bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition effects of furfural on alcohol dehydrogenase, aldehyde dehydrogenase and pyruvate dehydrogenase
Authors: MODIG Tobias , LIDÉN Gunnar , TAHERZADEH Mohammad J.
Published: August 2015

The kinetics of furfural inhibition of the enzymes alcohol dehydrogenase (ADH; EC 1.1.1.1), aldehyde dehydrogenase (AlDH; EC 1.2.1.5) and the pyruvate dehydrogenase (PDH) complex were studied in vitro. At a concentration of less than 2mM furfural was found to decrease the activity of both PDH and AlDH by more than 90%, whereas the ADH activity decreased by less than 20% at the same concentration. Furfural inhibition of ADH and AlDH activities could be described well by a competitive inhibition model, whereas the inhibition of PDH was best described as non-competitive. The estimated Km value of AlDH for furfural was found to be about 5μM, which was lower than that for acetaldehyde (10μM). For ADH, however, the estimated Km value for furfural (1.2mM) was higher than that for acetaldehyde (0.4mM). The inhibition of the three enzymes by 5-hydroxymethylfurfural (HMF) was also measured. The inhibition caused by HMF of ADH was very similar to that caused by furfural. However, HMF did not inhibit either AlDH or PDH as severely as furfural. The inhibition effects on the three enzymes could well explain previously reported in vivo effects caused by furfural and HMF on the overall metabolism of Saccharomyces cerevisiae, suggesting a critical role of these enzymes in the observed inhibition.
A novel pathway for adrenergic stimulation of cAMP-response-element-binding protein (CREB) phosphorylation: mediation via α1-adrenoceptors and protein kinase C activation
Authors: THONBERG Håkan , FREDRIKSSON J. Magnus , NEDERGAARD Jan , CANNON Barbara
Published: August 2015

Because of the central role of adrenergic mechanisms in the expression of crucial genes during brown adipocyte differentiation, we examined the activation (phosphorylation) of CREB (cAMP-response-element-binding protein) in mouse brown adipocytes in primary culture. We found that noradrenaline (‘norepinephrine’) stimulated CREB phosphorylation rapidly (maximum effect in ≤ 5min with slow decay) and efficiently (EC50, 6nM). The increase in CREB phosphorylation coincided with increased expression of an artificial cAMP-response-element-containing reporter construct. CREB phosphorylation was partly inhibitable, both by the β-adrenergic antagonist propranolol and by the α1-adrenergic antagonist prazosin. Adenylate cyclase hyperactivation (by forskolin) could stimulate CREB phosphorylation to the same extent as noradrenaline. The α1-adrenergic agonist cirazoline also increased CREB phosphorylation. An increase in intracellular [Ca2+] had, however, no effect, but protein kinase C activation by PMA was a potent stimulator. The cirazoline-stimulated (α1-adrenergic) CREB phosphorylation was inhibited by a desensitizing pretreatment with PMA, demonstrating that the α1-stimulation was mediated via protein kinase C activation; neither Src nor extracellular-signal-regulated kinases 1 and 2 activation was involved in the signalling process. We conclude that CREB phosphorylation in brown adipocytes is mediated not only through the classical β-adrenergic/cAMP pathway but also through a novel α1-adrenergic/protein kinase C/CREB pathway, which has not been described previously in any tissue.
Karyopherin α2: a control step of glucose-sensitive gene expression in hepatic cells
Authors: GUILLEMAIN Ghislaine , MUÑOZ-ALONSO Maria J. , CASSANY Aurélia , LOIZEAU Martine , FAUSSAT Anne-Marie , BURNOL Anne-Françoise , LETURQUE Armelle
Published: August 2015

Glucose is required for an efficient expression of the glucose transporter GLUT2 and other genes. We have shown previously that the intracytoplasmic loop of GLUT2 can divert a signal, resulting in the stimulation of glucose-sensitive gene transcription. In the present study, by interaction with the GLUT2 loop, we have cloned the rat karyopherin α2, a receptor involved in nuclear import. The specificity of the binding was restricted to GLUT2, and not GLUT1 or GLUT4, and to karyopherin α2, not α1. When rendered irreversible by a cross-linking agent, this transitory interaction was detected in vivo in hepatocytes. A role for karyopherin α2 in the transcription of two glucose-sensitive genes was investigated by transfection of native and inactive green fluorescent protein—karyopherin α2 in GLUT2-expressing hepatoma cells. The amount of inactive karyopherin α2 receptor reduced, in a dose-dependent manner, the GLUT2 and liver pyruvate kinase mRNA levels by competition with endogenous active receptor. In contrast, the overexpression of karyopherin α2 did not significantly stimulate GLUT2 and liver pyruvate kinase mRNA accumulation in green fluorescent protein-sorted cells. The present study suggests that, in concert with glucose metabolism, karyopherin α2 transmits a signal to the nucleus to regulate glucose-sensitive gene expression. The transitory tethering of karyopherin α2 to GLUT2 at the plasma membrane might indicate that the receptor can load the cargo to be imported locally.
Precursor convertases in the secretory pathway, cytosol and extracellular milieu
Authors: Seidah Nabil G , Prat Annik
Published: August 2015

