bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphoinositide 3-kinase-dependent regulation of phospholipase Cγ
Authors: Maffucci T. , Falasca M.
Published: March 2007

Activation of the enzyme PLC (phospholipase C) leads to the formation of second messengers Ins(1,4,5)P3 and diacylglycerol. RTKs (receptor tyrosine kinases) activate this reaction through PLCγ isoenzymes. It has been shown that PI3K (phosphoinositide 3-kinase) may regulate PLCγ activity through the interaction of PI3K product PtdIns(3,4,5)P3 and the PLCγ PH domain (pleckstrin homology domain). Here, we analyse the potential functional roles of the PI3K/PLC pathway.
Nutrient sensing in the mTOR/S6K1 signalling pathway
Authors: Gulati P. , Thomas G.
Published: March 2007

Nutrient overload induces constitutive S6K1 (S6 kinase 1) activation, which leads to insulin resistance by suppressing insulin-induced class I PI3K (phosphoinositide 3-kinase) signalling [Um, Frigerio, Watanabe, Picard, Joaquin, Sticker, Fumagalli, Allegrini, Kozma, Auwerx and Thomas (2004) Nature 431, 200–205]. This finding gave rise to the question of the mechanism by which nutrients, such as AAs (amino acids), enter the mTOR (mammalian target of rapamycin)/S6K1 signalling pathway. Counter to the prevailing view, our recent studies have shown that the AA input into the mTOR/S6K1 signalling pathway is not mediated by the tumour suppressor TSC1 (tuberous sclerosis complex 1)/TSC2 or its target, the proto-oncogene Rheb (Ras homologue enriched in brain). Instead, we found that the AA input was mediated by class 3 PI3K, or hVps34 (human vacuolar protein sorting 34). In brief, ectopic expression of hVps34 drives S6K1 activation, but only in the presence of AAs, and this effect is blocked by small interfering RNAs directed against hVps34. Moreover, stimulation of cells with AAs increases hVps34 activity, as indicated by the production of PI3P (phosphatidylinositol 3-phosphate). PI3P mediates the recruitment of proteins containing FYVE (Fab1p, YOTB, Vac1p and EEA1) or PX (Phox homology) domains to endosomal membranes, with PI3P-rich micro-domains acting as signalling platforms. Additional evidence indicating hVps34 as the mediator of AA input to S6K1 came from experiments in which S6K1 activation was attenuated by ectopic expression of a cDNA containing two FYVE domains, which bind to PI3P, preventing binding of proteins containing either FYVE or PX domains [Nobukuni, Joaquin, Roccio, Dann, Kim, Gulati, Byfield, Backer, Natt, Bos, Zwartkruis and Thomas (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 14238–14243].
Regulation of class III (Vps34) PI3Ks
Authors: Yan Y. , Backer J.M.
Published: March 2007

The class III PI3K (phosphoinositide 3-kinase), Vps34 (vacuolar protein sorting 34), was first identified as a regulator of vacuolar hydrolase sorting in yeast. Unlike other PI3Ks, the Vps34 lipid kinase specifically utilizes phosphatidylinositol as a substrate, producing the single lipid product PtdIns3P. While Vps34 has been studied for some time in the context of endocytosis and vesicular trafficking, it has more recently been implicated as an important regulator of autophagy, trimeric G-protein signalling, and the mTOR (mammalian target of rapamycin) nutrient-sensing pathway. The present paper will focus on studies that describe the regulation of hVps34 (human Vps34) intracellular targeting and enzymatic activity in yeast and mammalian cells.
Inhibiting PTEN
Authors: Rosivatz E.
Published: March 2007

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is well known as a tumour suppressor. In dephosphorylating the 3-position of the inositol ring of phosphoinositides such as PtdIns(3,4,5)P3, PTEN's lipid phosphatase activity is an important counteracting mechanism in PI3K (phosphoinositide 3-kinase) signalling. This is essential for cell motility and migration due to the achievement of a PtdIns(3,4,5)P3/PtdIns(4,5)P2 gradient that is also involved in metastasis. Furthermore, PTEN's tumour suppressor role is linked to the control of cell-cycle progression and cell proliferation by counteracting Akt (also called protein kinase B) signalling which is PtdIns(3,4,5)P3-dependent. Akt is upstream of several kinases involved in proliferation and apoptotic signalling which are often found to be deregulated or mutated in tumours. However, Akt is also the key enzyme in insulin signalling regulating glucose uptake and cell growth. Therefore PTEN has recently moved into the spotlight as a drug target in diabetes. This review summarizes studies undertaken on PTEN's role in glucose uptake, insulin resistance, diabetes and its controversial role in GLUT (glucose transporter)-mediated glucose uptake. Currently available techniques for inhibiting PTEN and the suitability of PTEN as a drug target will be discussed.
The role of secretory leucoprotease inhibitor in the resolution of inflammatory responses
Authors: Weldon S. , McGarry N. , Taggart C.C. , McElvaney N.G.
Published: March 2007

