bluuebunny/crossref_metadata_2025 huggingface dataset:
The GluR2 subunit inhibits proliferation by inactivating Src‐MAPK signalling and induces apoptosis by means of caspase 3/6‐dependent activation in glioma cells
Authors: Beretta Francesca , Bassani Silvia , Binda Elena , Verpelli Chiara , Bello Lorenzo , Galli Rossella , Passafaro Maria
Published: June 2009

Glioblastoma multiforme (GBM) is the most invasive and undifferentiated type of brain tumour, and so surgical interventions are ineffective. We found that GluR2 is absent in fast‐growing GBM‐derived tumour stem cells and high‐grade glioma specimens, but is expressed in slow‐growing stem cells and low‐grade glioma specimens. More remarkably, GluR2 overexpression in U‐87MG cells inhibits proliferation by inactivating extracellular signal‐regulated kinase (ERK)1/2‐Src phosphorylation and induces apoptosis. Mechanistically, we observed that the scaffold protein GRIP is essential for the effect of GluR2 on ERK‐Src inactivation. These findings indicate that the absence of the GluR2 subunit favours malignancy.
Molecular analysis of the phosphorus starvation response in Trichodesmium spp.
Authors: Orchard Elizabeth D. , Webb Eric A. , Dyhrman Sonya T.
Published: June 2009

The marine diazotroph Trichodesmium is a major contributor to primary production and nitrogen fixation in the tropical and subtropical oceans. These regions are often characterized by low phosphorus (P) concentrations, and P starvation of Trichodesmium could limit growth, and potentially constrain nitrogen fixation. To better understand how this genus responds to P starvation we examined four genes involved in P acquisition: two copies of a high‐affinity phosphate binding protein (pstS and sphX) and two putative alkaline phosphatases (phoA and phoX). Sequence analysis of these genes among cultured species of Trichodesmium (T. tenue, T. erythraeum, T. thiebautii and T. spiralis) showed that they all are present and conserved within the genus. In T. erythraeum IMS101, the expression of sphX, phoA and phoX were sensitive to P supply whereas pstS was not. The induction of alkaline phosphatase activity corresponded with phoA and phoX expression, but enzyme activity persisted after the expression of these genes returned to basal levels. Additionally, nifH (nitrogenase reductase; involved in nitrogen fixation) expression was downregulated under P starvation conditions. These data highlight molecular level responses to low P and lay a foundation for better understanding the dynamics of Trichodesmium P physiology in low‐P environments.
Chromosomal antioxidant genes have metal ion‐specific roles as determinants of bacterial metal tolerance
Authors: Harrison Joe J. , Tremaroli Valentina , Stan Michelle A. , Chan Catherine S. , Vacchi‐Suzzi Caterina , Heyne Belinda J. , Parsek Matthew R. , Ceri Howard , Turner Raymond J.
Published: June 2009

Microbiological metal toxicity involves redox reactions between metal species and cellular molecules, and therefore, we hypothesized that antioxidant systems might be chromosomal determinants affecting the susceptibility of bacteria to metal toxicity. Here, survival was quantified in metal ion‐exposed planktonic cultures of several Escherichia coli strains, each bearing a mutation in a gene important for redox homeostasis. This characterized ∼250 gene–metal combinations and identified that sodA, sodB, gor, trxA, gshA, grxA and marR have distinct roles in safeguarding or sensitizing cells to different toxic metal ions (Cr2O72–, Co2+, Cu2+, Ag+, Zn2+, AsO2–, SeO32– or TeO32–). To shed light on these observations, fluorescent sensors for reactive oxygen species (ROS) and reduced thiol (RSH) quantification were used to ascertain that different metal ions exert oxidative toxicity through disparate modes‐of‐action. These oxidative mechanisms of metal toxicity were categorized as involving ROS and thiol‐disulfide chemistry together (AsO2–, SeO32–), ROS predominantly (Cu2+, Cr2O72–) or thiol‐disulfide chemistry predominantly (Ag+, Co2+, Zn2+, TeO32–). Corresponding to this, promoter‐luxCDABE fusions showed that toxic doses of different metal ions up‐ or downregulate the transcription of gene sets marking distinct pathways of cellular oxidative stress. Altogether, our findings suggest that different metal ions are lethal to cells through discrete pathways of oxidative biochemistry, and moreover, indicate that chromosomally encoded antioxidant systems may have metal ion‐specific physiological roles as determinants of bacterial metal tolerance.
A mid‐gut microbiota is not required for the pathogenicity of Bacillus thuringiensis to diamondback moth larvae
Authors: Raymond Ben , Johnston Paul R. , Wright Denis J. , Ellis Richard J. , Crickmore Neil , Bonsall Michael B.
Published: June 2009

