bacteria package much of the enzyme into polyhedral organelles, the carboxysomes. The carboxysome genes are located adjacent to cbb genes, which are often, but not always, clustered in large operons. The availability of carbon and reduced substrates control the expression of cbb genes in concert with the LysR-type transcriptional regulator, CbbR. Additional regulatory proteins may also be involved. All of these, as well as related topics, are discussed in detail in this review.
NOSOCOMIAL OUTBREAKS/PSEUDO OUTBREAKS CAUSED BY NONTUBERCULOUS MYCOBACTERIA
Authors: Wallace Richard J. , Brown Barbara A. , Griffith David E.
Published: July 2002

▪ Abstract  Nosocomial outbreaks and pseudo-outbreaks caused by the nontuberculous mycobacteria (NTM) have been recognized for more than 20 years and continue to be a problem. Most of these outbreaks have involved the rapidly growing mycobacterial species Mycobacterium fortuitum and M. abscessus. The reservoir for these outbreaks is generally municipal and (often separate) hospital water supplies. These mycobacterial species and others are incredibly hardy, able to grow in municipal and distilled water, thrive at temperatures of 45°C or above (M. xenopi and M. avium complex), and resist the activity of organomercurials, chlorine, 2% concentrations of formaldehyde and alkaline glutaraldehyde, and other commonly used disinfectants. Disease outbreaks usually involve sternal wound infections, plastic surgery wound infections, or postinjection abscesses. Pseudo-outbreaks most commonly relate to contaminated bronchoscopes and endoscopic cleaning machines (M. abscessus) and contaminated hospital water supplies (M. xenopi). Knowledge of the reservoir of these species, their great survival capabilities within the hospital, and newer molecular techniques for strain comparison have helped control and more quickly identify current nosocomial outbreaks or pseudo-outbreaks caused by the NTM.
Bacterial Biocatalysts: Molecular Biology, Three-Dimensional Structures, and Biotechnological Applications of Lipases
Authors: Jaeger K-E. , Dijkstra B. W. , Reetz M. T.
Published: July 2002

▪ Abstract  Bacteria produce and secrete lipases, which can catalyze both the hydrolysis and the synthesis of long-chain acylglycerols. These reactions usually proceed with high regioselectivity and enantioselectivity, and, therefore, lipases have become very important stereoselective biocatalysts used in organic chemistry. High-level production of these biocatalysts requires the understanding of the mechanisms underlying gene expression, folding, and secretion. Transcription of lipase genes may be regulated by quorum sensing and two-component systems; secretion can proceed either via the Sec-dependent general secretory pathway or via ABC transporters. In addition, some lipases need folding catalysts such as the lipase-specific foldases and disulfide-bond–forming proteins to achieve a secretion-competent conformation. Three-dimensional structures of bacterial lipases were solved to understand the catalytic mechanism of lipase reactions. Structural characteristics include an α/β hydrolase fold, a catalytic triad consisting of a nucleophilic serine located in a highly conserved Gly-X-Ser-X-Gly pentapeptide, and an aspartate or glutamate residue that is hydrogen bonded to a histidine. Four substrate binding pockets were identified for triglycerides: an oxyanion hole and three pockets accommodating the fatty acids bound at positions sn-1, sn-2, and sn-3. The differences in size and the hydrophilicity/hydrophobicity of these pockets determine the enantiopreference of a lipase. The understanding of structure-function relationships will enable researchers to tailor new lipases for biotechnological applications. At the same time, directed evolution in combination with appropriate screening systems will be used extensively as a novel approach to develop lipases with high stability and enantioselectivity.
Mechanisms for Redox Control of Gene Expression
Authors: Bauer Carl E. , Elsen Sylvie , Bird Terry H.
Published: July 2002

▪ Abstract  This review discusses various mechanisms that regulatory proteins use to control gene expression in response to alterations in redox. The transcription factor SoxR contains stable [2Fe-2S] centers that promote transcription activation when oxidized. FNR contains [4Fe-4S] centers that disassemble under oxidizing conditions, which affects DNA-binding activity. FixL is a histidine sensor kinase that utilizes heme as a cofactor to bind oxygen, which affects its autophosphorylation activity. NifL is a flavoprotein that contains FAD as a redox responsive cofactor. Under oxidizing conditions, NifL binds and inactivates NifA, the transcriptional activator of the nitrogen fixation genes. OxyR is a transcription factor that responds to redox by breaking or forming disulfide bonds that affect its DNA-binding activity. The ability of the histidine sensor kinase ArcB to promote phosphorylation of the response regulator ArcA is affected by multiple factors such as anaerobic metabolites and the redox state of the membrane. The global regulator of anaerobic gene expression in α-purple proteobacteria, RegB, appears to directly monitor respiratory activity of cytochrome oxidase. The aerobic repressor of photopigment synthesis, CrtJ, seems to contain a redox responsive cysteine. Finally, oxygen-sensitive rhizobial NifA proteins presumably bind a metal cofactor that senses redox. The functional variability of these regulatory proteins demonstrates that prokaryotes apply many different mechanisms to sense and respond to alterations in redox.
Phytoplasma: Phytopathogenic Mollicutes
Authors: Lee Ing-Ming , Davis Robert E. , Gundersen-Rindal Dawn E.
Published: July 2002

