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At least 649 records · Page 36Linked to original sources
PubMed2006

Expression, purification and characterization of the membrane-associated HrcA repressor protein of Helicobacter pylori.

Helicobacter pylori, a microaerophilic, gram-negative bacterium is a human pathogen that colonizes the gastric niche and is associated with several acute and chronic stomach diseases. In order to survive in the gastric environment and become pathogenic, the bacterium relies on a plethora of virulence factors, which also include heat shock proteins. We previously showed that two out of the three operons encoding the major cellular chaperone machineries are transcriptionally repressed by two regulators, HrcA and HspR. Till now, molecular studies aimed at the understanding of the role of each protein in controlling transcription was hampered by toxicity and insolubility of HrcA in heterologous expression systems. Similar problems were encountered by many other groups studying HrcA from different bacteria. In this study, we analyzed the amino acid sequence of HrcA that predicted association of this protein to the inner membrane, which was experimentally verified. Subsequently, we implemented a dedicated induction protocol which enabled the overexpression of the recombinant His-HrcA protein in the soluble fraction of Escherichia coli cells. Moreover, we developed a purification procedure for His-HrcA that allowed us to obtain highly pure preparation of the protein. The functionality of the purified protein was then confirmed with an in vitro DNA-binding assay.

Amino Acid Sequence↗
PubMed2005

Novel frenatins from the skin of the Australasian giant white-lipped tree frog, Litoria infrafrenata: cloning of precursor cDNAs and identification in defensive skin secretion.

The Australasian anuran amphibian genus Litoria, contains many phenotypically-diverse species as a result of radial evolution of an ancestral species into different biotopes much in the manner of the indigenous marsupial mammals. In common with members of the Central/South American genus Phyllomedusa, their specialized skin granular glands are factories for the production of a plethora of biologically-active peptides. Here we report a more detailed study of those present in the defensive skin secretion of the Australasian giant white-lipped tree frog, Litoria infrafrenata, and, for the first time, we have identified three novel frenatins by deduction of primary structures from cDNAs that were cloned from a library constructed from lyophilized skin secretion using a recently-developed technique. All open-reading frames consisted of a putative signal peptide and an acidic pro-region followed by a single copy of a frenatin peptide. Processed peptides corresponding in molecular mass to the deduced molecular masses of frenatins (named 1.1, 3, 3.1 and 4.1) were identified in the same secretion sample using HPLC and mass spectroscopy. The application of this technique thus permits parallel peptidomic and transcriptomic analyzes on the same lyophilized skin secretion sample circumventing sacrifice of specimens from endangered herpetofauna.

Amphibian Proteins↗
PubMed2004

A glance at G-protein-coupled receptors for lipid mediators: a growing receptor family with remarkably diverse ligands.

A plethora of lipid-like molecules known to act as intracellular second messengers are now recognized to signal cells through plasma membrane 7 transmembrane G-protein-coupled receptors (GPCRs). This has been the result of a decade-long genetic hunt for novel sequences encoding 7 transmembrane receptor proteins and the efforts to pair novel sequences with biologically active substances of (partly) unknown molecular mechanism of action. Identification of novel GPCR ligand pairs represents the first step to shed more light into the mode of action of novel cellular signaling molecules in human health and disease and might represent a fruitful source for the development of new drugs, judged on the successful history of GPCR as drug targets. Since 2000, more than 16 reports became available on lipid mediators--as diverse as lysophospholipids, arachidonic acid metabolites, short-, medium-, and long-chain fatty acids as well as steroid-like molecules--exerting their effects as extracellular mediators via rhodopsin-like family GPCRs. These reports have opened new avenues for research in human lipid receptor physiology and pharmacology. Here, the current knowledge on the recently deorphanized lipid receptors, including their isolation, expression pattern, function, and possible physiological or pathological roles will be reviewed.

Animals↗
PubMed2005

Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis.

Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. To date, 3 distinct NOS isoforms have been identified: neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3). Biochemically, NOS consists of a flavin-containing reductase domain, a heme-containing oxygenase domain, and regulatory sites. NOS catalyse an overall 5-electron oxidation of one Nomega-atom of the guanidino group of L-arginine to form NO and L-citrulline. NO exerts a plethora of biological effects in the cardiovascular system. The basal formation of NO in mitochondria by a mitochondrial NOS seems to be one of the main regulators of cellular respiration, mitochondrial transmembrane potential, and transmembrane proton gradient. This review focuses on recent advances in the understanding of the role of enzyme and enzyme-independent NO formation, regulation of NO bioactivity, new aspects of NO on cardiac function and morphology, and the clinical impact and perspectives of these recent advances in our knowledge on NO-related pathways.

Animals↗
PubMed2006

How can we best use structural information on P-glycoprotein to design inhibitors?

This year marks the 30th anniversary of the discovery of the multidrug resistance (MDR) ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp). Since then a considerable research effort has attempted to provide a greater understanding of the biological enigma of "multidrug" efflux. Moreover, the growing correlation between P-gp expression and a negative prognosis or poor outcome for chemotherapy has sparked significant interest in the generation of inhibitors. How close are we to overcoming the unwanted actions of P-gp in resistant cancer following 30 years of research? The initial inhibitors were pre-existing clinically used compounds and exploited the broad specificity of P-gp. Unfortunately, the concentrations required to inhibit P-gp meant that these compounds generated considerable toxicity. Pharmacological investigations progressed to rational design using the 1st generation compounds as a template structure. Inherent toxicity of the drugs was reduced; however, pharmacokinetic interactions with the anticancer drugs were unsustainable. Generation of the most recent of inhibitors employed combinatorial chemistry to produce a handful of potent and selective P-gp inhibitors. Some of these drugs have progressed to clinical trials with poor results or in some cases, undisclosed progress. There remains a clear need for the generation of P-gp inhibitors and this review describes the potential for a structure-based design to facilitate this undertaking. In particular, the plethora of functional data can provide important regions on the protein that could conceivably be exploited as inhibitor targets.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Circadian rhythms in cognitive performance: methodological constraints, protocols, theoretical underpinnings.

The investigation of time-of-day effects on cognitive performance began in the early days of psychophysiological performance assessments. Since then, standardised, highly controlled protocols (constant routine and forced desynchrony) and a standard performance task (psychomotor vigilance task) have been developed to quantify sleep-wake homeostatic and internal circadian time-dependent effects on human cognitive performance. However, performance assessment in this field depends on a plethora of factors. The roles of task difficulty, task duration and complexity, the performance measure per se, practice effects, inter-individual differences, and ageing are all relevant aspects. Therefore, well-defined theoretical approaches and standard procedures are needed for tasks pinpointing higher cortical functions along with more information about time-dependent changes in the neural basis of task performance. This promises a fascinating challenge for future research on sleep-wake related and circadian aspects of different cognitive domains.

Behavioral Research↗
PubMed2006

Ophiobolin E and 8-epi-ophiobolin J produced by Drechslera gigantea, a potential mycoherbicide of weedy grasses.

Drechslera gigantea, a fungal pathogen isolated from large crabgrass (Digitaria sanguinalis) and proposed as a potential mycoherbicide of grass weeds, produces phytotoxic metabolites in liquid and solid cultures. Ophiobolin A and three minor ophiobolins i.e., 6-epi-ophiobolin A, 3-anhydro-6-epi-ophiobolin A and ophiobolin I were obtained from the liquid culture broths. Interestingly and unexpectedly, ophiobolins also appeared in cultures of this fungus and they were isolated together with the known ophiobolins B and J, and designed as ophiobolin E and 8-epi-ophiobolin J. They were characterized using essentially spectroscopic methods. It is noteworthy that D. gigantea produces such a plethora of bioactive organic substances. Some structure-activity relationship results are also discussed in this report.

Ascomycota↗
PubMed2004

Biopsychosocial pain medicine and mind-brain-body science.