Precursor proteins that transit through the secretory pathway often require processing at specific sites in order to release their bioactive entities. The most prevalent limited proteolysis occurs at single or paired basic residues, and is achieved by one or more of the seven subtilisin-like proprotein convertases (PCs); Furin, PC1, PC2, PACE4 (paired basic amino acid converting enzyme 4), PC4, PC5 and PC7. Other types of cleavages occur at hydophobic residues, some of which are performed by subtilisin/kexin-like isozyme-1 (SKI-1), which is also known as site-1 protease. Together, the PCs and SKI-1 regulate the activity of a large variety of cellular proteins, including growth factors, neuropeptides, receptors, enzymes and even toxins and glycoproteins from infectious retroviruses. These processing events are exquisitely regulated by multiple zymogen-activation steps, as well as by specific subcellular localization signals. The above mentioned convertases are implicated in a number of pathologies such as cancer, neurodegenerative diseases, endocrine disorders and inflammation. Recently, it was recognized that the metalloendopeptidase N-arginine dibasic convertase (NRDc; nardilysin), which cleaves at the N-terminus side of basic residues in dibasic pairs, is localized both in the cytosol and at the cell surface or in the extracellular milieu. While NRDc binds heparin-binding epidermal growth factor (HB-EGF) at the cell surface and potentiates its physiological effect, HB-EGF potently inhibits the NRDc's activity. NRDc could represent the equivalent of the PCs in the cytosol or the extracellular space.
Shedding of membrane proteins by ADAM family proteases
Authors: Moss Marcia L , Lambert Millard H
Published: August 2015

Many membrane-bound proteins undergo proteolytic release from the membrane, a process known as 'shedding'. Some of the processing events are carried out by enzymes of the ADAM (a disintegrin and metalloproteinase) family, which are also membrane bound. One of the most well known ADAM family members is TACE (tumour necrosis factor-alpha-converting enzyme. TACE was the first ADAM family member to have a known physiological substrate, namely, precursor tumour necrosis factor-alpha. Inhibitors of TACE block the release of the soluble form of this inflammatory cytokine, and are currently being studied in drug discovery projects for the treatment of arthritis. Since the discovery of TACE, physiological substrates for other ADAMs have been determined. This review focuses on the shedding events carried out by TACE and other ADAM family proteinases.
Apoptosis and development
Authors: McCarthy Justin V
Published: August 2015

Apoptosis is an evolutionarily conserved process used by multicellular organisms to developmentally regulate cell number or to eliminate cells that are potentially detrimental to the organism. The large diversity of regulators of apoptosis in mammalian cells and their numerous interactions complicate the analysis of their individual functions, particularly in development. The remarkable conservation of apoptotic mechanisms across species has allowed the genetic pathways of apoptosis determined in lower species, such as the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, to act as models for understanding the biology of apoptosis in mammalian cells. Though many components of the apoptotic pathway are conserved between species, the use of additional model organisms has revealed several important differences and supports the use of model organisms in deciphering complex biological processes such as apoptosis.
Nuclear receptors in disease: the oestrogen receptors
Authors: Nilsson Maria , Dahlman-Wright Karin , Gustafsson Jan-Åke
Published: August 2015

For several decades, it has been known that oestrogens are essential for human health. The discovery that there are two oestrogen receptors (ERs), ERalpha and ERbeta, has facilitated our understanding of how the hormone exerts its physiological effects. The ERs belong to the family of ligand-activated nuclear receptors, which act by modulating the expression of target genes. Studies of ER-knockout (ERKO) mice have been instrumental in defining the relevance of a given receptor subtype in a certain tissue. Phenotypes displayed by ERKO mice suggest diseases in which dysfunctional ERs might be involved in aetiology and pathology. Association between single-nucleotide polymorphisms (SNPs) in ER genes and disease have been demonstrated in several cases. Selective ER modulators (SERMs), which are selective with regard to their effects in a certain cell type, already exist. Since oestrogen has effects in many tissues, the goal with a SERM is to provide beneficial effects in one target tissue while avoiding side effects in others. Refined SERMs will, in the future, provide improved therapeutic strategies for existing and novel indications.
The role of the ubiquitin–proteasome system in ER quality control
Authors: Ye Yihong
Published: August 2015

Misfolded endoplasmic reticulum (ER) proteins are eliminated by the retrotranslocation pathway in eukaryotes, which is an important physiological adaptation to ER stress. This pathway can be hijacked by certain viruses to destroy folded cellular proteins, such as MHC class I heavy chain. Recent studies have highlighted the importance of the ubiquitin–proteasome system (UPS) in this process.
The ubiquitin–proteasome system and skeletal muscle wasting
Authors: Attaix Didier , Ventadour Sophie , Codran Audrey , Béchet Daniel , Taillandier Daniel , Combaret Lydie
Published: August 2015

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.
Gene doping
Authors: Harridge Stephen D.R. , Velloso Cristiana P.
Published: August 2015