▪ Abstract  During the past decade, research has yielded new knowledge about the plant and insect host ranges, geographical distribution, and phylogenetic relationships of phytoplasmas, and a taxonomic system has emerged in which distinct phytoplasmas are named as separate “Candidatus phytoplasma species.” In large part, this progress has resulted from the development and use of molecular methods to detect, identify, and classify phytoplasmas. While these advances continue, research has recently begun on the phytoplasma genome, how phytoplasmas cause disease, the role of mixed phytoplasmal infections in plant diseases, and molecular/genetic phenomena that underlie symptom development in plants. These and other recent advances are laying the foundation for future progress in understanding the mechanisms of phytoplasma pathogenicity, organization of the phytoplasma genome, evolution of new phytoplasma strains and emergence of new diseases, bases of insect transmissibility and specificity of transmission, and plant gene expression in response to phytoplasmal infection, as well as the design of novel approaches to achieve effective control of phytoplasmal diseases.
Bacterial Virulence Gene Regulation: An Evolutionary Perspective
Authors: Cotter Peggy A. , DiRita Victor J.
Published: July 2002

▪ Abstract  Coevolution between bacteria and their plant or animal hosts determines characteristics of the interaction, the bacterial virulence genes involved, and the regulatory systems controlling expression of virulence genes. The long-standing association between Salmonellae and their animal hosts has resulted in the acquisition by Salmonella subspecies of a variety of virulence genes and the evolution of complex regulatory networks. The particular repertoire of virulence genes acquired by different Salmonella enterica subspecies and the regulatory systems that control them dictate subspecies-specific infection characteristics. Although the association between Vibrio cholerae and humans appears to be more recent, to reflect a simpler pathogenic strategy, and to involve fewer virulence genes than that of Salmonellae, complex virulence-regulatory networks have nonetheless evolved. In contrast, there is no evidence for acquisition of virulence genes by horizontal gene transfer in bordetellae, and their virulence regulon is less complex in overall structure than those of salmonellae and Vibrio cholerae. In Bordetellae, subspecies-specific differences in pathogenic strategy appear to result from differential gene expression within and across Bordetella subspecies.
Horizontal Gene Transfer in Prokaryotes: Quantification and Classification
Authors: Koonin Eugene V. , Makarova Kira S. , Aravind L.
Published: July 2002

▪ Abstract  Comparative analysis of bacterial, archaeal, and eukaryotic genomes indicates that a significant fraction of the genes in the prokaryotic genomes have been subject to horizontal transfer. In some cases, the amount and source of horizontal gene transfer can be linked to an organism's lifestyle. For example, bacterial hyperthermophiles seem to have exchanged genes with archaea to a greater extent than other bacteria, whereas transfer of certain classes of eukaryotic genes is most common in parasitic and symbiotic bacteria. Horizontal transfer events can be classified into distinct categories of acquisition of new genes, acquisition of paralogs of existing genes, and xenologous gene displacement whereby a gene is displaced by a horizontally transferred ortholog from another lineage (xenolog). Each of these types of horizontal gene transfer is common among prokaryotes, but their relative contributions differ in different lineages. The fixation and long-term persistence of horizontally transferred genes suggests that they confer a selective advantage on the recipient organism. In most cases, the nature of this advantage remains unclear, but detailed examination of several cases of acquisition of eukaryotic genes by bacteria seems to reveal the evolutionary forces involved. Examples include isoleucyl-tRNA synthetases whose acquisition from eukaryotes by several bacteria is linked to antibiotic resistance, ATP/ADP translocases acquired by intracellular parasitic bacteria, Chlamydia and Rickettsia, apparently from plants, and proteases that may be implicated in chlamydial pathogenesis.
ADHESION MOLECULES AND INHERITED DISEASES OF THE HUMAN NERVOUS SYSTEM
Authors: Kamiguchi H. , Hlavin M. L. , Yamasaki M. , Lemmon V.
Published: July 2002