This article reviews how emotions, behavior, and psychiatric comorbidity influence the course and outcome of chronic pain disorders and addresses methods of identifying and managing these problems in clinical practice. Successful medical rehabilitation for patients with chronic pain requires (1) appreciating the effects of biopsychosocial factors in the onset, course, and outcomes of pain disorders; (2) understanding neurobiologic mechanisms linking mind, brain, and body in the functions of pain perception and modulation; and (3) being able to review critically and use selectively the plethora of new medications and interventional technologies that are proposed in the literature. Deficits in these skills now are recognized as hazardous to the public health so that medical school education and post residency training in pain medicine is now mandatory in some states.

Analgesia↗
PubMed2004

Energy metabolism in mammalian brain during development.

Production of energy for the maintenance of ionic disequilibria necessary for generation and transmission of nerve impulses is one of the primary functions of the brain. This review attempts to link the plethora of information on the maturation of the central nervous system with the ontogeny of ATP metabolism, placing special emphasis on variations that occur during development in different brain regions and across the mammalian species. It correlates morphological events and markers with biochemical changes in activities of enzymes and pathways that participate in the production of ATP. The paper also evaluates alterations in energy levels as a function of age and, based on the tenet that ATP synthesis and utilization cannot be considered in isolation, investigates maturational profiles of the key processes that utilize energy. Finally, an attempt is made to assess the relevance of currently available animal models to improvement of our understanding of the etiopathology of various disease states in the human infant. This is deemed essential for the development and testing of novel strategies for prevention and treatment of several severe neurological deficits.

Adenosine Triphosphate↗
PubMed2005

N-methyl-D-aspartate (NMDA) and the regulation of mitogen-activated protein kinase (MAPK) signaling pathways: a revolving neurochemical axis for therapeutic intervention?

Excitatory synaptic transmission in the central nervous system (CNS) is mediated by the release of glutamate from presynaptic terminals onto postsynaptic channels gated by N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA and KA) receptors. Extracellular signals control diverse neuronal functions and are responsible for mediating activity-dependent changes in synaptic strength and neuronal survival. Influx of extracellular calcium ([Ca(2+)](e)) through the NMDA receptor (NMDAR) is required for neuronal activity to change the strength of many synapses. At the molecular level, the NMDAR interacts with signaling modules, which, like the mitogen-activated protein kinase (MAPK) superfamily, transduce excitatory signals across neurons. Recent burgeoning evidence points to the fact that MAPKs play a crucial role in regulating the neurochemistry of NMDARs, their physiologic and biochemical/biophysical properties, and their potential role in pathophysiology. It is the purpose of this review to discuss: (i) the MAPKs and their role in a plethora of cellular functions; (ii) the role of MAPKs in regulating the biochemistry and physiology of NMDA receptors; (iii) the kinetics of MAPK-NMDA interactions and their biologic and neurochemical properties; (iv) how cellular signaling pathways, related cofactors and intracellular conditions affect NMDA-MAPK interactions and (v) the role of NMDA-MAPK pathways in pathophysiology and the evolution of disease conditions. Given the versatility of the NMDA-MAPK interactions, the NMDA-MAPK axis will likely form a neurochemical target for therapeutic interventions.

Animals↗
PubMed2006

Experimental strategies to promote spinal cord regeneration--an integrative perspective.

Detailed pathophysiological findings of secondary damage phenomena after spinal cord injury (SCI) as well as the identification of inhibitory and neurotrophic proteins have yielded a plethora of experimental therapeutic approaches. Main targets are (i) to minimize secondary damage progression (neuroprotection), (ii) to foster axon conduction (neurorestoration) and (iii) to supply a permissive environment to promote axonal sprouting (neuroregenerative therapies). Pre-clinical studies have raised hope in functional recovery through the antagonism of growth inhibitors, application of growth factors, cell transplantation, and vaccination strategies. To date, even though based on successful pre-clinical animal studies, results of clinical trials are characterized by dampened effects attributable to difficulties in the study design (patient heterogeneity) and species differences. A combination of complementary therapeutic strategies might be considered pre-requisite for future synergistic approaches. Here, we line out pre-clinical interventions resulting in improved functional neurological outcome after spinal cord injury and track them on their intended way to bedside.

Animals↗
PubMed2006

Psychosis: a costly by-product of social brain evolution in Homo sapiens.