Gene doping is the misuse of gene therapy to enhance athletic performance. It has recently been recognised as a potential threat and subsequently been prohibited by the World Anti-Doping Agency. Despite concerns with safety and efficacy of gene therapy, the technology is progressing steadily. Many of the genes/proteins which are involved in determining key components of athletic performance have been identified. Naturally occurring mutations in humans as well as gene-transfer experiments in adult animals have shown that altered expression of these genes does indeed affect physical performance. For athletes, however, the gains in performance must be weighed against the health risks associated with the gene-transfer process, whereas the detection of such practices will provide new challenges for the anti-doping authorities.
The chemistry of lipid alkoxyl radicals and their role in metal-amplified lipid peroxidation
Authors: Marnett Lawrence J. , Wilcox Allan L.
Published: August 2015

Reaction of polyunsaturated fatty acid hydroperoxides with metal complexes generates lipid alkoxyl radicals and metal-oxo complexes. Lipid alkoxyl radicals are presumed to be the species responsible for metal-amplified lipid peroxidation because of the chemical analogy of simple organic alkoxyl radicals to the hydroxyl radical. However, polyunsaturated fatty acid alkoxyl radicals exhibit a rich and diverse chemistry that is dominated by intramolecular cyclization to epoxyallylic radicals. Studies described herein demonstrate that the equilibrium between cyclization and ring-opening of epoxyallylic radicals lies overwhelmingly toward cyclization. Thus lipid alkoxyl radicals have a steady-state concentration that is so low that their contribution to metal-amplified lipid peroxidation is insignificant. In fact, the species responsible for metal amplification of lipid peroxidation appears to be the epoxyperoxyl radical formed by coupling the epoxyallylic radical to molecular oxygen.
Biological and biochemical effects of air pollutants: synergistic effects of sulphite
Authors: Hippeli Susanne , Elstner Erich F.
Published: August 2015

Air pollution has become a major public and political concern since the beginning of industrialization, particularly motor exhaust over the past three decades. Epidemiological studies, together with clinical trials and experiments in exposition chambers (including biochemical model reactions), have contributed to our knowledge of potential dangers and increased our understanding of the corresponding mechanisms and dose-response effects. Comparison of the threatening reports that appear almost daily in the press with the digest of over 800 scientific publications allows the statement that the impact of ozone and nitric oxide on the health and performance of plants and animals is widely overestimated and appears to be used as a political instrument. In contrast, the combination of SO2 with soot and asbestos particles may represent an underestimated toxic potential. In this communication, we shall concentrate on basic redox mechanisms involving SO2 and important target molecules, as well as looking at the cooperative effects of sulphite and soot particles.
Nitric oxide, cytochrome c and mitochondria
Authors: Brown Guy C. , Borutaite Vilmante
Published: August 2015

Nitric oxide (NO) and its derivative, peroxynitrite (ONOO-), inhibit mitochondrial respiration, and this inhibition may contribute to both the physiological and cytotoxic actions of NO. Nanomolar concentrations of NO rapidly and reversibly inhibited cytochrome oxidase in competition with oxygen, as shown with isolated cytochrome oxidase, mitochondria, brain nerve terminals and cells. Cultured astrocytes and macrophages activated (by cytokines and endotoxin) to express the inducible form of NO synthase produced up to 1 μM NO, and inhibited their own respiration and that of co-incubated cells via reversible NO inhibition of cytochrome oxidase. NO-induced inhibition of respiration in brain nerve terminals resulted in rapid glutamate release, which might contribute to the neurotoxicity of NO. NO inhibition of cytochrome oxidase is reversible; however, incubation of cells with NO donors for 4 hours resulted in an inhibition of complex I, which was reversible by light and thiol reagents and may be due to nitrosylation of thiols in complex I. NO also caused the acute inhibition of catalase, stimulation of hydrogen peroxide production by mitochondria, and reaction with hydrogen peroxide on superoxide dismutase to produce peroxynitrite. Peroxynitrite inhibited complexes I, II and V (the ATP synthase), aconitase, creatine kinase, and increases the proton leak in isolated mitochondria. Peroxynitrite also caused opening of the permeability transition pore, resulting in the release of cytochrome c, which might then trigger apoptosis. Hypoxia/ischaemia also resulted in an acute reversible inhibition of cytochrome oxidase. Heart ischaemia caused the release of cytochrome c from mitochondria into the cytosol, and at the same time caspase-3-like-protease activity was activated in the cytoplasm. Addition of cytochrome c to non-ischaemic cytosol also caused activation of this protease activity, suggesting that caspase activation and consequent apoptosis is at least partly a result of this cytochrome c release.
Mutations of the mitochondrial genome: clinical overview and possible pathophysiology of cell damage
Authors: Rothman Steven M.
Published: August 2015