Chronic lung disease is one of the most common causes of death and disability worldwide. This group of diseases is characterized by a protease burden, an infective process and a dominant pro-inflammatory profile. While SLPI (secretory leucoprotease inhibitor) was initially identified as a serine protease inhibitor, it has since been shown that SLPI possesses other properties distinct from those associated with its antiprotease capabilities that play an important role in protecting the host from infection and injury. In the course of this review, we will highlight the findings from a range of studies that illustrate the multiple functions of SLPI and its role in the resolution of the immune response.
Impact of post-translational modifications of proteins on the inflammatory process
Authors: Ito K.
Published: March 2007

PTM (post-translational modification) is the chemical modification of a protein after its translation. The well-studied PTM is phosphorylation, but, recently, PTMs have been re-focused by extensive studies on histone modifications and the discovery of the ubiquitin system. Histone acetylation is the well-established epigenetic regulator for gene expression. Recent studies show that different patterns of PTMs and cross-talk of individual modifications (acetylation, methylation, phosphorylation) are keys of gene regulation (known as the ‘histone code’). As well as histone, non-histone proteins are also targets of acetylation. For instance, NF-κB (nuclear factor κB), a transcriptional factor, is regulated dynamically by acetylation/deacetylation. Acetylation of NF-κB [RelA (p65)] at Lys310 enhances its transcriptional activity, which is inhibited by SIRT1 deacetylase, type III HDAC (histone deacetylase). We also found that acetylated NF-κB preferentially bound to the IL-8 (interleukin 8) gene promoter, but not to GM-CSF (granulocyte/macrophage colony-stimulating factor), suggesting NF-κB acetylation is involved in selective gene induction as well as an increased level of transcription. A receptor of glucocorticoid, a potent anti-inflammatory agent, is also a target of acetylation. The glucocorticoid receptor is highly acetylated after ligand binding but its deacetylation is necessary for gene repression through binding to NF-κB. As well as acetylation, other PTMs, such as nitration, carbonylation and ubiquitination on transcriptional/nuclear factors, are taking part in the inflammatory process. Cross-talk of individual modifications on proteins deserves further evaluation in the future (as ‘protein code’).
Oxidative stress and macrophage function: a failure to resolve the inflammatory response
Authors: Kirkham P.
Published: March 2007

The suppression of pro-inflammatory gene expression along with the clearance of apoptotic cells by phagocytosis can play an important role in resolving the inflammatory response. Any impairment of these processes can therefore lead to a chronic inflammatory state. Oxidative stress can have both direct and indirect effects on macrophage function. This mini-review highlights a mechanism through which oxidative stress via the production of reactive carbonyls alters the ECM (extracellular matrix) environment of macrophages, thereby altering their behaviour. Carbonyl modification of ECM proteins causes increased macrophage adhesion and activation through receptors that are also involved in phagocytosis. Moreover, interaction of macrophages with these carbonyl-modified ECM proteins leads to decreased phagocytic activity towards apoptotic cells. At a more direct level, both oxidative and carbonyl stress inhibits activity of the transcriptional co-repressor HDAC-2 (histone deacetylase 2), which under normoxic conditions helps to suppress pro-inflammatory gene expression. Consequently, macrophages activated under conditions of oxidative or carbonyl stress can lead to a more enhanced inflammatory response. Coupled with an impairment of the phagocytic response, this can lead to ineffective clearance of apoptotic cells and secondary necrosis, with the result being failure to resolve the inflammatory response and the establishment of a chronic inflammatory state.
Modulation of granulocyte apoptosis can influence the resolution of inflammation
Authors: Rossi A.G. , Hallett J.M. , Sawatzky D.A. , Teixeira M.M. , Haslett C.
Published: March 2007

Apoptosis of granulocytes and the subsequent clearance of apoptotic cells are important processes for the successful resolution of inflammation. Signalling pathways, including those involving NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) have been shown to be key regulators of inflammatory cell survival and apoptosis in vitro. In addition, manipulation of such pathways in vivo has indicated that they also play a role in the resolution of inflammation. Furthermore, manipulation of proteins directly involved in the control of apoptosis, such as Bcl-2 family members and caspases, can be targeted in vivo to influence inflammatory resolution. Recently, it has been shown that CDK (cyclin-dependent kinase) inhibitor drugs induce caspase-dependent human neutrophil apoptosis possibly by altering levels of the anti-apoptotic Bcl-2 family member, Mcl-1. Importantly, CDK inhibitor drugs augment the resolution of established ‘neutrophil-dominant’ inflammation by promoting apoptosis of neutrophils. Thus manipulation of apoptotic pathways, together with ensuring macrophage clearance of apoptotic cells, appears to be a viable pharmacological target for reducing established inflammation.
Inflammation and polyamine catabolism: the good, the bad and the ugly
Authors: Babbar N. , Murray-Stewart T. , Casero R.A.
Published: March 2007