▪ Abstract  Mutations in the human genes for the adhesion molecules Po, L1, and merosin cause severe abnormalities in nervous system development. Po and merosin are required for normal myelination in the nervous system, and L1 is essential for development of major axon pathways such as the corticospinal tract and corpus callosum. While mutations that lead to a loss of the adhesive function of these molecules produce severe phenotypes, mutations that disrupt intracellular signals or intracellular interactions are also deleterious. Geneticists have found that more than one clinical syndrome can be caused by mutations in each of these adhesion molecules, confirming that these proteins are multifunctional. This review focuses on identifying common mechanisms by which mutations in adhesion molecules alter neural development.
STRESS AND HIPPOCAMPAL PLASTICITY
Authors: McEwen Bruce S.
Published: July 2002

▪ Abstract  The hippocampus is a target of stress hormones, and it is an especially plastic and vulnerable region of the brain. It also responds to gonadal, thyroid, and adrenal hormones, which modulate changes in synapse formation and dendritic structure and regulate dentate gyrus volume during development and in adult life. Two forms of structural plasticity are affected by stress: Repeated stress causes atrophy of dendrites in the CA3 region, and both acute and chronic stress suppresses neurogenesis of dentate gyrus granule neurons. Besides glucocorticoids, excitatory amino acids and N-methyl-d-aspartate (NMDA) receptors are involved in these two forms of plasticity as well as in neuronal death that is caused in pyramidal neurons by seizures and by ischemia. The two forms of hippocampal structural plasticity are relevant to the human hippocampus, which undergoes a selective atrophy in a number of disorders, accompanied by deficits in declarative, episodic, spatial, and contextual memory performance. It is important, from a therapeutic standpoint, to distinguish between a permanent loss of cells and a reversible atrophy.
THE CELL BIOLOGY OF THE BLOOD-BRAIN BARRIER
Authors: Rubin L. L. , Staddon J. M.
Published: July 2002

▪ Abstract  The blood-brain barrier (BBB) is formed by brain capillary endothelial cells (ECs). In the late embryonic and early postnatal period, these cells respond to inducing factors found in the brain environment by adopting a set of defined characteristics, including high-electrical-resistance tight junctions. Although the factors have not been identified definitively, a great deal of information about brain ECs has been obtained, especially recently. This review concentrates on a cell biological analysis of the BBB, with an emphasis on regulation of the specialized intercellular junctions. The development of these junctions seems to depend on two primary processes: the appearance of high levels of the tight junction protein occludin and intracellular signaling processes that control the state of phosphorylation of junctional proteins. Recent studies have revealed that the BBB can be modulated in an ongoing way to respond to environmental stimuli.
PRESYNAPTIC IONOTROPIC RECEPTORS AND THE CONTROL OF TRANSMITTER RELEASE
Authors: MacDermott Amy B. , Role Lorna W. , Siegelbaum Steven A.
Published: July 2002

▪ Abstract  The quantity of neurotransmitter released into the synaptic cleft, the reliability with which it is released, and the response of the postsynaptic cell to that transmitter all contribute to the strength of a synaptic connection. The presynaptic nerve terminal is a major regulatory site for activity-dependent changes in synaptic function. Ionotropic receptors for the inhibitory amino acid GABA, expressed on the presynaptic terminals of crustacean motor axons and vertebrate sensory neurons, were the first well-defined mechanism for the heterosynaptic transmitter-mediated regulation of transmitter release. Recently, presynaptic ionotropic receptors for a large range of transmitters have been found to be widespread throughout the central and peripheral nervous systems. In this review, we first consider some general theoretical issues regarding whether and how presynaptic ionotropic receptors are important regulators of presynaptic function. We consider the criteria that should be met to identify a presynaptic ionotropic receptor and its regulatory function and review several examples of presynaptic receptors that meet at least some of those criteria. We summarize the classic studies of presynaptic inhibition mediated by GABA-gated Cl channels and then focus on presynaptic nicotinic ACh receptors and presynaptic glutamate receptors. Finally, we briefly discuss evidence for other types of presynaptic ionotropic receptors.
Mechanisms of Visual Attention in the Human Cortex
Authors: Ungerleider Sabine Kastner and Leslie G.
Published: July 2002