The mode of action of the entomopathogenic bacterium Bacillus thuringiensis (Bt) remains a matter of debate. Recent reports have claimed that aseptic lepidopteran hosts were not susceptible to Bt and that inoculation with mid‐gut bacteria restores pathogenicity. These claims are controversial because larvae were rendered aseptic by consuming antibiotics, although the effect of these antibiotics on Bt was not examined. We tested the generality of the mid‐gut bacteria hypothesis in the diamondback moth, Plutella xylostella using properly controlled experiments that investigated the effect of antibiotic consumption and absence of gut microbiota separately. We found that purified Bt toxin and spore/toxin mixtures were fully pathogenic to larvae reared aseptically. Persistence of antibiotics in larval tissues was implicated in reducing host mortality because larval consumption of the antibiotic rifampicin reduced the pathogenicity of rifampicin‐sensitive Bt strains but not rifampicin‐resistant strains. Inoculating larvae with Enterobacter sp. Mn2 reduced the mortality of larvae feeding on Bt HD‐1 and the presence of a culturable gut microbiota also reduced the pathogenicity of the Bt toxin Cry1Ac, in agreement with other studies indicating that an intestinal microbiota can protect taxonomically diverse hosts from pathogen attack. As ingestion of antibiotics suppresses host mortality the vegetative growth of Bt in the host must be important for its pathogenicity. Furthermore, claims that aseptic larvae are not susceptible to Bt must be supported by experiments that control for the effect of administering antibiotics.
Comparison of the prognostic value of tumour‐ and patient‐related factors in patients undergoing potentially curative surgery for colon cancer
Authors: Roxburgh C. S. D. , Wallace A. M. , Guthrie G. K. , Horgan P. G. , McMillan D. C.
Published: June 2009

Aim  To comprehensively compare the prognostic value of tumour‐ and patient‐related factors in patients undergoing curative surgery for colon cancer.

Method  From a database of 287 patients who underwent elective resection between 1997 and 2005, tumour factors including stage and host factors including systemic inflammatory response [modified Glasgow Prognostic Score (mGPS)] were identified.

Results  Median follow‐up was 65 months. Over this period, 125 patients died, 80 from cancer. On multivariate analysis of all significant patient and tumour related factors, Dukes stage (P < 0.01), vascular invasion (P < 0.01) and the mGPS (P < 0.01) were independently associated with cancer‐survival. Of the patient‐related factors, age (P < 0.01), haemoglobin (P < 0.01), white‐cell (P < 0.01), neutrophil (P < 0.01) and platelet (P < 0.01) counts, and alkaline phosphatase (P < 0.01) were most significantly associated with the mGPS.

Conclusion  In addition to tumour‐related factors such as Dukes stage and vascular invasion, the preoperative mGPS should be included to guide prognosis in patients undergoing curative resection for colon cancer.
The impact of lymph node yield on Duke’s B and C colorectal cancer survival
Authors: Fretwell V. L. , Ang C. W. , Tweedle E. M. , Rooney P. S.
Published: June 2009

Aim  The number of positive lymph nodes retrieved following colorectal cancer (CRC) resection impacts on the staging and further treatment of the disease. We compared 5‐year survival by lymph node yield for Duke’s B and C patients to assess the impact on prognosis.

Method  A retrospective methodology was employed to review patients who underwent operative resection for Duke’s B or C CRC between 1999 and 2003.

Results  A total of 351 patients were included in our analyses. Lymph node yield, N‐stage and extramural vascular invasion were independent predictors of overall 5‐year survival. A significant difference in 5‐year survival by lymph node yield was seen among Duke’s B patients (< 9 nodes vs≥ 9 nodes, 45.2%vs 68.4%; P = 0.0043) and Duke’s C patients (< 10 nodes vs≥ 10 nodes, 25.6%vs 48.8%; P = 0.0099). There was a significant reduction in the relative risk of 2.8% in mortality for each additional node sampled in Duke’s B and C patients (RR 0.972, 95% confidence interval 0.949–0.994, P = 0.0102). Duke’s B patients who had < 9 lymph node yield and no neoadjuvant/adjuvant treatment had a similar survival to all Duke’s C patients (47.8%vs 41.7%, P = 0.5136).

Conclusion  Lymph node yield independently predicts for survival in patients with Duke’s B and C CRC. Duke’s B patients with < 9 lymph node yield have no better survival than patients with Duke’s C disease. Therefore, prospective randomized studies are required to examine if inadequate lymph node yield could be one of the deciding factors in offering adjuvant therapy among Duke’s B cancer patients.
Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes
Authors: Lund S. S. , Tarnow L. , Astrup A. S. , Hovind P. , Jacobsen P. K. , Alibegovic A. C. , Parving I. , Pietraszek L. , Frandsen M. , Rossing P. , Parving H.‐H. , Vaag A. A.
Published: June 2009

Background: In addition to its glucose‐lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study, we report the effect of a 1‐year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control.

Methods: One hundred T1DM patients with haemoglobinA1c (HbA1c) ≥8.5% during the year before enrolment entered a 1‐month run‐in period on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1000 mg twice daily) or placebo for 12 months (double masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. Outcomes were assessed at baseline and after 1 year.

Results: After 1 year, in those patients who did not start or stop statin therapy during the trial, metformin treatment significantly reduced total and LDL cholesterol by approximately 0.3 mmol/l compared with placebo (p = 0.021 and p = 0.018 respectively). Adjustment for statin use or known cardiovascular disease did not change conclusions. In statin users (metformin: n = 22, placebo: n = 13), metformin significantly lowered levels of LDL and non‐HDL cholesterol by approximately 0.5 mmol/l compared with placebo (adjusted for changes in statin dose or agent: p = 0.048 and p = 0.033 respectively). HbA1c (previously reported) was not significant different between treatments.