The induction of polyamine catabolism by specific anti-tumour polyamine analogues has increased interest in the roles polyamine catabolism play in cell growth, death and response to various anti-tumour agents. The relatively recent finding of an inducible mammalian spermine oxidase (SMO/PAOh1), in addition to the two-step spermidine/spermine N1-acetyltransferanse (SSAT)/N1-acetylpolyamine oxidase (APAO) catabolic pathway, underscores the complexities of the regulation of polyamine catabolism by various stimuli. Furthermore, recent data indicate that infectious agents and mediators of inflammation can also up-regulate polyamine catabolism. Induction of SSAT by these agents can reduce intracellular polyamine concentrations and cell growth rate, thus providing a beneficial mechanism by which cells may adapt to inflammatory stress. However, increased polyamine catabolism can also result in substantial increases in intracellular reactive oxygen species (ROS) through the production of H2O2 as a by-product of either APAO or SMO/PAOh1 activity. This increased generation of ROS can have different results, depending on the mechanism of induction and cell types involved. Targeted killing of tumour cells by agents that stimulate SSAT/APAO and/or SMO/PAOh1 is obviously a ‘good’ effect. However, induction of SMO/PAOh1 by inflammation or infectious agents has the potential to produce sufficient ROS in normal, non-tumour cells to lead to DNA damage, mutation and, potentially, carcinogenic transformation (‘bad’). The variation in the induction of these polyamine catabolic enzymes, as well as the level and timing of this induction will dictate the cellular outcome in the presence of both desirable and undesirable effects (‘ugly’). Here we discuss the relative role of each of the steps in polyamine catabolism in response to inflammatory stress.
Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy
Authors: Mitchell J.L.A. , Thane T.K. , Sequeira J.M. , Thokala R.
Published: March 2007

One strategy for inhibiting tumour cell growth is the use of polyamine mimetics to depress endogenous polyamine levels and, ideally, obstruct critical polyamine-requiring reactions. Such polyamine analogues make very unusual drugs, in that extremely high intracellular concentrations are required for growth inhibition or cytotoxicity. Cells exposed to even sub-micromolar concentrations of such analogues can achieve effective intracellular levels because these compounds are incorporated by the very aggressive polyamine uptake system. Once incorporated to these levels, many of these analogues induce the synthesis of a regulatory protein, antizyme, which inhibits both polyamine synthesis and the transporter they used to enter the cell. Thus this feedback system allows steady-state maintenance of effective cellular doses of such analogues. Accordingly, effective cellular levels of polyamine analogues are generally inversely related to their capacity to induce antizyme. Antizyme activity is down-regulated by interaction with several binding partners, most notably antizyme inhibitor, and at least a few tumour tissues exhibit deficiencies in antizyme expression. Our studies explore the role of antizyme induction by several polyamine analogues in their physiological response and the possibility that cell-to-cell differences in antizyme expression may contribute to variable sensitivities to these agents.
Reducing the availability of polyamines for a developing tumour
Authors: Pryme I.F.
Published: March 2007

To sustain growth and support metabolic requirements, mammals assimilate energy-producing molecules and nutrients from food. These molecules are distributed throughout the body in order to meet the requirements of the internal organs. The various demands of the different organs are to a large extent met by regulatory processes consisting of a complex interaction between hormones, growth factors and cytokines. Normal metabolic activity and partitioning of nutrients between individual organs is affected by a number of events such as stress, a limited supply of nutrients, infection or tumour growth. Since the intestine has the highest metabolic activity of all the internal organs, a tumour will initially compete with the gut for nutrients and energy-providing molecules. The polyamines represent a class of molecules where the demand in the body increases during tumour growth. A tumour can partly obtain the polyamines required to support its growth by up-regulating its own biosynthetic capacity and partly by increasing uptake from the body pool. Rather than limiting the exogenous supply of dietary polyamines we have used another approach to manipulate polyamine pools in mice. When the lectin phytohaemagglutinin is included in the diet, a fully reversible dose-dependent growth of the small intestine occurs leading to an extensive accumulation of polyamines in the intestinal epithelia. This approach of reducing the availability of exogenous polyamines to a growing tumour will be discussed.
MDL 72527 and spermine oxidation products induce a lysosomotropic effect and mitochondrial alterations in tumour cells
Authors: Agostinelli E. , Tempera G. , Dalla Vedova L. , Condello M. , Arancia G.
Published: March 2007

Cytotoxic products of polyamines generated in situ by an enzyme-catalysed reaction may be useful as a new avenue in combating cancer. This study demonstrated that MDR (multidrug-resistant) cancer cells (colon adenocarcinoma and melanoma) are significantly more sensitive than the corresponding WT (wild-type) ones to H2O2 and aldehydes, the products of BSAO (bovine serum amine oxidase)-catalysed oxidation of spermine. Moreover, cytotoxicity was considerably greater when the treatment was carried out at 42°C than at 37°C. TEM (transmission electron microscopy) observations showed major ultrastructural alterations of the mitochondria. These were more pronounced in MDR than in WT cells. After treatment with BSAO/spermine, a higher mitochondrial membrane depolarization and an increased mitochondrial activity in drug-resistant cells were observed.
Histamine in food: is there anything to worry about?
Authors: Fogel W.A. , Lewinski A. , Jochem J.
Published: March 2007

Biogenic mono-, di- and poly-amines are widely distributed among living organisms. The amines fulfil many important functions in the human body both in the periphery and brain. Some authors suggest that foods rich in biogenic amines, especially histamine, present high health hazards for consumers. However, this is conditional on a range of other factors. The alimentary tract is well equipped with enzymes that inactivate amines and the blood–brain barrier prevents them entering the brain from the circulation. Oxidative deamination, methylation, acetylation and transglutamylation are the degradation pathways which operate efficiently in the stomach, intestines and liver. Particularly important is oxidative deamination. Food histamine poisoning or cheese reaction, manifested itself in patients treated with drugs that inhibit amine oxidases or in patients showing an enterocytic diamine oxidase deficit. It is rather food allergy, which should worry us more, as endogenous histamine release from mast cells is more dangerous. Preventive measures should be undertaken against increases in food allergies.
Polyamine metabolism and cancer prevention
Authors: Saunders F.R. , Wallace H.M.
Published: March 2007