A typical scene contains many different objects that, because of the limited processing capacity of the visual system, compete for neural representation. The competition among multiple objects in visual cortex can be biased by both bottom-up sensory-driven mechanisms and top-down influences, such as selective attention. Functional brain imaging studies reveal that, both in the absence and in the presence of visual stimulation, biasing signals due to selective attention can modulate neural activity in visual cortex in several ways. Although the competition among stimuli for representation is ultimately resolved within visual cortex, the source of top-down biasing signals derives from a network of areas in frontal and parietal cortex.
The Central Autonomic Nervous System: Conscious Visceral Perception and Autonomic Pattern Generation
Authors: Saper Clifford B.
Published: July 2002

▪ Abstract  The overall organization of the peripheral autonomic nervous system has been known for many decades, but the mechanisms by which it is controlled by the central nervous system are just now coming to light. In particular, two major issues have seen considerable progress in the past decade. First, the pathways that provide visceral sensation to conscious perception at a cortical level have been elucidated in both animals and humans. The nociceptive system runs in parallel to the pathways carrying visceral sensation from the cranial nerves and may be considered in itself a component of visceral sensation. Second, structures in the central nervous system that generate patterns of autonomic response have been identified. These pattern generators are located at multiple levels of the central nervous system, and they can be combined in temporal and spatial patterns to subserve a wide range of behavioral needs.
Beyond Phrenology: What Can Neuroimaging Tell Us About Distributed Circuitry?
Authors: Friston Karl
Published: July 2002

▪ Abstract  Unsupervised models of how the brain identifies and categorizes the causes of its sensory input can be divided into two classes: those that minimize the mutual information (i.e., redundancy) among evoked responses and those that minimize the prediction error. Although these models have the same goal, the way that goal is attained, and the functional architectures required, are fundamentally different. This review describes the differences, in the functional anatomy of sensory cortical hierarchies, implied by the two models. We then consider how neuroimaging can be used to disambiguate between them. The key distinction reduces to whether backward connections are employed by the brain to generate a prediction of sensory inputs. To ascertain whether backward influences are evident empirically requires a characterization of functional integration among brain systems. This review summarizes the approaches to measuring functional integration in terms of effective connectivity and proceeds to address the question posed by the theoretical considerations. In short, it will be shown that the conjoint manipulation of bottom-up and top-down inputs to an area can be used to test for interactions between them, in elaborating cortical responses. The conclusion, from these sorts of neuroimaging studies, points to the prevalence of top-down influences and the plausibility of generative models of sensory brain function.
RECEPTOR-MEDIATED ENDOCYTOSIS OF COBALAMIN (VITAMIN B12)
Authors: Seetharam Bellur
Published: July 2002

▪ Abstract  Dietary cobalamin (Cbl) (vitamin B12) is utilized as methyl-Cbl and the coenzyme 5′-deoxyadenosyl Cbl by cells of the body that have the enzymes methionine synthase and methyl malonyl CoA mutase, which convert homocysteine to methionine and methyl malonyl CoA to succinyl CoA, respectively. Prior to conversions and utilizations as the active alkyl forms of Cbl, dietary Cbl is absorbed and transported across cellular plasma membranes by two receptor-mediated events. First, dietary and biliary Cbl bound to gastric intrinsic factor (IF) presented apically to the ileal absorptive enterocytes is transported to the circulation by receptor-mediated endocytosis via apically expressed IF–Cbl receptor. Second, Cbl bound to plasma transcobalamin (TC) II is taken up from the circulation by all cells via a TC II receptor expressed in the plasma membrane of these cells, and in polarized cells via a TC II receptor expressed in the basolateral membranes. This review updates recent work and focuses on (a) the molecular and cellular aspects of Cbl binding protein ligands, IF and TC II, and their cell-surface receptors, IF–Cbl receptor and TC II receptor; (b) the cellular sorting pathways of internalized Cbl bound to IF and TC II in polarized epithelial cells; and (c) the absorption and transport disorders that cause Cbl deficiency.
Apolipoprotein B: mRNA Editing, Lipoprotein Assembly, and Presecretory Degradation
Authors: Davidson Nicholas O. , Shelness Gregory S.
Published: July 2002