Conclusion: In patients with poorly controlled T1DM, at similar glycaemic levels, adjunct metformin therapy during 1 year significantly lowered levels of proatherogenic cholesterolaemia independent of statin therapy.
The dentition of Goodrichthys, a Carboniferous ctenacanthiform shark from Scotland
Authors: Ginter Michal
Published: June 2009

Study of three sets of chondrichthyan teeth from the Mississippian (Viséan) of Glencartholm, Scotland, namely the dentition of the holotype of a ctenacanthiform shark Goodrichthys eskdalensis, the dentition of a recently found, yet undescribed shark (NMS 2000.14.2), and a group of isolated teeth probably found in a nodule, tentatively suggests that all of them represent the same species. The combined characters of these teeth show that the dentition of Goodrichthys was moderately heterodont, of a cladodont design, in which larger teeth may have had three, and smaller ones only two, lateral cusps on each side of a prominent, coarsely cristated median cusp. The base is similar to that of Cladodus and Famennian representatives of Ctenacanthus, with a prominent, undivided basolabial shelf and an almost straight orolingual ridge.
Dhammapada Traditions and Translations
Authors: FRIEDLANDER PETER GERARD
Published: June 2009

The Dhammapada is probably the most frequently translated Buddhist text in the world today. This article looks at the history of translations of the Dhammapada since it was first translated into English in the nineteenth century. I start by comparing the little known first English translation by Daniel Gogerly from 1840 with the influential 1870 translation by Max Müller. The paper then examines the main translations which have appeared since the mid‐twentieth century. I show how they represent Buddhist, Hindu and other views on the Dhammapada and that they continue to be influenced by the pioneering nineteenth‐century translations. I argue that translations of the Dhammapada are conditioned not only by the viewpoints of the translators but also by the existence of a tradition of translating the Dhammapada. Both factors I conclude have contributed to the importance placed on the Dhammapada as a representative Buddhist text.
The Risk Microstructure of Corporate Bonds: A Case Study from the German Corporate Bond Market
Authors: Frühwirth Manfred , Schneider Paul , Sögner Leopold
Published: June 2009

This article presents joint econometric analysis of interest rate risk, issuer‐specific risk (credit risk) and bond‐specific risk (liquidity risk) in a reduced‐form framework. We estimate issuer‐specific and bond‐specific risk from corporate bond data in the German market. We find that bond‐specific risk plays a crucial role in the pricing of corporate bonds. We observe substantial differences between different bonds with respect to the relative influence of issuer‐specific vs. bond‐specific spread on the level and the volatility of the total spread. Issuer‐specific risk exhibits strong autocorrelation and a strong impact of weekday effects, the level of the risk‐free term structure and the debt to value ratio. Moreover, we can observe some impact of the stock market volatility, the respective stock's return and the distance to default. For the bond‐specific risk we find strong autocorrelation, some impact of the stock market index, the stock market volatility, weekday effects and monthly effects as well as a very weak impact of the risk‐free term structure and the specific stock's return. Altogether, the determinants of the spread components vary strongly between different bonds/issuers.
Does Fiscal Stress Induce Privatization? Correlates of Private and Intermunicipal Contracting, 1992–2002
Authors: ZULLO ROLAND
Published: June 2009

Using Census of Governments data, preferences for private and intermunicipal contracting by U.S. counties during the 1992–2002 period are modeled as a function of established economic and political factors. After distinguishing between private and intermunicipal contracting, there is no evidence that fiscal stress induces privatization. High debt levels are associated with fewer publicly delivered services, but counties with high debt are as likely to partner with neighboring municipalities as they are with private firms. Political factors are weak predictors of either form of contracting. The strongest and most reliable predictor of both private and intermunicipal contracting is the creation of new public services. These findings imply the strategic use of contracting for trial, temporary, or contingent services.
Institutional Change in the International Governance of Agriculture: A Revised Account
Authors: KAY ADRIAN , ACKRILL ROBERT
Published: June 2009

This article traces the evolution of the international governance of agriculture as a sequential process, in which the negotiation of new trading and enforcement rules interacts with legal disputes over the interpretation of existing rules. The interaction between negotiation and litigation has produced a governance trajectory from vague to precise commitments and a strengthened dispute settlement process. We contest standard histories, which identify the Uruguay Round Agreement on Agriculture as the singular event that established agriculture for the first time under the auspices of the World Trade Organization and which claim this represents the legalization of the agricultural trade regime. The case of agriculture contains important lessons for broader debates on international governance by articulating: (1) dynamic feedback processes, challenging the view that bargaining and enforcement aspects of international agreements are concluded simultaneously, and (2) key mechanisms underlying the greater precision of institutional commitments that tend to emerge over time.
Modelling the dynamic biogeography of the wildcat: implications for taxonomy and conservation
Authors: Kitchener A. C. , Rees E. E.
Published: June 2009