Colorectal cancer is one of a number of cancers that may be amenable to prevention. The NSAIDs (non-steroidal anti-inflammatory drugs) have been shown to be effective chemopreventative agents in humans, but their mechanism of action is not clear. The polyamines are cellular polycations that are essential for cell growth and are overproduced in cancer cells. It is our hypothesis that inhibition of polyamine metabolism is an integral part of the mechanism of cancer prevention mediated by NSAIDs.
Vibrational spectroscopy studies on linear polyamines
Authors: Marques M.P.M. , Batista de Carvalho L.A.E.
Published: March 2007

Vibrational spectroscopy [both Raman and INS (inelastic neutron scattering)], coupled to quantum mechanical calculations, was used in order to perform a thorough structural analysis of linear polyamines and polynuclear polyamine metal chelates [e.g. with Pt(II) and Pd(II)] with potential anticancer activity. The complementarity of the Raman and INS spectroscopies was exploited in order to gain a better knowledge of the conformational behaviour of these systems. Moreover, the conjugation of the experimental spectroscopic data to the theoretical results allows us to obtain valuable information on the structural preferences of this kind of system, which may lead to the establishment of SARs (structure–activity relationships) ruling their biological activity. Some of the most significant results obtained by the ‘Molecular Physical-Chemistry’ Research Group of the University of Coimbra (Portugal) are reviewed here.
The usefulness of post-genomics tools for characterization of the amine cross-talk in mammalian cells
Authors: Sánchez-Jiménez F. , Montañez R. , Correa-Fiz F. , Chaves P. , Rodríguez-Caso C. , Urdiales J.L. , Aldana J.F. , Medina M.A.
Published: March 2007

Evidence is growing in favour of a relationship between cancer and chronic inflammation, and particularly of the role of a polyamine and histamine metabolic interplay involved in these physiopathological problems, which are indeed highly complex biological systems. Decodification of the complex inter- and intra-cellular signalling mechanisms that control these effects is not an easy task, which must be helped by systems biology technologies, including new tools for location and integration of database-stored information and predictive mathematical models, as well as functional genomics and other experimental molecular approaches necessary for hypothesis validation. We review the state of the art and present our latest efforts in this area, focused on the amine metabolism field.
Potassium channel blockers quinidine and caesium halt cell proliferation in C6 glioma cells via a polyamine-dependent mechanism
Authors: Weiger T.M. , Colombatto S. , Kainz V. , Heidegger W. , Grillo M.A. , Hermann A.
Published: March 2007

Potassium channels are ubiquitous in cells and serve essential functions in physiology and pathophysiology. Potassium channel blockers have been shown to block tumour growth by arresting cells at the G0/G1 checkpoint of the cell cycle. We investigated the effect of quinidine and caesium (Cs+) on cell proliferation, LDH (lactate dehydrogenase) release, free internal calcium, membrane potential, polyamine concentration, ODC (ornithine decarboxylase) activity and polyamine uptake in C6 glioma cells. The EC50 for reducing cell proliferation was 112 μM for quinidine, whereas Cs+ was less effective with an EC50 of 4.75 mM. KCl or sucrose did not affect proliferation. LDH release was augmented by quinidine. Quinidine caused a transient increase in free internal calcium but decreased calcium after a 48 h incubation period. Further 300 μM quinidine depolarized the cell membrane in a similar range as did 30 mM KCl. Quinidine decreased cellular putrescine beyond detection levels while spermidine and spermine remained unaffected. ODC activity was reduced. Addition of putrescine could not override the antiproliferative effect owing to a reduced activity of the polyamine transporter. Our study indicates that the antiproliferative effect of quinidine is not due to a simple membrane depolarization but is caused by a block of ODC activity.
Role of the FAD-dependent polyamine oxidase in the selective formation of N1,N8-bis(γ- glutamyl)spermidine protein cross-links
Authors: Lentini A. , Mattioli P. , Provenzano B. , Abbruzzese A. , Caraglia M. , Beninati S.
Published: March 2007

Protein-bound γ-glutamylpolyamines have highlighted a new pathway in polyamine metabolism. Human foreskin keratinocytes offer a suitable model for this study. Indeed, they develop polymerized envelopes, as they differentiate, rich in ϵ-(γ-glutamyl)lysine and N1,N8-bis(γ-glutamyl)spermidine cross-links. We have found that the selective oxidation of N1-(γ-glutamyl)spermidine and N-(γ-glutamyl)spermine by FAD-dependent polyamine oxidase (PAO) may be one of the cellular mechanisms regulating the preferential formation of a sterically defined bis(γ-glutamyl)spermidine cross-link. The significance of this finding is unknown, but it suggests that the target of this PAO-modulation is to achieve the biochemical prerequisite for production of a normal epidermal stratum corneum.
Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection
Authors: Hennigan A. , O'Callaghan R.M. , Kelly Á.M.
Published: March 2007