Mitochondria possess their own DNA and transcription and translation machinery for the synthesis of 13 protein subunits for the oxidative phosphorylation system, two rRNAs and 22 tRNAs. In 1988 the first human neurodegenerative diseases associated with mutations in the mitochondrial genome were described. The most recent biochemical and genetic research suggests that mitochondrial disorders are best categorized as: (i) primary mutations of the mitochondrial DNA, either sporadic or maternally inherited; (ii) nuclear mutations that result in alterations in mitochondrial DNA or intergenomic signalling defects; or (iii) Mendelian defects that affect the respiratory chain in the absence of mitochondrial DNA mutations. There is still little information about the pathophysiology of these different disorders. In order to obtain some insight into the cellular mechanisms of neurodegeneration, we examined cultured fibroblasts from patients with the MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome, which is most frequently caused by a mutation in the mitochondrial tRNA for leucine. We found that their basal level of ionized calcium was elevated and that they could not normally sequester calcium influxes induced by depolarization. In addition, they were unable to maintain normal mitochondrial membrane potentials, as determined using a voltage-sensitive fluorescent indicator. Despite these physiological perturbations, the MELAS fibroblasts had normal concentrations of ATP. If neurons in MELAS patients have similar physiological abnormalities, their functional properties and long-term viability may be compromised.
Confocal microscopy of the mitochondrial permeability transition in necrotic and apoptotic cell death
Authors: Lemasters John J. , Qian Ting , Trost Lawrence C. , Herman Brian , Cascio Wayne E. , Bradham Cynthia A. , Brenner David A. , Nieminen Anna-Liisa
Published: August 2015

Opening of a high-conductance pore in the mitochondrial inner membrane induces onset of the mitochondrial permeability transition (mPT). Cyclosporin A and trifluoperazine inhibit this pore and block necrotic cell death in oxidative stress, Ca2+ ionophore toxicity, Reye-related drug toxicity, pH-dependent ischaemia/reperfusion injury and other models of cell injury. Confocal fluorescence microscopy directly visualizes the increased mitochondrial membrane permeability of the mPT from the movement of calcein from the cytosol into the matrix space. Pyridine nucleotide oxidation, increased mitochondrial Ca2+ and mitochondrial generation of reactive oxygen species (ROS) all contribute to the onset of the mPT in situ. Confocal microscopy also shows directly that the mPT is a critical link in apoptotic signalling by tumour necrosis factor-alpha at a point downstream of caspase 8 and upstream of caspase 3. Cyclosporin A blocks this mPT, preventing release of pro-apoptotic cytochrome c from mitochondria and subsequent apoptotic cell killing. Progression to necrosis or apoptosis after the mPT depends on the availability of ATP, which blocks necrosis but promotes the apoptotic programme. Given the pathophysiological importance of the mPT, development of agents to modulate the mPT represents an important new goal for pharmaceutical drug discovery.
Apolipoprotein E gene and Alzheimer's disease: is tau the link?
Authors: Lovestone Simon , Anderton Brian , Betts Joanna , Dayanandan Rejith , Gibb Graham , Ljungberg Cecilia , Pearce Janice
Published: August 2015

The finding that APOE (the gene encoding apolipoprotein E) polymorphic variation was associated with an altered risk of developing Alzheimer's disease (AD) was a significant advance and immediately prompted a search for the mechanisms responsible for this alteration. Some 6 years later, a number of different hypotheses remain that might account for this influence on pathogenesis with no single mechanism being unequivocally accepted. The different approaches to understanding these mechanisms can be broadly categorized as: those suggesting a remote effect, such as different rates of vascular risk factors in those with the different APOE alleles; those proposing altered neuronal vulnerability, perhaps due to apolipoprotein E (ApoE)-isoform-specific differences in local cholesterol transport; and those hypotheses postulating an ApoE interaction with the two key lesions of AD, plaques and tangles. In this chapter we will review the evidence for and against an interaction between ApoE and the neuronal cytoskeleton, in particular with the microtubule-associated protein tau.
Comparative aspects of glycosyltransferases
Authors: Breton Christelle , Heissigerová Helena , Jeanneau Charlotte , Moravcová Jitka , Imberty Anne
Published: August 2015

Glycosyltransferases, the enzymes that build oligosaccharides and glycoconjugates, have received much interest in recent years owing to their biological functions and their potential uses in biotechnology. Despite the fact that many glycosyltransferases recognize similar donor or acceptor substrates, there is surprisingly limited sequence identity between different classes. On the one hand, the glycosyltransferases are found in a large number of families, by sequence-based classification. On the other hand, only two structural folds have been identified among the fewer than one dozen glycosyltransferases that have been crystallized at present. Detection of conserved motifs that have a direct role in the functional aspects of glycosyltransferases is one approach for identifying remote similarity. With the availability of more crystal structures, the use of the fold-recognition approach is also very promising.
Roles of galectins in vivo
Authors: Poirier Françoise
Published: August 2015

The mutational analysis of the galectin family is shedding a different light of this class of molecules. On the one hand, it appears that galectin 1 and galectin 3 are not required for the survival of mice in normal animal house conditions, while on the other hand, there seems to be several subtle, but very complex, consequences of lacking galectins during development.
MS screening strategies: investigating the glycomes of knockout and myodystrophic mice and leukodystrophic human brains
Authors: Sutton-Smith Mark , Morris Howard R. , Grewal Prabhjit K. , Hewitt Jane E. , Bittner Reginald E. , Goldin Ehud , Schiffmann Raphael , Dell Anne
Published: August 2015