There is still no clear consensus on how to relate geographical variation in the morphology and genetics of the globally widespread wildcatFelis silvestristo its taxonomy and systematics. Reconstructing the dynamic biogeography of the wildcat provides insight into how current geographical patterns of morphological and molecular variation may have developed. A geographical information system was used to infer climate‐change influences using a deduced distribution model (DDM) to reconstruct the wildcat's geographical distribution at four points in time from the Last Glacial Maximum [LGM; 18 000 years before present (bp)] until today. The DDM for 9000 bp, when mean global temperatures were 2 °C more than today, provides insight into how current global warming will affect the wildcat's distribution 50–100 years into future. Modelled distributions were assessed against known geographical barriers or unsuitable habitats, which may have separated populations and led to known morphological and genetic divergence. The DDMtodaycorresponds well with known contemporary wildcat distribution records, except where wildcats would be expected to be excluded (e.g. high human population densities, potential competitors, inaccessible islands). The DDMtodayalso corresponds closely with the results of recent studies on skull morphometrics and phylogeography, which support hypothesized colonizations of Africa and Asia from Europe during the late Pleistocene. Although DDM palaeo‐distributions are more uncertain, they correspond to expected dramatic declines in northern Eurasia during the LGM, and significant distributional decline in central Asia, the Sahara and southern Africa, owing to increased aridity during climate cooling. From the DDM9000model moderate global warming is hypothesized to impact minimally on wildcats, except in the Middle East and south‐west Asia.
Effects of AT1 receptor and beta1 receptor blocking on blood pressure, peripheral hemodynamic and lipid profile in statin‐treated hypertensive hypercholesterolemic patients
Authors: Cicero Arrigo F.G. , Veronesi Maddalena , Prandin Maria Grazia , Di Gregori Valentina , Ambrosioni Ettore , Borghi Claudio
Published: June 2009

Recent evidences suggest a relationship between angiotensin 1 (AT1) receptor gene expression and low density lipoprotein cholesterol (LDL‐C) plasma level. We enrolled 16 untreated hypertensive hypercholesterolemic patients (57.4 ± 7 years old) in a randomized, single‐blind, cross‐over design. All the patients were allocated to treatment with simvastatin 20 mg/day for 2 weeks, then randomly assigned to telmisartan (40–80 mg/day) or bisoprolol (5–10 mg/day). After 4 weeks the antihypertensive drugs have been withdrawn for a wash‐out period of 2 weeks when they were treated with simvastatin alone, then they have been allocated to the alternative antihypertensive treatment for four additional weeks. We measured: systolic (SBP) and diastolic BP (DBP), 24‐h mean BP (MBP), Baseline and post‐ischemia forearm blood flow (FBF) and vascular resistance (FVR), and Lipid profile. After 2 weeks of treatment with Simvastatin, baseline and post‐ischemic FBF increased (both P < 0.05), while baseline and post‐ischemic FVR decreased (both P < 0.05). Standing DBP and MBP were reduced more after treatment with telmisartan than with bisoprolol (P < 0.05). Basal and post‐ischemic FBF were significantly increased (P < 0.05 and P < 0.005, respectively) and basal and post‐ischemic FVR significantly decreased (both P < 0.005) only after treatment with telmisartan, as well as plasma triglycerides (TG) (P < 0.05). From this preliminary study carried out on hypercholesterolemic hypertensive patients it appears that the association of telmisartan and simvastatin (but not of bisoprolol and simvastatin) could exert positive effects on a large quantity of vascular functionality parameters, just after a short treatment.
Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants
Authors: Park Sang‐Kyu , Kim Kyoungmi , Page Grier P. , Allison David B. , Weindruch Richard , Prolla Tomas A.
Published: June 2009

We used DNA microarrays to identify panels of transcriptional markers of aging that are differentially expressed in young (5 month) and old (25 month) mice of multiple inbred strains (129sv, BALB/c, CBA, DBA, B6, C3H and B6C3F1). In the heart, age‐related changes of five genes were studied throughout the mouse lifespan: complement component 4, chemokine ligand 14, component of Sp100‐rs, phenylalanine hydroxylase and src family associated phosphoprotein 2. A similar analysis in the brain (cerebellum) involved complement component 1q (alpha polypeptide), complement component 4, P lysozyme structural, glial fibrillary acidic protein and cathepsin S. Caloric restriction (CR) inhibited age‐related expression of these genes in both tissues. Parametric analysis of gene set enrichment identified several biological processes that are induced with aging in multiple mouse strains. We also tested the ability of dietary antioxidants to oppose these transcriptional markers of aging. Lycopene, resveratrol, acetyl‐l‐carnitine and tempol were as effective as CR in the heart, and α‐lipoic acid and coenzyme Q10 were as effective as CR in the cerebellum. These findings suggest that transcriptional biomarkers of aging in mice can be used to estimate the efficacy of aging interventions on a tissue‐specific basis.
A pseudo‐stochastic approach for optimal decision making under limited information: a case of an aggregate production system
Authors: Herbon Avi , Khmelnitsky Eugene
Published: June 2009