It is beyond doubt that the neurotrophin family of proteins plays key roles in determining the fate of the neuron, not only during embryonic development, but also in the adult brain. Neurotrophins such as NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) can play dual roles: first, in neuronal survival and death, and, secondly, in activity-dependent plasticity. The neurotrophins manifest their effects by binding to two discrete receptor subtypes: the Trk (tropomyosin receptor kinase) family of RTKs (receptor tyrosine kinases) and the p75NTR (p75 neurotrophin receptor). The differential activation of these receptors by the mature neurotrophins and their precursors, the proneurotrophins, renders analysis of the biological functions of these receptors in the adult brain highly complex. Here, we briefly give a broad review of current knowledge of the roles of neurotrophins in the adult brain, including expression of hippocampal plasticity, neurodegeneration and exercise-induced neuroprotection.
Clinical performance of a resin‐modified glass‐ionomer and two polyacid‐modified resin composites in cervical lesions restorations: 1‐year follow‐up
Authors: Chinelatti M. A. , Ramos R. P. , Chimello D. T. , Palma‐Dibb R. G.
Published: March 2007

summary  The aim of this study was to assess the clinical performance of a resin‐modified glass–ionomer cement (VitremerTM) and two polyacid‐modified resin composites (F2000TM and FreedomTM) over 1 year. Nineteen patients with at least three cervical lesions were selected, providing an initial sample size of 87 restorations (29 per material), being 78 to non‐carious and nine to carious lesions. Restorations were evaluated at baseline, 6 months and 1 year after placement, using modified US Public Health Service criteria: colour match, marginal discoloration, caries, anatomical form, marginal integrity and surface texture. At baseline, restorations were considered as acceptable for all criteria. At 1‐year recall, 21 restorations per material were re‐examined. FreedomTM was rated Bravo or Charlie for all the examined criteria and VitremerTM earned an Alfa rating solely for the criterion caries. On the contrary, F2000TM showed the best overall results, although presenting significant alteration in colour match. Statistical analysis of data was performed using chi‐square and Mc Nemar tests. As to the evaluated periods, significant difference was observed solely between baseline and 1‐year recall. FreedomTM and VitremerTM were statistically different (P < 0·01) as to anatomical form and surface texture. For F2000TM, significant difference (P < 0·05) was noticed as to colour match and anatomical form. After 1‐year follow‐up, F2000TM showed the most acceptable results as to the analysed criteria.
Effects of calcium hydroxide paste medication on coronal leakage
Authors: Sevimay S. , Öztan M. D. , Dalat D.
Published: March 2007

summary  The purpose of this in vitro study was to examine the coronal leakage of canals medicated with Ca(OH)2 compared with the canals which did not receive Ca(OH)2 medication before obturation with laterally condensed gutta‐percha points and sealer. Sixty‐one single rooted permanent canines and premolars were used. The crowns were removed from the cemento‐enamel junction. After the canals were chemomechanically prepared, the roots were divided into three experimental groups as group 1, 2 and 3. The canals in group 1 and 2 were treated with ethylenediaminetetraacetic acid (EDTA) and NaOCl in order to remove the smear layer and then the canals were filled with Ca(OH)2 paste. The coronal 3 mm of the cavities were sealed with Cavit and the samples were kept in an incubator at 37 °C for 7 days. No intra‐canal medication was applied in group 3. The root canals were irrigated with NaOCl in group 1 and with EDTA and NaOCl in group 2, in order to remove Ca(OH)2 before obturation. Two samples from group 1 and two from group 2 were examined under SEM in order to reveal the removal of Ca(OH)2 paste. Following this, the canals in the experimental groups were obturated with gutta‐percha and sealer. The roots were placed in India ink for 7 days and the linear dye penetration was evaluated. No significant statistical difference was found in the amount of coronal dye leakage between experimental groups (P > 0·05). The results of the present study indicated that the application of Ca(OH)2 as a temporary dressing material had no effect on coronal leakage.
Adherence of Streptococcus mutans to various restorative materials in a continuous flow system
Authors: Eick S. , Glockmann E. , Brandl B. , Pfister W.
Published: March 2007

summary  A continuous flow system was developed to evaluate the adhesion of Streptococcus mutans ATCC 25175 to filling materials (Ariston, Tetric, Dyract, Compoglass, Vitremer, Aqua Ionofil, Ketac Fil, amalgam, Galloy and ceramics as controls). Streptococcus mutans was added to saliva‐coated test specimens, and a nutrient broth permanently supplied over a time period of 48 h and then the weight of plaque, the number and viability of the bacteria adhering to the materials were determined. The weights of artificial plaque on all filling materials tested were higher than those on ceramics, the highest values were measured on the glass–ionomers. The amount of plaque correlates with the surface roughness, whereas there was no correlation of the surface roughness with the number of colony‐forming units (CFU) of S. mutans. The CFU of adhering S. mutans also depends on the viability of the bacteria. The plaque on Ketac Fil contained a high number of viable bacteria. The fluorides of glass–ionomers do not efficiently prevent the attachment and the viability of S. mutans.
Oral kinesiology. A new postgraduate programme in the Netherlands
Authors: Lobbezoo F. , Van der Zaag J. , Visscher C. M. , Naeije M.
Published: March 2007