Apolipoprotein (apo)B circulates in two distinct forms, apoB100 and apoB48. Human liver secretes apoB100, the product of a large mRNA encoding 4536 residues. The small intestine of all mammals secretes apoB48, which arises following C-to-U deamination of a single cytidine base in the nuclear apoB transcript, introducing a translational stop codon. This process, referred to as apoB RNA editing, operates through a multicomponent enzyme complex that contains a single catalytic subunit, apobec-1, in addition to other protein factors that have yet to be cloned. ApoB RNA editing also exhibits stringent cis-acting requirements that include both structural and sequence-specific elements—specifically efficiency elements that flank the minimal cassette, an AU-rich RNA context, and an 11-nucleotide mooring sequence—located in proximity to a suitably positioned (usually upstream) cytidine. C-to-U RNA editing may become unconstrained under circumstances where apobec-1 is overexpressed, in which case multiple cytidines in apoB RNA, as well as in other transcripts, undergo C-to-U editing. ApoB RNA editing is eliminated following targeting of apobec-1, establishing that there is no genetic redundancy in this function. Under physiological circumstances, apoB RNA editing exhibits developmental, hormonal, and nutritional regulation, in some cases related to transcriptional regulation of apobec-1 mRNA. ApoB and the microsomal triglyceride transfer protein (MTP) are essential for the assembly and secretion of apoB-containing lipoproteins. MTP functions by transferring lipid to apoB during its translation and by transporting triglycerides into the endoplasmic reticulum to form apoB-free lipid droplets. These droplets fuse with nascent apoB-containing particles to form mature, very low-density lipoproteins or chylomicrons. In cultured hepatic cells, lipid availability dictates the rate of apoB production. Unlipidated or underlipidated forms of apoB are subjected to presecretory degradation, a process mediated by retrograde transport from the lumen of the endoplasmic reticulum to the cytosol, coupled with multiubquitination and proteasomal degradation. Although control of lipid secretion in vivo is primarily achieved at the level of lipoprotein particle size, regulation of apoB production by presecretory degradation may be relevant in some dyslipidemic states.
THE HEME OXYGENASE SYSTEM:A Regulator of Second Messenger Gases
Authors: Maines Mahin D.
Published: July 2002

▪ Abstract  The heme oxygenase (HO) system consists of two forms identified to date: the oxidative stress–inducible protein HO-1 (HSP32) and the constitutive isozyme HO-2. These proteins, which are different gene products, have little in common in primary structure, regulation, or tissue distribution. Both, however, catalyze oxidation of heme to biologically active molecules: iron, a gene regulator; biliverdin, an antioxidant; and carbon monoxide, a heme ligand. Finding the impressive heme-degrading activity of brain led to the suggestion that “HO in brain has functions aside from heme degradation” and to subsequent exploration of carbon monoxide as a promising and potentially significant messenger molecule. There is much parallelism between the biological actions and functions of the CO- and NO-generating systems; and their regulation is intimately linked. This review highlights the current information on molecular and biochemical properties of HO-1 and HO-2 and addresses the possible mechanisms for mutual regulatory interactions between the CO- and NO-generating systems.
QUANTITATIVE PREDICTION OF IN VIVO DRUG CLEARANCE AND DRUG INTERACTIONS FROM IN VITRO DATA ON METABOLISM, TOGETHER WITH BINDING AND TRANSPORT
Authors: Ito K. , Iwatsubo T. , Kanamitsu S. , Nakajima Y. , Sugiyama Y.
Published: July 2002

▪ Abstract  It is of great importance to predict in vivo pharmacokinetics in humans based on in vitro data. We summarize recent findings of the quantitative prediction of the hepatic metabolic clearance from in vitro studies using human liver microsomes, hepatocytes, or P450 isozyme recombinant systems. Furthermore, we propose a method to predict pharmacokinetic alterations caused by drug-drug interactions that is based on in vitro metabolic inhibition studies using human liver microsomes or human enzyme expression systems. Although we attempt to avoid the false negative prediction, the inhibitory effect was underestimated in some cases, indicating the possible contribution of the active transport into hepatocytes and/or interactions at the processes other than the hepatic metabolism, such as the metabolism and transport processes during gastrointestinal absorption.
REGULATION OF GENE EXPRESSION BY REACTIVE OXYGEN
Authors: Dalton Timothy P. , Shertzer Howard G. , Puga Alvaro
Published: July 2002

▪ Abstract  Reactive oxygen intermediates are produced in all aerobic organisms during respiration and exist in the cell in a balance with biochemical antioxidants. Excess reactive oxygen resulting from exposure to environmental oxidants, toxicants, and heavy metals perturbs cellular redox balance and disrupts normal biological functions. The resulting imbalance may be detrimental to the organism and contribute to the pathogenesis of disease and aging. To counteract the oxidant effects and to restore a state of redox balance, cells must reset critical homeostatic parameters. Changes associated with oxidative damage and with restoration of cellular homeostasis often lead to activation or silencing of genes encoding regulatory transcription factors, antioxidant defense enzymes, and structural proteins. In this review, we examine the sources and generation of free radicals and oxidative stress in biological systems and the mechanisms used by reactive oxygen to modulate signal transduction cascades and redirect gene expression.
Metabolism of Fluorine-Containing Drugs
Authors: Park B Kevin , Kitteringham Neil R , O'Neill Paul M
Published: July 2002