The implementation of highly sensitive and rapid mass spectrometric screening strategies for defining the glycosylation repertoires of organs in knockout mice is helping to reveal the roles that glycans play in health and disease. Thus novel glycosylation pathways have been uncovered in two such knockouts, namely α-mannosidase II null mice and UDP-N-acetylglucosamine:α6-d-mannosideϐ1,2-N-acetylglucosaminyltransferase II null mice. This chapter documents the glycosylation profiles of a wide range of organs from the normal mouse which should facilitate future glycomics studies of knockout mice. Furthermore, we report applications of our screening technology in studies of the myodystrophy mouse and a human leukodystrophy.
Substrate specificity and inducibility of TACE (tumour necrosis factor α-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity
Authors: Black Roy A. , Doedens John R. , Mahimkar Rajeev , Johnson Richard , Guo Lin , Wallace Alison , Virca Duke , Eisenman June , Slack Jennifer , Castner Beverly , Sunnarborg Susan W. , Lee David C. , Cowling Rebecca , Jin Guixian , Charrier Keith , Peschon Jacques J. , Paxton Ray
Published: August 2015

Tumour necrosis factor α (TNFα)-converting enzyme (TACE/ADAM-17, where ADAM stands for a disintegrin and metalloproteinase) releases from the cell surface the extracellular domains of TNF and several other proteins. Previous studies have found that, while purified TACE preferentially cleaves peptides representing the processing sites in TNF and transforming growth factor α, the cellular enzyme nonetheless also sheds proteins with divergent cleavage sites very efficiently. More recent work, identifying the cleavage site in the p75 TNF receptor, quantifying the susceptibility of additional peptides to cleavage by TACE and identifying additional protein substrates, underlines the complexity of TACE-substrate interactions. In addition to substrate specificity, the mechanism underlying the increased rate of shedding caused by agents that activate cells remains poorly understood. Recent work in this area, utilizing a peptide substrate as a probe for cellular TACE activity, indicates that the intrinsic activity of the enzyme is somehow increased.
Proteolysis of the collagen fibril in osteoarthritis
Authors: Poole A Robin , Nelson Fred , Dahlberg Leif , Tchetina Elena , Kobayashi Masahiko , Yasuda Tadashi , Laverty Sheila , Squires Ginette , Kojima Toshihisa , Wu William , Billinghurst R. Clark
Published: August 2015

The development of cartilage pathology in osteoarthritis involves excessive damage to the collagen fibrillar network, which appears to be mediated primarily by the chondrocyte-generated cytokines interleukin-1 and tumour necrosis factor α and the collagenases matrix metalloproteinase-1 (MMP-1) and MMP-13. The damage to matrix caused by these and other MMPs can result in the production of sufficient degradation products that can themselves elicit further degradation, leading to chondrocyte differentiation and eventually matrix mineralization and cell death. Knowledge of these MMPs, cellular receptors and cytokine pathways, and the ability to selectively antagonize them by selective blockade of function, may provide valuable therapeutic opportunities in the treatment of osteoarthritis and other joint diseases involving cartilage resorption, such as rheumatoid arthritis. The ability to detect the products of these degradative events released into body fluids of patients may enable us to monitor disease activity, predict disease progression and determine more rapidly the efficacy of new therapeutic agents.
Proteolytic 'defences' and the accumulation of oxidized polypeptides in cataractogenesis and atherogenesis
Authors: Dean Roger T. , Dunlop Rachael , Hume Peter , Rodgers Ken J.
Published: August 2015

Over the last few years, it has been clearly established that normal plasma contains low levels of oxidized polypeptides, and that these accumulate in tissues during several age-related pathologies. In contrast, normal mammalian aging, contrary to conventional dogma, is not clearly associated with enhanced levels of oxidized proteins, except in extracellular connective tissues, whose proteins can, for example, be oxidized by the neutrophil oxidative burst. Since mildly oxidized proteins are susceptible to accelerated degradation in most experimental systems, the question arises as to how the accumulation of oxidized proteins can take place. Such accumulation requires an excess of production (or deposition) over removal, which might reflect alterations in capacity or rate of production or removal. This chapter discusses our presently limited knowledge of rates and control of proteolysis of oxidized proteins in two pathologies, cataractogenesis and atherogenesis. It commences with a brief summary of current understanding of the mechanisms of protein oxidation, and of the observed accumulation of oxidized proteins in several pathologies.
Nitric oxide signalling: insect brains and photocytes
Authors: Trimmer Barry A. , Aprille June , Modica-Napolitano Josephine
Published: August 2015