Summary  As one of the dental differentiations in The Netherlands, temporomandibular disorders (TMD) focuses on the diagnosis and treatment of pain and dysfunction of the masticatory system. Bruxism (i.e. tooth clenching and/or grinding) is thought to play an important aetiological role in TMD. Among others, bruxism may result in TMD pain and dental attrition. The close relationship between TMD, bruxism, and attrition necessitates an integrated approach to these clinical problems. This could be achieved through the multidisciplinary differentiation ‘oral kinesiology’, that covers not only the diagnosis and treatment of TMD and bruxism but also the restoration of worn dentitions. This article focuses on the background of oral kinesiology, as well as on the rationale to develop a curriculum for the postgraduate training of dentist–kinesiologists in the Netherlands. Further, the oral kinesiology curriculum of the Academic Centre for Dentistry Amsterdam will be introduced. This curriculum will ensure that specialized professionals, who are able to approach the different aspects of oral kinesiology in an integrated manner, are available not only for general dental practice but also for centres for special dental care and university departments. This will lead to improved care for patients, whose management is until now dispersed between various dental specialists.
Tracking Wildebeest, Locating Knowledge: Maasai and Conservation Biology Understandings of Wildebeest Behavior in Northern Tanzania
Authors: Goldman Mara
Published: March 2007

In this paper I argue for building dialogues between scientific and Maasai knowledge articulations, utilizing knowledge of wildebeest as an example. By locating Maasai and scientific knowledges regarding a particular subject (wildebeest) in relation to each other—in discourse and in practice—my intention is to create the space for their active engagement. I strive to (1) expose the situatedness, strengths, and weaknesses of both Maasai knowledge and scientific knowledge, and (2) illustrate the conditions within which collaborative dialogues can be constructed between the situated knowledges or knowledge spaces embodied by Maasai and conservation scientists. In doing so I hope to contribute to a shift in theoretical debates regarding knowledge integration for natural-resource management, away from ‘building bridges’ and towards the building of dialogues.
Skills for Heterogeneous Associations: The Whiteboys, Collective Experimentation, and Subaltern Political Ecologies
Authors: Featherstone David
Published: March 2007

Bruno Latour's Politics of Nature (2004, Harvard University Press) argues for a new ‘common sense’ for political ecology that disabuses it of any foundational grounding in nature. In this paper I interrogate Latour's project in relation to struggles that might be termed ‘subaltern political ecologies’. I argue that Latour's account of the political as bearing on the ‘progressive composition of the world’ offers insights for engaging with the inventiveness of subaltern political activity. I suggest that subaltern political ecologies offer both resources and challenges to the project of reworking the common sense of political ecology. To demonstrate this, I engage with the struggles against unequal social and material relations of the 18th-century Irish peasant movement, the Whiteboys. I follow the movement of their forms of political activity to London's dockside spaces. I suggest two skills that subaltern political ecologies ‘add’ to the politics of ‘heterogeneous associations’: the configuring of strategic arrangements of humans and nonhumans in antagonistic ways and the making of solidarities as ongoing interventions in the constitution of networks. This reworking of key political processes as active engagements in world-building activities seeks to foreground forms of political identity and agency which have often been marginalised, ignored, or dismissed.
Placing and Scaling the Nation
Authors: Jones Rhys , Fowler Carwyn
Published: March 2007

In this paper we discuss the geographical contexts within which nations are reproduced. Although geographers have carried out much interesting and insightful work in their studies of nationalism, we contend that the majority of authors have tended to focus on the way in which particular sites and landscapes come to represent nations. Less attention has been directed towards the geographical concepts and processes that inform the ongoing reproduction of nations. We elaborate on the potential for geographers to explore more systematically the way in which key geographical concepts such as place and scale are imbricated in the reproduction of nations. We do so, first, at a conceptual level before, second, discussing empirical evidence that is drawn from an oral history research project based in Wales. We conclude by arguing that geographers should be at the forefront of attempts to comprehend better the multiple places and scales of the reproduction of the nation.
Crystal structure of the carbapenemase OXA-24 reveals insights into the mechanism of carbapenem hydrolysis
Authors: Santillana Elena , Beceiro Alejandro , Bou Germán , Romero Antonio
Published: March 2007

Combating bacterial resistance to β-lactams, the most widely used antibiotics, is an emergent and clinically important challenge. OXA-24 is a class D β-lactamase isolated from a multiresistant epidemic clinical strain of
Acinetobacter baumannii
. We have investigated how OXA-24 specifically hydrolyzes the last resort carbapenem antibiotic, and we have determined the crystal structure of OXA-24 at a resolution of 2.5 Å. The structure shows that the carbapenem's substrate specificity is determined by a hydrophobic barrier that is established through the specific arrangement of the Tyr-112 and Met-223 side chains, which define a tunnel-like entrance to the active site. The importance of these residues was further confirmed by mutagenesis studies. Biochemical and microbiological analyses of specific point mutants selected on the basis of structural criteria significantly reduced the catalytic efficiency (
k
cat
/
K
m
) against carbapenems, whereas the specificity for oxacillin was noticeably increased. This is the previously unrecognized crystal structure that has been obtained for a class D carbapenemase enzyme. Accordingly, this information may help to improve the development of effective new drugs to combat β-lactam resistance. More specifically, it may help to overcome carbapenem resistance in
A. baumannii
, probably one of the most worrying infectious threats in hospitals worldwide.
The answer to concerted versus step-wise controversy for the double proton transfer mechanism of 7-azaindole dimer in solution
Authors: Takeuchi Satoshi , Tahara Tahei
Published: March 2007