This article reviews current knowledge of the metabolism of drugs that contain fluorine. The strategic value of fluorine substitution in drug design is discussed in terms of chemical structure and basic concepts in drug metabolism and drug toxicity.
Pharmacology of the Lower Urinary Tract
Authors: de Groat William C , Yoshimura Naoki
Published: July 2002

The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the urinary bladder, urethra, and external urethral sphincter. This activity is in turn controlled by neural circuits in the brain, spinal cord, and peripheral ganglia. Various neurotransmitters, including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide, and neuropeptides, have been implicated in the neural regulation of the lower urinary tract. Injuries or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce voiding dysfunctions such as urinary frequency, urgency, and incontinence or inefficient voiding and urinary retention. This chapter will review recent advances in our understanding of the pathophysiology of voiding disorders and the targets for drug therapy.
Compartmentation of G Protein-Coupled Signaling Pathways in Cardiac Myocytes
Authors: Steinberg Susan F , Brunton Laurence L
Published: July 2002

There is a large body of functional data that supports the existence of subcellular compartmentation of the components of cyclic AMP action in the heart. Data from isolated perfused hearts and from purified ventricular myocytes imply a fixed and hormone-specific spatial relationship amongst components of cyclic AMP synthesis, response, and degradation. Available data demonstrate that within a cardiac myocyte, not all cyclic AMP gains access to all cyclic AMP-dependent protein kinase (PKA), that not all PKA interacts with all possible cellular substrates of PKA, and that only a subset of the myocyte's phosphodiesterases (PDEs) may degrade cyclic AMP after a given synthetic stimulus. Molecular mechanisms contributing to compartmentation are being discovered: localization of receptors, G proteins, and adenylyl cyclases in caveolar versus noncaveolar regions of the sarcolemma; localization of PKA by A-kinase anchoring proteins; localization of PKA substrates, PDE isoforms, and phosphoprotein phosphatases in discrete subcellular regions; and differential regulation of multiple isoforms of adenylyl cyclase, phosphoprotein phosphatase, and PDE in distinct subcellular compartments.
Glycopeptide Antibiotic Resistance
Authors: Pootoolal Jeff , Neu John , Wright Gerard D.
Published: July 2002

Glycopeptide antibiotics are integral components of the current antibiotic arsenal that is under strong pressures as a result of the emergence of a variety of resistance mechanisms over the past 15 years. Resistance has manifested itself largely through the expression of genes that encode proteins that reprogram cell wall biosynthesis and thus evade the action of the antibiotic in the enterococci, though recently new mechanisms have appeared that afford resistance and tolerance in the more virulent staphylococci and streptococci. Overcoming glycopeptide resistance will require innovative approaches to generate new antibiotics or otherwise to inhibit the action of resistance elements in various bacteria. The chemical complexity of the glycopeptides, the challenges of discovering and successfully exploiting new targets, and the growing number of distinct resistance types all increase the difficulty of the current problem we face as a result of the emergence of glycopeptide resistance.
TIME-RESOLVED DYNAMICS OF PROTON TRANSFER IN PROTEINOUS SYSTEMS
Authors: Gutman M. , Nachliel E.
Published: July 2002

▪ Abstract  The dynamics of proton dissociation from an acidic moiety and its subsequent dispersion in the bulk is regulated by the physical chemical properties of the solvent. The solvent has to provide a potential well to accommodate the discharged proton, screen it from the negative charge of the conjugated base, and provide an efficient mode for the diffusion of the proton to the bulk. On measuring the dynamics of proton dissociation in the time-resolved domain, the kinetic analysis of the reaction can quantitate the properties of the immediate environment.