The success of insects arises partly from extraordinary biochemical and physiological specializations. For example, most species lack glutathione peroxidase, glutathione reductase and respiratory-gas transport proteins and thus allow oxygen to diffuse directly into cells. To counter the increased potential for oxidative damage, insect tissues rely on the indirect protection of the thioredoxin reductase pathway to maintain redox homoeostasis. Such specializations must impact on the control of reactive oxygen species and free radicals such as the signalling molecule NO. This chapter focuses on NO signalling in the insect central nervous system and in the light-producing lantern of the firefly. It is shown that neural NO production is coupled to both muscarinic and nicotinic acetylcholine receptors. The NO-mediated increase in cGMP evokes changes in spike activity of neurons controlling the gut and body wall musculature. In addition, maps of NO-producing and -responsive neurons make insects useful models for establishing the range and specificity of NO's actions in the central nervous system. The firefly lantern also provides insight into the interplay of tissue anatomy and cellular biochemistry in NO signalling. In the lantern, nitric oxide synthase is expressed in tracheal end cells that are interposed between neuron terminals and photocytes. Exogenous NO can activate light production and NO scavengers block evoked flashes. NO inhibits respiration in isolated lantern mitochondria and this can be reversed by bright light. It is proposed that NO controls flashes by transiently inhibiting oxygen consumption and permitting direct oxidation of activated luciferin. It is possible that light production itself contributes to the restoration of mitochondrial activity and consequent cessation of the flash.
Redox signalling: from nitric oxide to oxidized lipids
Authors: Shiva Sruti , Moellering Doug , Ramachandran Anup , Levonen Anna-Liisa , Landar Aimee , Venkatraman Aparna , Ceaser Erin , Ulasova Elena , Crawford Jack H. , Brookes Paul S. , Patel Rakesh P. , Darley-Usmar Victor M.
Published: August 2015

Cellular redox signalling is mediated by the post-translational modification of proteins in signal-transduction pathways by ROS/RNS (reactive oxygen species/reactive nitrogen species) or the products derived from their reactions. NO is perhaps the best understood in this regard with two important modifications of proteins known to induce conformational changes leading to modulation of function. The first is the addition of NO to haem groups as shown for soluble guanylate cyclase and the newly discovered NO/cytochrome c oxidase signalling pathway in mitochondria. The second mechanism is through the modification of thiols by NO to form an S-nitrosated species. Other ROS/RNS can also modify signalling proteins although the mechanisms are not as clearly defined. For example, electrophilic lipids, formed as the reaction products of oxidation reactions, orchestrate adaptive responses in the vasculature by reacting with nucleophilic cysteine residues. In modifying signalling proteins ROS/RNS appear to change the overall activity of signalling pathways in a process that we have termed 'redox tone'. In this review, we discuss these different mechanisms of redox cell signalling, and give specific examples of ROS/RNS participation in signal transduction.
Regulation of vascular function by haemoglobin
Authors: Crawford Jack H. , Chacko Balu K. , Patel Rakesh P.
Published: August 2015

A critical element in the ability of endothelial NO to function in the vasculature is preventing its reaction with erythrocytic Hb (haemoglobin). Emerging concepts suggest that the biophysical and rheological properties of the red blood cell are important in meeting this criterion. It has been recognized for some time that cell-free Hb may react with endothelial NO and that this may underlie the problems with Hb-based blood substitutes. More recent data extend these concepts to haemolytic diseases, including sickle cell disease, and have also identified novel therapeutic strategies to prevent interactions of cell-free Hb with NO. In this overview we have hypothesized that production of high concentrations of NO can overcome the diffusional barriers presented by the red cell and result in formation of S-nitrosohaemoglobin. By doing so, it is hypothesized that Hb may mediate the vasodilatory potential of NO and contribute to the hypotensive responses observed in acute inflammatory diseases, including sepsis.
Modulation of RNA polymerase core functions by basal transcription factor TFB/TFIIB
Authors: Werner Finn , Wiesler Simone , Nottebaum Sven , Weinzierl Robert O.J.
Published: August 2015

The archaeal basal transcriptional machinery consists of TBP (TATA-binding protein), TFB (transcription factor B; a homologue of eukaryotic TFIIB) and an RNA polymerase that is structurally very similar to eukaryotic RNA polymerase II. This constellation of factors is sufficient to assemble specifically on a TATA box-containing promoter and to initiate transcription at a specific start site. We have used this system to study the functional interaction between basal transcription factors and RNA polymerase, with special emphasis on the post-recruitment function of TFB. A bioinformatics analysis of the B-finger of archaeal TFB and eukaryotic TFIIB reveals that this structure undergoes rapid and apparently systematic evolution in archaeal and eukaryotic evolutionary domains. We provide a detailed analysis of these changes and discuss their possible functional implications.
Regulation of NF-κB function
Authors: Campbell Kirsteen J. , Perkins Neil D.
Published: August 2015

In the 20 years since its discovery, research into the NF-κB (nuclear factor-κB) family of transcription factors has revealed an amazing diversity of functions. NF-κB proteins are regulators of the immune, inflammatory, stress, proliferative and apoptotic responses of a cell to a very large number of different stimuli. NF-κB complexes can be found in all cell types, indicating that the number of different contexts in which NF-κB can become induced is enormous. Moreover, many reports suggest apparently opposing or contradictory functions for NF-κB. It is clear that it is not simply enough to understand the pathways leading to nuclear localization and DNA binding of NF-κB subunits. It is also important that we comprehend the regulation of NF-κB subunit functionality if we are to understand the NF-κB pathway as a whole. These issues include the mechanisms controlling the specificity and timing of genes regulated by NF-κB under particular circumstances. They also include the reasons why NF-κB subunits can sometimes repress rather than activate transcription and how the NF-κB response is integrated with other important transcription factor pathways in the cell, such as the induction of the p53 tumour suppressor following DNA damage or oncogene activation. Understanding the mechanisms that regulate NF-κB function has important implications for our understanding of the role that NF-κB subunits play in human inflammatory diseases and cancer, and could also impact on the use of future NF-κB-based clinical therapies.
Fluorescence resonance energy transfer as a method for dissecting in vivo mechanisms of transcriptional activation
Authors: Evans Sara K. , Aiello David P. , Green Michael R.
Published: August 2015