The plethora of varied and often conflictual research evidence on the functional psychoses calls for a unifying explanatory framework. An evolutionary framework is appropriate in view of the paradoxical epidemiology of the disorders. Evolutionary models that rely on balanced polymorphism or group selection models are not supported by the evidence. Rather, a hypothesis is presented arguing that the spectrum of psychoses should be regarded as a costly by-product of social brain evolution in Homo sapiens. Under social selective pressures, hominid ancestors evolved a sophisticated neural network supporting social cognition and adaptive interpersonal behaviour--this is termed the 'social brain'. The functional psychoses (and schizophrenia in particular) are characterised by functional and structural deficits in these fronto-temporal and fronto-parietal circuits; hence the epithet 'social brain disorders' is fitting. I argue that accumulating evidence for an evolved social brain calls for a new philosophy of mind; a philosophy focussed on the social and interpersonal nature of human experience and derived from the philosophies of Fromm, Heidegger and Merleau-Ponty. Such a paradigm shift would aid modern neuroscience in finally abandoning Cartesian dualism and would guide psychiatry towards an integrated and 'socio-neurologically' embedded understanding of mental disorders.

Biological Evolution↗
PubMed2004

Intravascular schistosomes and complement.

Schistosomes are exposed to a variety of immunological effectors, such as host complement, in the bloodstream of their definitive hosts. The parasites are reported to possess a plethora of regulatory proteins, including molecules acquired from the host, which impede the complement cascade. Evidence for the presence of a surface C2-binding protein, a C3-binding protein and a C8- and C9-binding protein has been reported. In addition, a surface Fc receptor might bind immunoglobulin and limit its ability to fix complement. However, the actual protective role of these proteins in vivo remains unresolved.

Animals↗
PubMed2004

Apoptosis and systemic lupus erythematosus.

Reduced clearance of dying cells by macrophages or increased apoptosis provokes accumulation of cellular fragments in various tissues. This process seems to induce the uptake of autoantigens from apoptotic nuclei or chromatin by dendritic cells (DCs). Then, the DCs present altered self-epitopes to naive T cells. Thus, autoreactive T cells are activated accidentally and may now provide T-cell help for B cells that present peptides processed from secondary necrotic/late apoptotic prey. Impaired phagocytic removal of early apoptotic cells may cause accumulation of secondary necrotic cells and debris in the germinal centers of secondary lymph organs. The latter bind complement and can, therefore, be trapped on the surfaces of follicular DCs (FDCs). B cells may get in contact with intracellular autoantigens that had been released during late stages of apoptotic cell death and are immobilized by FDCs. Consecutively, B cells that had, for example, gained specificity for nuclear auto-antigens during random somatic mutations can receive a short-term survival signal. After migration into the mantle zone, these autoreactive B cells may finally be activated by autoreactive CD4+ T helper cells. B cells then differentiate into memory or plasma cells. The plasma cells produce those pathogenic nuclear autoantibodies. Many defects are known with respect to the clearance of apoptotic cells and cell material, especially that of nuclear origin. Reflecting on the plethora of defects of clearance of apoptotic material already demonstrated in systemic lupus erythematosus, it is reasonable to argue that, for many patients, failure of clearance is at the heart of their disease.

Apoptosis↗
PubMed2006

Measurement of breathlessness in advanced disease: a systematic review.

BACKGROUND: There is a plethora of assessment tools available to measure breathlessness, the most common and disabling symptom of advanced cardio-respiratory disease. The aim of this systematic review was to identify all measures available via standard search techniques and review their usefulness for patients with advanced disease. METHODS: A systematic literature search was performed in Medline. All studies focusing on the development or evaluation of tools for measuring breathlessness in chronic respiratory disease, cardiac disease, cancer, or MND were identified. Their characteristics with regard to validity, reliability, appropriateness and responsiveness to change were described. The tools were then examined for their usefulness in measuring significant aspects of breathlessness in advanced disease. RESULTS: Thirty-five tools were initially identified, two were excluded. Twenty-nine were multidimensional of which 11 were breathlessness-specific and 18 disease-specific. Four tools were unidimensional, measuring the severity of breathlessness. The majority of disease-specific scales were validated for chronic obstructive pulmonary disease (COPD), few were applicable in other conditions. No one tool assessed all the dimensions of this complex symptom, which affects the psychology and social functioning of the affected individual and their family--most focused on physical activity. CONCLUSION: As yet there is no one scale that can accurately reflect the far-reaching effects of breathlessness on the patient with advanced disease and their family. Therefore, at present, we would recommend combining a unidimensional scale (e.g. VAS) with a disease-specific scale (where available) or a multidimensional scale in conjunction with other methods (such as qualitative techniques) to gauge psychosocial and carer distress for the assessment of breathlessness in advanced disease.