The dynamics and mechanism of the double proton transfer reaction of the 7-azaindole dimer was investigated in solution by excitation wavelength dependence in steady-state and femtosecond time-resolved fluorescence spectroscopy. Femtosecond measurements in the UV region revealed that the dynamics of the dimer fluorescence exhibits remarkable change as the excitation wavelength was scanned from 280 to 313 nm. The fluorescence showed a biexponential decay (0.2 and 1.1 ps) with 280-nm excitation, whereas it exhibited a single exponential decay (1.1 ps) with 313-nm excitation (the red-edge of the dimer absorption). This observation clearly indicates that the 0.2-ps component is irrelevant to the proton transfer. In the visible region, we found that the tautomer fluorescence rises in accordance with the decay of the dimer fluorescence with a common time constant of 1.1 ps. This finding unambiguously denies the appearance of any intermediate species in between the dimer and tautomer excited states, indicating that the double proton transfer reaction is essentially a single-step process. We conclude that the double proton transfer of the 7-azaindole dimer in solution proceeds in the concerted manner from the lowest excited state with the 1.1-ps time constant. On the basis of the experimental data obtained, we discuss the long-lasting concerted versus step-wise controversy for the double proton transfer mechanism in solution.
An
in vivo
correlate of exercise-induced neurogenesis in the adult dentate gyrus
Authors: Pereira Ana C. , Huddleston Dan E. , Brickman Adam M. , Sosunov Alexander A. , Hen Rene , McKhann Guy M. , Sloan Richard , Gage Fred H. , Brown Truman R. , Small Scott A.
Published: March 2007

With continued debate over the functional significance of adult neurogenesis, identifying an
in vivo
correlate of neurogenesis has become an important goal. Here we rely on the coupling between neurogenesis and angiogenesis and test whether MRI measurements of cerebral blood volume (CBV) provide an imaging correlate of neurogenesis. First, we used an MRI approach to generate CBV maps over time in the hippocampal formation of exercising mice. Among all hippocampal subregions, exercise was found to have a primary effect on dentate gyrus CBV, the only subregion that supports adult neurogenesis. Moreover, exercise-induced increases in dentate gyrus CBV were found to correlate with postmortem measurements of neurogenesis. Second, using similar MRI technologies, we generated CBV maps over time in the hippocampal formation of exercising humans. As in mice, exercise was found to have a primary effect on dentate gyrus CBV, and the CBV changes were found to selectively correlate with cardiopulmonary and cognitive function. Taken together, these findings show that dentate gyrus CBV provides an imaging correlate of exercise-induced neurogenesis and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging.
Intensification of Pacific storm track linked to Asian pollution
Authors: Zhang Renyi , Li Guohui , Fan Jiwen , Wu Dong L. , Molina Mario J.
Published: March 2007

Indirect radiative forcing of atmospheric aerosols by modification of cloud processes poses the largest uncertainty in climate prediction. We show here a trend of increasing deep convective clouds over the Pacific Ocean in winter from long-term satellite cloud measurements (1984–2005). Simulations with a cloud-resolving weather research and forecast model reveal that the increased deep convective clouds are reproduced when accounting for the aerosol effect from the Asian pollution outflow, which leads to large-scale enhanced convection and precipitation and hence an intensifed storm track over the Pacific. We suggest that the wintertime Pacific is highly vulnerable to the aerosol–cloud interaction because of favorable cloud dynamical and microphysical conditions from the coupling between the Pacific storm track and Asian pollution outflow. The intensified Pacific storm track is climatically significant and represents possibly the first detected climate signal of the aerosol–cloud interaction associated with anthropogenic pollution. In addition to radiative forcing on climate, intensification of the Pacific storm track likely impacts the global general circulation due to its fundamental role in meridional heat transport and forcing of stationary waves.
Fuzzy Empiricism and Fuzzy-Set Causality: What Is All the Fuzz About?
Authors: Cat Jordi
Published: March 2007

This paper examines a novel notion of causality, namely, fuzzy-set-theoretic causality. Over the last decade, a number of conceptual models of causality, in the language of fuzzy-set theory, have appeared in the scientific literature and have been applied to empirical research. They have circulated widely from one scientific discipline to another, weaving a unifying thread through them. However, they have received no philosophical attention. In this paper, I will discuss the value and limitations of this type of model and will read into its application several dimensions of philosophical significance.
Belief, Evidence, and Conditioning
Authors: Kyburg Henry E.
Published: March 2007

Since Ramsey, much discussion of the relation between probability and belief has taken for granted that there are degrees of belief, i.e., that there is a real-valued function, B, that characterizes the degree of belief that an agent has in each statement of his language. It is then supposed that B is a probability. It is then often supposed that as the agent accumulates evidence, this function should be updated by conditioning:$B^{E}(\cdot) $
should be$B(\cdot \wedge E) / B(E) $
. Probability is also important in classical statistics, where it is generally supposed that probabilities are frequencies, and that inference proceeds by controlling error and not by conditioning. I will focus on the tension between these two approaches to probability, and in the main part of the paper show where and when Bayesian conditioning conflicts with error based statistics and how to resolve these conflicts.
Heisenberg Meets Kuhn: Closed Theories and Paradigms
Authors: Bokulich Alisa
Published: March 2007