The first step in transcriptional activation of protein-coding genes involves the assembly on the promoter of a large PIC (pre-initiation complex) comprising RNA polymerase II and a suite of general transcription factors. Transcription is greatly enhanced by the action of promoter-specific activator proteins (activators) that function, at least in part, by increasing PIC formation. Activator-mediated stimulation of PIC assembly is thought to result from a direct interaction between the activator and one or more components of the transcription machinery, termed the ‘target’. The unambiguous identification of direct, physiologically relevant in vivo targets of activators has been a considerable challenge in the transcription field. The major obstacle has been the lack appropriate experimental methods to measure direct interactions with activators in vivo. The development of spectral variants of green fluorescent protein has made it possible to perform FRET (fluorescence resonance energy transfer) analysis in living cells, thereby allowing the detection of direct protein–protein interactions in vivo. Here we discuss how FRET can be used to identify activator targets and to dissect in vivo mechanisms of transcriptional activation.
Our FABulous VACation: a decade of phosphatidylinositol 3,5-bisphosphate
Authors: Dove Stephen K. , Johnson Zoë E.
Published: August 2015

PtdIns(3,5)P2 was discovered about a decade ago and much of the machinery that makes, degrades and senses it has been uncovered. Despite this, we still lack a complete understanding of how the pieces fit together but some patterns are beginning to emerge. Molecular functions for PtdIns(3,5)P2 are also elusive, but the identification of effectors offers a way into some of these processes. An examination of the defects associated with loss of synthesis of PtdIns(3,5)P2 in lower and higher eukaryotes begins to suggest a unifying theme; this lipid regulates membrane retrieval via retrograde trafficking from distal compartments to organelles that are more proximal in the endocytic/lysosomal system. Another unifying theme is stress signalling to organelles, possibly both to change their morphology in response to external insults and to maintain the lumenal pH or membrane potential of organelles. The next few years seem likely to uncover details of the molecular mechanisms underlying the biology of this fascinating lipid. This review also highlights some areas where further research is needed.
Phosphoinositides in phagolysosome and autophagosome biogenesis
Authors: Deretic Vojo , Singh Sudha , Master Sharon , Kyei George , Davis Alex , Naylor John , de Haro Sergio , Harris James , Delgado Monica , Roberts Esteban , Vergne Isabelle
Published: August 2015

Interconversions of phosphoinositides play a pivotal role during phagocytosis and at the subsequent stages of phagosomal maturation into the phagolysosome. Several model systems have been used to study the role of phosphoinositides in phagosomal membrane remodelling. These include phagosomes formed by inanimate objects such as latex beads, or pathogenic bacteria, e.g. Mycobacterium tuberculosis. The latter category provides naturally occurring tools to dissect membrane trafficking processes governing phagolysosome biogenesis. M. tuberculosis persists in infected macrophages by blocking Rab conversion and affecting Rab effectors. One of the major Rab effectors involved in this process is the type III phosphatidylinositol 3-kinase hVPS34. The lipid kinase hVPS34 and its enzymatic product PtdIns3P are critical for the default pathway of phagosomal maturation into phagolysosomes. Mycobacteria block PtdIns3P production and thus arrest phagosomal maturation. PtdIns3P is also critical for the process of autophagy, recently recognized as an effector of innate immunity defenses. Induction of autophagy by pharmacological, physiological, or immunological means, overcomes mycobacterial phagosome maturation block in a PtdIns3P generation dependent manner and eliminates intracellular M. tuberculosis. PtdIns3P and PtdIns3P-dependent processes represent an important cellular nexus where fundamental trafficking processes, disease causing host–pathogen interactions, and innate and adaptive immunity defense mechanisms meet.
Performance improvement of a three‐phase phase‐locked‐loop algorithm under utility voltage disturbances using non‐autonomous adaptive filters
Authors: Bacon Vinícius Dario , Oliveira da Silva Sérgio Augusto
Published: August 2015

This study proposes phase‐locked‐loop (PLL) algorithms, which are employed to improve the performance related to the estimation of the phase angle, as well as the frequency, in three‐phase systems under utility voltage disturbances. The proposed PLL schemes are based on the three‐phase instantaneous active power (3pPLL), which is composed of non‐autonomous adaptive filters (AFs) operating in conjunction with a positive‐sequence detectors (PSDs), yielding the AF‐PSD‐3pPLL algorithms operating in both three‐phase (abc‐axis) and two‐phase (αβ‐axis) stationary reference frames. The AFs are used to extract the fundamental components of the utility voltages, allowing an adequate rejection of harmonic disturbances, whereas the PSDs at fundamental utility frequency are employed for rejecting the power quality problem related to the utility unbalances. A complete stability analysis of the PLL systems is carried out. In addition, to validate the theoretical development, the dynamic response and the robustness of the proposed AF‐PSD‐3pPLL schemes are evaluated by means of simulation and experimental tests, taking into account utility disturbances, such as voltage harmonics and unbalances, voltage sags, phase‐angle jumps and frequency variations. The effectiveness of the proposed PLL schemes are emphasised by means of a comparative analysis with the conventional 3pPLL algorithm.
A Global Measure of Judicial Independence, 1948–2012
Authors: Linzer Drew A. , Staton Jeffrey K.
Published: August 2015