In this study, which is both analytical and numerical, we compute the effective information horizon (EIH), i.e., the minimal time interval over which future information is relevant for optimal control and for measuring the performance of a single part‐type production system. Optimal control modeling and process solving, which consider aspects of decision making with limited forecast, are exemplified by a single part‐type production system. Specifically, the analysis reveals practical situations in which there is both a performance loss as well as feasibility violation when only information expected within the planning horizon is considered. The analysis is carried out by developing a pseudo‐stochastic model. We follow previous “pseudo‐stochastic” approaches that solve stochastic control problems by using deterministic, optimal control methods. However, we model the expected influences of all future events, including those that are beyond the planning horizon, as encapsulated by their density functions and not only by their mean values.
Drug‐induced QT interval shortening: potential harbinger of proarrhythmia and regulatory perspectives
Authors: Shah Rashmi R
Published: June 2009

ATP‐dependent potassium channel openers such as pinacidil and levcromakalim have long been known to shorten action potential duration and to be profibrillatory in non‐clinical models, raising concerns on the clinical safety of drugs that shorten QT interval. Routine non‐clinical evaluation of new drugs for their potential to affect cardiac repolarization has revealed that drugs may also shorten QT interval. The description of congenital short QT syndrome in 2000, together with the associated arrhythmias, suggests that drug‐induced short QT interval may be proarrhythmic, and an uncanny parallel is evolving between our appreciation of the short and the long QT intervals. Epidemiological studies report an over‐representation of short QT interval values in patients with idiopathic ventricular fibrillation. Therefore, as new compounds that shorten QT interval are progressed further into clinical development, questions will inevitably arise on their safety. Arising from the current risk‐averse clinical and regulatory environment and concerns on proarrhythmic safety of drugs, together with our lack of a better understanding of the clinical significance of short QT interval, new drugs that substantially shorten QT interval will likely receive an unfavourable regulatory review unless these drugs fulfil an unmet clinical need. This review provides estimates of parameters of QT shortening that may be of potential clinical significance. Rufinamide, a recently approved anticonvulsant, illustrates the current regulatory approach to drugs that shorten QT interval. However, to further substantiate or confirm the safety of these drugs, their approval may well be conditional upon large‐scale post‐marketing studies with a focus on cardiac safety.

This article is commented on by Malik, pp. 70–76 of this issue and is part of a themed section on QT safety. To view this issue visithttp://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010
Induction of a reversible, non‐cytotoxic S‐phase delay by resveratrol: implications for a mechanism of lifespan prolongation and cancer protection
Authors: Zhou Ru , Fukui Masayuki , Choi Hye Joung , Zhu Bao Ting
Published: June 2009

Background and purpose:  Resveratrol (RES) has been shown to prolong lifespan and prevent cancer formation. At present, the precise cellular mechanisms of RES actions are still not clearly understood, and this is the focus of this study.

Experimental approach:  Using human hepatocellular carcinoma‐derived HepG2 cells as a model, we studied RES‐induced changes in cell growth, cell cycle progression and apoptosis.

Key results:  RES at lower concentrations induced a strong but reversible S‐phase delay and mild DNA synthesis inhibition, yet without causing apoptotic or necrotic cell death. At high concentrations, RES induced apoptosis, which is mainly mediated by the mitochondrial pathway. Overall, RES was a relatively weak apoptotic agent. Mechanistically, MEK inhibition was identified as an important early signalling event for RES‐induced apoptosis. In comparison, activation of CDK2 and checkpoint kinase 2, and inhibition of phosphatidylinositol 3′‐kinase/Akt signalling pathway contributed to the induction by RES of a reversible, non‐cytotoxic S‐phase delay.

Conclusion and implications:  It is hypothesized that the induction of a non‐cytotoxic S‐phase delay may represent a useful mechanistic strategy for lifespan prolongation and cancer prevention. When cell cycles are selectively slowed down in the S phase, it would cumulatively increase the total lifespan of an organism if the total numbers of cell divisions of a given organism are assumed to remain basically constant. Likewise, when cells proceed through the cell cycles at a reduced pace during DNA replication, it may allow cells more time to repair the damaged DNA, and thereby reduce the chances for mutagenesis and tumour initiation.
Sphingolipids in inflammation: pathological implications and potential therapeutic targets
Authors: Nixon Graeme F.
Published: June 2009

Sphingolipids are formed via the metabolism of sphingomyelin, a constituent of the plasma membrane, or by de novo synthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1‐phosphate and sphingosine 1‐phosphate (S1P), are likely to have an integral role in inflammation. This can involve, for example, activation of pro‐inflammatory transcription factors in different cell types and induction of cyclooxygenase‐2, leading to production of pro‐inflammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide‐rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high‐affinity G‐protein‐coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on inflammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in inflammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and inflammatory bowel disease, which involve important inflammatory components. A significant body of research now indicates that sphingolipids are intimately involved in the inflammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological inflammation.

This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Analysis of binding site for the novel small‐molecule TLR4 signal transduction inhibitor TAK‐242 and its therapeutic effect on mouse sepsis model
Authors: Takashima K , Matsunaga N , Yoshimatsu M , Hazeki K , Kaisho T , Uekata M , Hazeki O , Akira S , Iizawa Y , Ii M
Published: June 2009

Background and purpose:  TAK‐242, a novel synthetic small‐molecule, suppresses production of multiple cytokines by inhibiting Toll‐like receptor (TLR) 4 signalling. In this study, we investigated the target molecule of TAK‐242 and examined its therapeutic effect in a mouse sepsis model.