Dyspnea↗
PubMed2005

A protein canyon in the FGF-FGF receptor dimer selects from an à la carte menu of heparan sulfate motifs.

Heparan sulfate (HS) is an essential and dynamic regulator of fibroblast growth factor (FGF) signaling. Two fundamentally different crystallographic models have been proposed to explain, at the molecular level, how HS/heparin enables FGF and FGF receptor (FGFR) to assemble into a functional dimer on the cell surface. In the symmetric 'two-end' model, the heparin-binding sites of FGF and FGFR merge to form a basic canyon that recruits two HS for binding. Within this canyon, the HS molecules primarily act to orchestrate and fortify multivalent and cooperative protein-protein contacts within the dimer that are the foundations of dimerization. In contrast, in the asymmetric model, which mechanistically resembles the previously proposed trans FGF dimer model, a single heparin molecule facilitates dimerization by cross-linking two FGFs into a trans dimer that brings together the two FGFRs. Interestingly, the crystal structure upon which the asymmetric model is based contains a symmetric dimer reminiscent of the symmetric two-end model, suggesting that a different interpretation of the crystal structure has led to the postulation of the asymmetric model. Importantly, the symmetric two-end model provides an intriguing solution to the problem of how HS selectivity is achieved in FGF signaling. The model reveals that, within the canyon, FGF and FGFR no longer adhere to their individual HS binding specificities, but instead act in unison to search for a unique HS motif from a plethora of HS epitopes that are expressed in a tissue-specific and developmentally regulated fashion. Primary sequence differences within the heparin-binding sites of FGFs and FGFRs, together with ligand-induced changes in FGFR conformation, lead to the formation of distinct canyons with unique HS specificity for individual FGF-FGFR complexes.

Animals↗
PubMed2005

The many faces of nitric oxide in schizophrenia. A review.

Intense research has been conducted in an effort to identify specific biological markers of schizophrenia. The gas nitric oxide (NO) is one of the most important signaling molecules involved in a plethora of cellular events that take place in the cardiovascular, immune and nervous systems of animals. This survey aims to demonstrate that NO and its metabolites play important roles in schizophrenia and have a significant influence on our understanding of the development, progression and treatment of the disease. Special emphasis is given to the impact of NO metabolism on processes known to be disturbed in schizophrenia (i.e., cell migration, formation of synapses, NMDA receptor mediated neurotransmission, membrane pathology and cognitive abilities). However, when comparing data on the NO metabolism in the brain tissue and body fluids of schizophrenics with those obtained from patients with other neurological and psychiatric diseases, it becomes clear that alterations of NO metabolism are not unique to, or indicative of, schizophrenia. Thus, NO and its metabolites are not suitable diagnostic tools to distinguish schizophrenia from psychically healthy control cases or from other brain disorders.

Animals↗
PubMed2005

ETV6: a versatile player in leukemogenesis.

Alterations of the ets family transcription factor ETV6 (TEL) and the RUNT domain transcription factor RUNX1 (AML1) play pivotal roles in the leukemogenesis of various types of leukemia. While only three fusion partners of RUNX1 namely ETO, ETV6 and MTG16 have been described so far, there is a plethora of ETV6 fusion partners with about 20 partners described so far. Apart from forming fusion genes there are other genetic alterations of ETV6 including deletions, point mutations and possible alterations at the promoter level that might contribute to the malignant phenotype. This review will focus on ETV6 and on the different mechanisms that are used by this gene to cause leukemia.

Animals↗