In this review we implement the kinetic analysis for evaluating the properties of small cavities in proteins and the diffusion of protons within narrow channels. On the basis of this analysis,we discuss how the clustering of proton-binding sites on a surface can endow the surface with enhanced capacity to attract protons and to funnel them toward a specific site.
“STRONG” HYDROGEN BONDS IN CHEMISTRY AND BIOLOGY
Authors: Perrin Charles L. , Nielson Jennifer B.
Published: July 2002

▪ Abstract  Hydrogen bonds are a key feature of chemical structure and reactivity. Recently there has been much interest in a special class of hydrogen bonds called “strong” or “low-barrier” and characterized by great strength, short distances, a low or vanishing barrier to hydrogen transfer, and distinctive features in the NMR spectrum. Although the energy of an ordinary hydrogen bond is ca 5 kcal mol−1, the strength of these hydrogen bonds may be ≥10 kcal mol−1. The properties of these hydrogen bonds have been investigated by many experimental techniques, as well as by calculation and by correlations among those properties. Although it has been proposed that strong, short, low-barrier hydrogen bonds are important in enzymatic reactions, it is concluded that the evidence for them in small molecules and in biomolecules is inconclusive.
INTERFACES AND THIN FILMS AS SEEN BY BOUND ELECTROMAGNETIC WAVES
Authors: Knoll Wolfgang
Published: July 2002

▪ Abstract  This contribution summarizes the use of plasmon surface polaritons and guided optical waves for the characterization of interfaces and thin organic films. After a short introduction to the theoretical background of evanescent wave optics, examples are given that show how this interfacial “light” can be employed to monitor thin coatings at a solid/air or solid/liquid interface. Examples are given for a very sensitive thickness determination of samples ranging from self-assembled monolayers, to multilayer assemblies prepared by the Langmuir/Blodgett/Kuhn technique or by the alternate polyelectrolyte deposition. These are complemented by the demonstration of the potential of the technique to also monitor time-dependent processes in a kinetic mode. Here, we put an emphasis on the combination set-up of surface plasmon optics with electrochemical techniques, allowing for the on-line characterization of various surface functionalization strategies, e.g. for (bio-) sensor purposes.
THE CHLORIDE CELL:Structure and Function in the Gills of Freshwater Fishes
Authors: Perry Steve F.
Published: July 2002

▪ Abstract  This review focuses on the structure and function of the branchial chloride cell in freshwater fishes. The mitochondria-rich chloride cell is believed to be the principal site of trans-epithelial Ca2+and Cl−influxes. Though currently debated, there is accruing evidence that the pavement cell is the site of Na+uptake via channels linked electrically to an apical membrane vacuolar H+-ATPase (proton pump).

Chloride cells perform an integral role in acid-base regulation. During conditions of alkalosis, the surface area of exposed chloride cells is increased, which serves to enhance base equivalent excretion as the rate of Cl−/HCO3−exchange is increased. Conversely, during acidosis, the chloride cell surface area is diminished by an expansion of the adjacent pavement cells. This response reduces the number of functional Cl−/HCO3−exchangers.

Under certain conditions that challenge ion regulation, chloride cells proliferate on the lamellae. This response, while optimizing the Ca2+and Cl−transport capacity of the gill, causes a thickening of the blood-to-water diffusion barrier and thus impedes respiratory gas transfer.
ROLE OF TIGHT JUNCTIONS IN ESTABLISHING AND MAINTAINING CELL POLARITY
Authors: Cereijido Marcelino , Valdés Jesús , Shoshani Liora , Contreras Rubén G.
Published: July 2002

▪ Abstract  The tight junction (TJ) is not randomly located on the cell membrane, but occupies a precise position at the outermost edge of the intercellular space and, therefore, is itself considered a polarized structure. This article reviews the most common experimental approaches for studying this relationship. We then discuss three main topics. (a) The mechanisms of polarization that operate regardless of the presence of TJs: We explore a variety of polarization mechanisms that operate at stages of the cell cycle in which TJs may be already established. (b) TJs and polarity as partners in highly dynamic processes: Polarity and TJs are steady state situations that may be drastically changed by a variety of signaling events. (c) Polarized distribution of membrane molecules that depend on TJs: This refers to molecules (mainly lipids) whose polarized distribution, although not the direct result of TJs, depends on these structures to maintain such distribution.
CODEPENDENCE OF RENAL CALCIUM AND SODIUM TRANSPORT
Authors: Friedman Peter A.
Published: July 2002

▪ Abstract  Calcium and sodium absorption by the kidney normally proceed in parallel. However, a number of physiological, pharmacological, pathological, and genetic conditions dissociate this relation. In each instance, the dissociation can be traced to the distal convoluted tubule, where calcium and sodium transport are inversely related. Based on the identification of the relevant sodium transporters in these cells and on analysis of the mechanism of calcium transport, an explanation for this inverse relation can be developed. Apical membrane calcium entry is mediated by voltage-sensitive calcium channels that are activated upon membrane hyperpolarization. Basolateral calcium efflux is effected primarily by Na+/Ca2+ exchange. According to the model, inhibition of sodium entry through either the Na-Cl cotransporter or the Na+ channel hyperpolarizes the cell, as does parathyroid hormone, thereby activating the calcium entry channel and increasing the driving force for diffusional entry. Membrane hyperpolarization also increases the driving force of calcium efflux through the Na+/Ca2+ exchanger. Thus sodium-dependent changes of calcium transport are indirect and occur secondarily through effects on membrane voltage.
THE PHYSIOLOGICAL BASIS OF DIVING TO DEPTH: Birds and Mammals
Authors: Kooyman G. L. , Ponganis P. J.
Published: July 2002