Experimental approach:  Binding assay with [3H]‐TAK‐242 and nuclear factor‐κB reporter assay were used to identify the target molecule and binding site of TAK‐242. Bacillus calmette guerin (BCG)‐primed mouse sepsis model using live Escherichia coli was used to estimate the efficacy of TAK‐242 in sepsis.

Key results:  TAK‐242 strongly bound to TLR4, but binding to TLR2, 3, 5, 9, TLR‐related adaptor molecules and MD‐2 was either not observed or marginal. Mutational analysis using TLR4 mutants indicated that TAK‐242 inhibits TLR4 signalling by binding to Cys747 in the intracellular domain of TLR4. TAK‐242 inhibited MyD88‐independent pathway as well as MyD88‐dependent pathway and its inhibitory effect was largely unaffected by lipopolysaccharide (LPS) concentration and types of TLR4 ligands. TAK‐242 had no effect on the LPS‐induced conformational change of TLR4‐MD‐2 and TLR4 homodimerization. In mouse sepsis model, although TAK‐242 alone did not affect bacterial counts in blood, if co‐administered with ceftazidime it inhibited the increases in serum cytokine levels and improved survival of mice.

Conclusions and implications:  TAK‐242 suppressed TLR4 signalling by binding directly to a specific amino acid Cys747 in the intracellular domain of TLR4. When co‐administered with antibiotics, TAK‐242 showed potent therapeutic effects in an E. coli‐induced sepsis model using BCG‐primed mice. Thus, TAK‐242 may be a promising therapeutic agent for sepsis.
Pals‐associated tight junction protein functionally links dopamine and angiotensin II to the regulation of sodium transport in renal epithelial cells
Authors: Chen Z , Leibiger I , Katz AI , Bertorello AM
Published: June 2009

Background and purpose:  Dopamine inhibits renal cell Na+,K+‐ATPase activity and cell sodium transport by promoting the internalization of active molecules from the plasma membrane, whereas angiotensin II (ATII) stimulates its activity by recruiting new molecules to the plasma membrane. They achieve such effects by activating multiple and distinct signalling molecules in a hierarchical manner. The purpose of this study was to investigate whether dopamine and ATII utilize scaffold organizer proteins as components of their signalling networks, in order to avoid deleterious cross talk.

Experimental approach:  Attention was focused on a multiple PDZ domain protein, Pals‐associated tight junction protein (PATJ). Ectopic expression of PATJ in renal epithelial cells in culture was used to study its interaction with components of the dopamine signalling cascade. Similarly, expression of PATJ deletion mutants was employed to analyse its functional relevance during dopamine‐, ATII‐ and insulin‐dependent regulation of Na+,K+‐ATPase.

Key results:  Dopamine receptors and components of its signalling cascade mediating inhibition of Na+,K+‐ATPase interact with PATJ. Inhibition of Na+,K+‐ATPase by dopamine was prevented by expression of mutants of PATJ lacking PDZ domains 2, 4 or 5; whereas the stimulatory effect of ATII and insulin on Na+,K+‐ATPase was blocked by expression of PATJ lacking PDZ domains 1, 4 or 5.

Conclusions and implications:  A multiple PDZ domain protein may add functionality to G protein‐coupled and tyrosine kinase receptors signalling during regulation of Na+,K+‐ATPase. Signalling molecules and effectors can be integrated into a functional network by the scaffold organizer protein PATJ via its multiple PDZ domains.
The phospholipase A2 inhibitor methyl indoxam suppresses diet‐induced obesity and glucose intolerance in mice
Authors: Hui DY , Cope MJ , Labonté ED , Chang H‐T , Shao J , Goka E , Abousalham A , Charmot D , Buysse J
Published: June 2009

Background and purpose:  Previous results have shown that mice lacking in the group 1B phospholipase A2 (Pla2g1b) are resistant to obesity and diabetes induced by feeding a diabetogenic high‐fat/high‐carbohydrate diet. This study examined the potential of using the Pla2g1b inhibitor methyl indoxam as therapy to suppress diet‐induced obesity and diabetes.

Experimental approach:  Male C57BL/6 mice were fed the diabetogenic diet with or without methyl indoxam supplementation. Body weight gain, fasting plasma glucose levels, glucose tolerance and postprandial lysophospholipid absorption were compared.

Key results:  Wild‐type C57BL/6 mice fed the diabetogenic diet without Pla2g1b inhibitor showed 31 and 69% body weight gain after 4 and 10 weeks respectively. These animals also showed elevated plasma glucose levels and were glucose intolerant. In contrast, C57BL/6 mice fed the diabetogenic diet with 90 mg·kg−1 of methyl indoxam gained only 5% body weight after 10 weeks. These animals were also euglycaemic and displayed normal glucose excursion rates in glucose tolerance test. Methyl indoxam suppression of diet‐induced body weight gain and glucose intolerance was correlated with the inhibition of Pla2g1b‐mediated postprandial lysophospholipid absorption.