We present a new cross-national measure of de facto judicial independence, which is available for 200 countries from 1948 to 2012. To do so, we introduce a statistical measurement model for uncovering latent concepts commonly encountered in time-series, cross-sectional analyses in comparative politics and international relations. Our approach addresses unique challenges that arise in these data: temporal dependence in the observed and unobserved variables, conceptual boundedness in the latent quantity, and substantial missing data and measurement error in the observable indicators. The resulting measures match a common conceptual definition of independence with greater reliability than existing alternatives. The model is extensible to many concepts in comparative politics and international relations.
Reflecting on hospitality management education through a practice lens
Authors: Stierand Marc , Zizka Laura
Published: August 2015

Purpose

– The purpose of this paper is to reflect on hospitality management education from a “practice epistemology” and discuss how a connecting ofsavoir(theoretical knowledge or “knowing”),savoir-faire(knowing how to do tasks, i.e. task-related skills) andsavoir-être (knowing how to be, i.e. behavior) can develop into practical knowledge.

Design/methodology/approach

– The purpose of the paper is achieved through novel reading of the literature on practical knowledge and formativeness applied to a higher education context.

Findings

– The paper suggests that it is only through the creation of context that a sensation of practicing for students can be provided, which ultimately may lead to practical knowledge. Context must be actively created through situations that invite participation to explore the logic of practice. Therefore,savoirshould be treated as “organizing knowing” andsavoir-faireandsavoir-êtreas “practicing knowing” to do and to be, respectively. The termssavoir,savoir-faireandsavoir-êtrewere chosen for this paper, as they were the common reference terms used in hospitality (master-) apprenticeship systems in Europe.

Originality/value

– The value of the paper is a personal reflection on a practice epistemology for hospitality management education from the perspective of two academic faculty members who have been practitioners in the hospitality industry and who regularly teach hospitality executives.
Developing practice oriented undergraduate courses in a quality framework
Authors: Whitelaw Paul A. , Wrathall Jeffrey
Published: August 2015

Purpose

– The purpose of this paper is to reflect upon the stakeholder, scholarly, academic and jurisdictional influences on course development for a vocationally oriented bachelor’s degree.

Design/methodology/approach

– This paper takes the form of a case study.

Findings

– Vocationally oriented bachelor’s courses can be developed, especially when the developers focus on scholarly rigour while paying due heed to jurisdictional requirements as well as the needs of key stakeholders.

Research limitations/implications

– This case study is limited to a specialist vocational college in Australia.

Practical implications

– The paper provides a framework by which others can develop vocationally oriented bachelor’s degrees.

Social implications

– The study can provide impetus to the development of scholarly, and academically rigorous, yet industrially relevant vocational degrees.

Originality/value

– This is a relatively novel paper from a non-self accrediting higher education provider.
Response Assessment of Thermal Papers from Four Continents to Fingerprint Development by Heat
Authors: Bond John W.
Published: August 2015

Latent fingerprint deposits on thermal paper sourced from the U.S., China, the U.K., and Australia have been visualized by heating. U.S. and Chinese sourced paper produced two distinct types of fingerprint development. In one type (type 1), the paper dye colors where the deposit is present (as previously reported) and in the other type (type 2) the ‘inverse’ of this gives paper coloring only in areas not coincident with the deposit. Both development types gave identifiable fingerprints, the majority fading within 24 h of heating. Fingerprint development from U.K. and Australian sourced paper was exclusively type 1 and resistant to fading. Temperatures for fingerprint visualization were higher for U.S. paper (64–71°C) and Chinese paper (75–95°C) than for U.K. and Australian sourced paper (43–50°C). Particularly for Chinese sourced paper, these temperatures were within a few degrees of the normal paper color temperature. A mechanism for type 2 fingerprint development is proposed.
A Test of the DSP Sexing Method on CT Images from a Modern French Sample
Authors: Mestekova Sarka , Bruzek Jaroslav , Veleminska Jana , Chaumoitre Kathia
Published: August 2015

The hip bone is considered to be one of the most reliable indicators in sex determination. The aim of this study was to test the reliability of the DSP method for the hip bone proposed by Murail et al. (Bull Mem Soc Anthropol Paris, 17, 2005, 167) on a sample from a present‐day population in France (52 males and 54 females). Ten linear measurements were collected from three‐dimensional models derived from computed tomography images (CTI). To quantify the proportions of correct sex determinations, a more rigorous posterior probability threshold of 0.95 was applied. Using all 10 measurements, 92.3% of males and 97.2% of females were sexed correctly. The percentage of undetermined specimens varied depending on the used combination of measurements; however, all sexes were assigned with a 100% accuracy. This study proves that DSP is an appropriate and reliable tool for sex determination, based on dimensions obtained from CTI.