The aim of this paper is to examine in detail the similarities and dissimilarities between Werner Heisenberg's account of closed theories and Thomas Kuhn's model of scientific revolutions. My analysis draws on a little-known discussion that took place between Heisenberg and Kuhn in 1963, in which Heisenberg, having just read Kuhn's Structure of Scientific Revolutions, compares Kuhn's views to his own account of closed theories. I conclude that while Heisenberg and Kuhn share a holist conception of theories, a revolutionary model of theory change, and even a notion of incommensurability, their views diverge fundamentally when it comes to the issue of scientific realism. I show that, contrary to popular opinion, Heisenberg is not an instrumentalist, but rather a pluralistic realist.
Essay Review of The Republic of Science: The Emergence of Popper's Social View of Science
Authors: Wettersten John
Published: March 2007

I. C. Jarvie interprets Popper's philosophy of science as a theory of the institution of science, explains how the social aspect of his theory developed, and suggests that an updated version of Popper's social theory should be used to study both scientific and nonscientific societies today. Although (1) Jarvie's description of the emergence of Popper's theory suffers because he takes no account Popper's research conducted before Logik der Forschung (1994), (2) his portrayal of Popper's framework overlooks important problems, and (3) his program is by no means new, his essay throws light on the relation between Popper's philosophy of science, his social theory, and his social studies of science.
Risk Factors for Death Due to Nosocomial Infection in Intensive Care Unit Patients: Findings From the Krankenhaus Infektions Surveillance System
Authors: Gastmeier P. , Sohr D. , Geffers C. , Behnke M. , Rüden H.
Published: March 2007

Objective.

To determine risk factors for death among patients with nosocomial pneumonia and patients with primary bloodstream infections (BSI) in intensive care units (ICUs).

Design.

Prospective cohort study.

Setting.

Data collected from January 1997 through June 2003 from ICUs registered with the Krankenhaus Infektions Surveillance System in Germany.

Patients.

A total of 8,432 patients with nosocomial pneumonia from 202 ICUs and 2,759 patients with nosocomial primary BSI from 190 ICUs.

Methods.

The following risk factors were considered in the analysis: age, sex, time in the ICU before onset of infection, type of ICU, type and size of hospital, intubation, central venous catheter use, total parenteral nutrition, and type of pathogen.

Results.

A total of 750 patients (8.9%) with nosocomial pneumonia and 302 patients (10.9%) with nosocomial primary BSI died. Multiple logistic regression analysis identified treatment in a medical or surgical ICU (odds ratio [OR], 1.55 [95% confidence interval {CI}, 1.32-1.82]) or a hospital with more than 1,000 beds (OR, 2.14 [95% CI, 1.81-2.56]), age older than 65 years (OR, 1.54 [95% CI, 1.31-1.81]), and infection with methicillin-resistant Staphylococcus aureus (OR, 2.39 [95% CI, 1.81-3.12]) or multidrug-resistant Pseudomonas aeruginosa (OR, 3.00 [95% CI, 1.90-4.63]) as independent determinants of death from nosocomial pneumonia. Age older than the median of 63 years (OR, 1.44 [95% CI, 1.12-1.86]) and methicillin-resistant S. aureus as the causative agent (OR, 2.98 [95% CI, 1.81-5.82]) were both associated with increased mortality from primary BSI. The types of infecting pathogens, particularly those resistant to multiple drugs, were also strong outcome predictors among ICU patients.

Conclusions.

The study results underline the need for further investigations of the role of antimicrobial resistance in the outcome of patients with nosocomial pneumonia and patients with primary BSI.
Usefulness of Severity-of-Illness Scores Based on Admission Data Only in Nosocomial Infection Surveillance Systems
Authors: Gastmeier Petra , Menzel Karin , Sohr Dorit , Rüden Henning
Published: March 2007

Background.

Surveillance of nosocomial infection (NI) and the use of reference data for comparison is recommended to improve the quality of patient care. In addition to standardization according to device use, another stratification of reference data according to patients' severity-of-illness scores is often required for benchmarking in intensive care units (ICUs).

Objective.

To determine whether severity-of-illness scores on admission to the ICU are sufficient data for predicting the development of NI.

Methods.

This study was performed in an interdisciplinary ICU at a teaching hospital. Two scores were studied: the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system and the Therapeutic Intervention Scoring System (TISS). The patient's clinical condition was evaluated on admission and reevaluated daily during the period before the development of NI. In addition, we recorded the number of intubations for every patient-day, the age and sex of the patients, and their history of operations. The Fisher exact test and the stepwise multiple logistic regression model were applied to identify significant predictors of NI.

Results.

During a 12-month period, 270 patients with ICU stays of more than 24 hours were included in the study. Sixty-nine NIs were identified (incidence, 25.6 cases per 100 patients [95% confidence interval, 19.9-32.3]). A mean APACHE II score and a mean TISS score above the median for these scores, duration of ventilation above the median in the period before the development of NI, and patient age were significantly associated with the development of NI; the score data on admission provided a clearly poorer prediction.

Conclusion.

The APACHE II and TISS scores on admission are not useful predictors for NI in ICUs.