Conclusions and implications:  These results show that oral supplementation of a diabetogenic diet with the Pla2g1b inhibitor methyl indoxam effectively suppresses diet‐induced obesity and diabetes in mice. This suggests that Pla2g1b inhibition may be a potentially effective oral therapeutic option for treatment of obesity and diabetes.
Dinucleoside polyphosphates: strong endogenous agonists of the purinergic system
Authors: Jankowski Vera , Van Der Giet Markus , Mischak Harald , Morgan Michael , Zidek Walter , Jankowski Joachim
Published: June 2009

The purinergic system is composed of mononucleosides, mononucleoside polyphosphates and dinucleoside polyphosphates as agonists, as well as the respective purinergic receptors. Interest in the role of the purinergic system in cardiovascular physiology and pathophysiology is on the rise. This review focuses on the overall impact of dinucleoside polyphosphates in the purinergic system. Platelets, adrenal glands, endothelial cells, cardiomyocytes and tubular cells release dinucleoside polyphosphates. Plasma concentrations of dinucleoside polyphosphates are sufficient to cause direct vasoregulatory effects and to induce proliferative effects on vascular smooth muscle cells and mesangial cells. In addition, increased plasma concentrations of a dinucleoside polyphosphate were recently demonstrated in juvenile hypertensive patients. In conclusion, the current literature accentuates the strong physiological and pathophysiological impact of dinucleoside polyphosphates on the cardiovascular system.
Reconciling people's livelihoods and environmental conservation in the rural landscapes in Kenya: Opportunities and challenges in the Amboseli landscapes
Authors: Okello Moses Makonjio , Ole Seno Simon K. , Nthiga Rita Wairimu
Published: June 2009

Two of the eight Millennium Development Goals (MDGs) adopted by the United Nations General Assembly in September 2000 are: eradication of extreme poverty and hunger; and ensuring environmental sustainability. The link between depressed livelihoods and unsustainable use of land and natural resources can be seen in Kenyan rangelands. Here, the local community is dependent on land and its resources for livelihoods, but the demand and competition is increasing, endangering both the resources they depend on and threatening environmental health. Amboseli is an Arid and Semi‐Arid Land (ASAL) area that experiences ecological constraints, resource limitations, and low economic investment. Local communities in such landscapes are resource‐dependent for their daily livelihoods, and have few socio‐economic opportunities. Pastoralism, which is the main source of their wealth, continues to decline and exploitation by a few local elites and poor local leadership further depresses livelihoods. Other challenges to these poor rural landscapes are increasing human population which increases demands on natural resources and environment; persistent hunger; low universal primary education; poor gender equality and empowerment of women; environmental degradation; and lack of local and global partnership for development. This paper focuses on the two Millennium Development Goals mentioned above. Linkages, challenges and opportunities in enhancing rural livelihoods while promoting environmental sustainability in rural landscapes of the Amboseli Rural Landscape are discussed.
Salt‐induced land and water degradation in the Aral Sea basin: A challenge to sustainable agriculture in Central Asia
Authors: Qadir Manzoor , Noble Andrew D. , Qureshi Asad S. , Gupta Raj K. , Yuldashev Tulkun , Karimov Akmal
Published: June 2009

Expansion of irrigated agriculture in the Aral Sea Basin in the second half of the twentieth century led to the conversion of vast tracks of virgin land into productive agricultural systems resulting in significant increases in employment opportunities and income generation. The positive effects of the development of irrigated agriculture were replete with serious environmental implications. Excessive use of irrigation water coupled with inadequate drainage systems has caused large‐scale land degradation and water quality deterioration in downstream parts of the basin, which is fed by two main rivers, the Amu‐Darya and Syr‐Darya. Recent estimates suggest that more than 50% of irrigated soils are salt‐affected and/or waterlogged in Central Asia. Considering the availability of natural and human resources in the Aral Sea Basin as well as the recent research addressing soil and water management, there is cause for cautious optimism. Research‐based interventions that have shown significant promise in addressing this impasse include: (1) rehabilitation of abandoned salt‐affected lands through halophytic plant species; (2) introduction of 35‐day‐old early maturing rice varieties to withstand ambient soil and irrigation water salinity; (3) productivity enhancement of high‐magnesium soils and water resources through calcium‐based soil amendments; (4) use of certain tree species as biological pumps to lower elevated groundwater levels in waterlogged areas; (5) optimal use of fertilizers, particularly those supplying nitrogen, to mitigate the adverse effects of soil and irrigation water salinity; (6) mulching of furrows under saline conditions to reduce evaporation and salinity buildup in the root zone; and (7) establishment of multipurpose tree and shrub species for biomass and renewable energy production. Because of water withdrawals for agriculture from two main transboundary rivers in the Aral Sea Basin, there would be a need for policy level interventions conducive for enhancing interstate cooperation to transform salt‐affected soil and saline water resources from an environmental and productivity constraint into an economic asset.
The miombo woodlands at the cross roads: Potential threats, sustainable livelihoods, policy gaps and challenges
Authors: Syampungani Stephen , Chirwa Paxie W. , Akinnifesi Festus K. , Sileshi Gudeta , Ajayi Oluyede C.
Published: June 2009