▪ Abstract  There is wide diversity in the animals that dive to depth and in the distribution of their body oxygen stores. A hallmark of animals diving to depth is a substantial elevation of muscle myoglobin concentration. In deep divers, more than 80% of the oxygen store is in the blood and muscles. How these oxygen stores are managed, particularly within muscle, is unclear. The aerobic endurance of four species has now been measured. These measurements provide a standard for other species in which the limits cannot be measured. Diving to depth requires several adaptations to the effects of pressure. In mammals, one adaptation is lung collapse at shallow depths, which limits absorption of nitrogen. Blood N2levels remain below the threshold for decompression sickness. No such adaptive model is known for birds. There appear to be two diving strategies used by animals that dive to depth. Seals, for example, seldom rely on anaerobic metabolism. Birds, on the other hand, frequently rely on anaerobic metabolism to exploit prey-rich depths otherwise unavailable to them.
AQUAPORIN-2 AND -3: Representatives of Two Subgroups of the Aquaporin Family Colocalized in the Kidney Collecting Duct
Authors: Sasaki S. , Ishibashi K. , Marumo F.
Published: July 2002

▪ Abstract  Since the molecular identification of the first aquaporin in 1992, the number of proteins known to belong to this family has been rapidly increasing. These members may be separated into two subgroups based on gene structure, sequence homology, and function. Regulation of the water permeability of the collecting ducts of the kidney is essential for urinary concentration. Aquaporin-2 and -3, which are representative of these subgroups, are colocalized in the collecting ducts. Understanding these subgroups will elucidate the differences between aquaporin-2 and -3. Aquaporin-2 is a vasopressin-regulated water channel located in the apical membrane, and aquaporin-3 is a constitutive water channel located in the basolateral membrane. In contrast to aquaporin-3, which appears to be less well regulated, many studies have now identified multiple regulational mechanisms at the gene, protein, and cell levels for aquaporin-2, thus reflecting its physiological importance. Evidence of the participation of aquaporin-2 in the pathophysiology of water-balance disorders is accumulating.
MECHANISMS OF CARDIAC PAIN
Authors: Foreman R. D.
Published: July 2002

▪ Abstract  Angina pectoris often results from ischemic episodes that excite chemosensitive and mechanoreceptive receptors in the heart. Ischemic episodes release a collage of chemicals, including adenosine and bradykinin, that excites the receptors of the sympathetic and vagal afferent pathways. Sympathetic afferent fibers from the heart enter the upper thoracic spinal cord and synapse on cells of origin of ascending pathways. This review focuses on the spinothalamic tract, but other pathways are excited as well. Excitation of spinothalamic tract cells in the upper thoracic and lower cervical segments, except C7 and C8 segments, contributes to the anginal pain experienced in the chest and arm. Cardiac vagal afferent fibers synapse in the nucleus tractus solitarius of the medulla and then descend to excite upper cervical spinothalamic tract cells. This innervation contributes to the anginal pain experienced in the neck and jaw. The spinothalamic tract projects to the medial and lateral thalamus and, based on positron emission tomography studies, activates several cortical areas, including the anterior cingulate gyrus (BA 24 and 25), the lateral basal frontal cortex, and the mesiofrontal cortex.
G Proteins and Phototransduction
Authors: Arshavsky Vadim Y. , Lamb Trevor D. , Pugh Edward N.
Published: July 2002

▪ Abstract  Phototransduction is the process by which a photon of light captured by a molecule of visual pigment generates an electrical response in a photoreceptor cell. Vertebrate rod phototransduction is one of the best-studied G protein signaling pathways. In this pathway the photoreceptor-specific G protein, transducin, mediates between the visual pigment, rhodopsin, and the effector enzyme, cGMP phosphodiesterase. This review focuses on two quantitative features of G protein signaling in phototransduction: signal amplification and response timing. We examine how the interplay between the mechanisms that contribute to amplification and those that govern termination of G protein activity determine the speed and the sensitivity of the cellular response to light.