The Miombo, the most extensive tropical woodland formation of Africa directly supports the livelihoods of over 100 million people through the provision of many tree products and ecosystem services essential to both the rural and urban communities. While the destruction of the Miombo has often been blamed on the rural communities dwelling near the forest resources, many urban dwellers depend heavily on the various products derived from the woodlands. This paper highlights the importance of the Miombo in the livelihoods of rural people, the potential threats to this ecosystem and opportunities for its sustainable management. About 70% of energy consumed in southern Africa is in the form of fuelwood or charcoal. The economic importance of the Miombo especially from non‐timber forest products (NTFPs) is usually understated due to their perceived non‐economic value yet they play an important role in sustaining livelihoods of forest dependent people in the miombo ecoregion. The Miombo also contributes to health services through the use of medicinal plant and products, in some cases, contributing up to 80% to rural health, including helping in coping with effects of HIV/AIDS, malaria and several diseases. The possibility of developing payment for environmental services schemes through public–private partnerships, and community‐based sustainable management models are proposed. Through conservation and commercialization of some of the products and services, there is a potential to provide income and improve the livelihood of people involved in the trade along the value chain.
Treatment of Bleeding in Dialysis Patients
Authors: Galbusera Miriam , Remuzzi Giuseppe , Boccardo Paola
Published: June 2009

Bleeding is a common and potentially serious complication of acute and chronic renal failure. The pathogenesis of bleeding in uremia is multifactorial; however, the major role is played by abnormalities in platelet–platelet and platelet–vessel wall interaction. Platelet dysfunction is partially due to uremic toxins present in circulating blood. Despite decreased platelet function, abnormalities of blood coagulation and fibrinolysis predispose the uremic patients to a hypercoagulable state carrying the risk of cardiovascular and thrombotic complications. Dialysis improves platelet abnormalities and reduces, but does not eliminate, the risk of hemorrhage. Hemodialysis can even contribute to the bleeding through the continuous platelet activation induced by the interaction between blood and artificial surfaces and the use of anticoagulants. Correction of anemia improves hemostasis in uremic patients. Therapeutic management of bleeding in patients with uremia is discussed.
Beyond The Current Paradigm: Recent Advances in The Understanding of Sodium Handling – Guest Editors: Stanley Shaldon and Joerg Vienken: Hyperosmolar Sodium Chloride, p38 Mitogen Activated Protein and Cytokine‐Mediated Inflammation
Authors: Dinarello Charles A.
Published: June 2009

Although there is increasing clinical evidence that high salt intake contributes to cardiovascular events and deaths seemingly independent of hypertension, the molecular mechanism for increased atherogenesis remains unclear. Vessel wall inflammation secondary to proinflammatory cytokines is one mechanism for atherogenesis. The role of mitogen activated protein kinase (MAPK) p38 in cytokine production such as IL‐1, TNF‐α, and IL‐8 are well established. The link between inflammation and salt intake likely includes p38 MAPK as hyperosmolar sodium chloride triggers phosphorylation of p38 MAPK and stimulates gene expression and synthesis of proinflammatory cytokines. Hence a possible link of high salt intake, inflammation, and atherogenesis may be one molecular mechanism for the association of high salt intake and cardiovascular events.
Beyond The Current Paradigm: Recent Advances in The Understanding of Sodium Handling – Guest Editors: Stanley Shaldon and Joerg Vienken: Water‐Free Sodium Accumulation
Authors: Titze Jens
Published: June 2009

The widely accepted concept of body fluid and electrolyte homeostasis is that Na+ is restricted mainly to the extracellular fluid and K+ to the intracellular space, where both ions act to hold water and thereby control the extracellular and intracellular fluid volume by their osmotic activity. Na+ accumulation thus inevitably leads to water retention. The constancy of the extracellular volume is the task of the kidneys, which control the total body Na+ content. More recent data have questioned this traditional view, suggesting that large amounts of Na+ can be accumulated without accompanying water retention by osmotically inactive Na+ retention, or by osmotically neutral Na+/K+ exchange. Besides the control of the body Na+ content by the kidneys, redistribution of body electrolytes hence provides an extrarenal regulatory alternative in the maintenance of body fluid volume and blood pressure control.
Beyond The Current Paradigm: Recent Advances in The Understanding of Sodium Handling – Guest Editors: Stanley Shaldon and Joerg Vienken: Reducing Sodium Intake in Hemodialysis Patients
Authors: Lindley Elizabeth J.
Published: June 2009

A low salt diet is beneficial for the whole population but has particular advantages for hemodialyis patients because of the role of salt restriction in the management of hypertension and interdialytic weight gain (IDWG). Education on dietary salt intake based on general healthy eating guidelines, such as the “DASH‐sodium” diet, should be provided for staff, families, and carers as well as patients. Anuric hemodialysis patients will need to take in approximately 1 l of water for every 8 g salt consumed. Patients who restrict salt intake to <6 g/day, and drink only when thirsty, should gain no more than 0.8 kg/day. Those with significantly greater weight gains, but predialysis serum sodium close to or higher than the dialysate sodium, need further review of their salt intake. Attempts to restrict fluid intake in these patients will be futile. Patients with high interdialytic weight gain (IDWG) and low predialysis sodium should be assessed for other reasons for fluid intake, such as high blood glucose or social drinking. For patients with poor tolerance of fluid removal during dialysis, and those who are hypertensive in the absence of fluid overload, a salt intake 5 g/day or less may be required. Dietary advice for these patients should be customized to ensure that they do not become malnourished.