bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells
Authors: Sekido Yoshitaka
Published: September 2009

Malignant mesothelioma (MM) is a tumor with poor prognosis associated with asbestos exposure. While it remains to be clarified how asbestos fibers confer genetic/epigenetic alterations and induce cellular transformation in normal mesothelial cells, the understanding of key molecular mechanisms of MM cell development, proliferation, and invasion has progressed. MM shows frequent genetic inactivation of tumor suppressor genes of p16INK4a/p14ARF and neurofibromatosis type 2 (NF2) which encodes Merlin, and epigenetic inactivation of RASSF1A. However, no frequent mutations of well‐known oncogenes such as K‐RAS and PIK3CA have been identified. Activation of multiple receptor tyrosine kinases including the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen‐activated protein kinase (MAPK) and phosphatidylinositol‐3‐kinase (PI3K)–AKT signaling cascades are frequently observed in most MM cells. The tumor suppressive function of Merlin in MM cells is also being investigated by dissecting its possible downstream signaling cascade called the Hippo pathway. Further comprehensive delineation of dysregulated signaling cascades in MM cells will lead to identification of key addiction pathways for cell survival and proliferation of MM cells, which strongly promote establishment of a new molecular target therapy for MM. (Cancer Sci 2009)
Oral delivery of tumor‐targeting Salmonella exhibits promising therapeutic efficacy and low toxicity
Authors: Chen Guo , Wei Dong‐Ping , Jia Li‐Jun , Tang Bo , Shu Luan , Zhang Kui , Xu Yun , Gao Jing , Huang Xiao‐Feng , Jiang Wen‐Hui , Hu Qin‐Gang , Huang Yan , Wu Qiang , Sun Zhi‐Hua , Zhang Jian‐Fa , Hua Zi‐Chun
Published: September 2009

Tumor‐targeting bacteria have been developed as powerful anticancer agents. Salmonella typhimurium VNP20009, a representative tumor‐targeting strain, has been systemically administered as a single‐agent therapy at doses of 1 × 106 to 3 × 106 colony‐forming unit (cfu)/mouse, or in combination with other antitumor agents at doses of 1 × 104 to 2 × 105 cfu/mouse. Recently, we reported that oral delivery of VNP20009 at the dose of 1 × 109 cfu/mouse induced significant anticancer effects comparable to that induced by systemic administration of this strain at 1 × 104 cfu/mouse. To further address the efficacy and safety of oral administration of bacteria, here we performed a systemically comparative analysis of anticancer efficacy and toxicity of VNP20009 administered: (i) orally at a dose of 1 × 109 cfu/mouse (VNP9‐oral); (ii) intraperitoneally at a dose of 1 × 104 cfu/mouse (VNP4‐i.p.); or (iii) intraperitoneally at a dose of 1 × 106 cfu/mouse in tumor‐free and tumor‐bearing murine models. The results showed that VNP9‐oral, similar to VNP4‐i.p., induced significant tumor growth inhibition whereas VNP6‐i.p. induced better anticancer effect in the B16F10 melanoma model. Among three treatments, VNP9‐oral induced the mildest and reversible toxicity whereas VNP6‐i.p. resulted in the most serious and irreversible toxicities when compared to other two treatments. Moreover, the combination of VNP9‐oral with a low dose of chemotherapeutics produced comparable antitumor effects but displayed significantly reduced toxicity when compared to VNP6‐i.p. The findings demonstrated that oral administration, as a novel avenue in the application of bacteria, is highly safe and effective. Moreover, the present preclinical study should facilitate the optimization of bacterial therapies with improved anticancer efficacy and reduced adverse effects in future clinical trials. (Cancer Sci 2009; 100: 2437–2443)
From bacterial avirulence genes to effector functions via the hrp delivery system: an overview of 25 years of progress in our understanding of plant innate immunity
Authors: MANSFIELD JOHN W.
Published: September 2009

Cloning the first avirulence (avr) gene has led not only to a deeper understanding of gene‐for‐gene interactions in plant disease, but also to fundamental insights into the suppression of basal defences against microbial attack. This article (focusing on Pseudomonas syringae) charts the development of ideas and research progress over the 25 years following the breakthrough achieved by Staskawicz and coworkers. Advances in gene cloning technology underpinned the identification of both avr and hrp genes, the latter being required for the activation of the defensive hypersensitive reaction (HR) and pathogenicity. The delivery of Avr proteins through the type III secretion machinery encoded by hrp gene clusters was demonstrated, and the activity of the proteins inside plant cells as elicitors of the HR was confirmed. Key roles for avr genes in pathogenic fitness have now been established. The rebranding of Avr proteins as effectors, proteins that suppress the HR and cell wall‐based defences, has led to the ongoing search for their targets, and is generating new insights into the co‐ordination of plant resistance against diverse microbes. Bioinformatics‐led analysis of effector gene distribution in genomes has provided a remarkable view of the interchange of effectors and also their functional domains, as the arms race of attack and defence drives the evolution of microbial pathogenicity. The application of our accrued knowledge for the development of disease control strategies is considered.
Expression of pathogenesis‐related protein PR‐10 in sorghum floral tissues in response to inoculation with Fusarium thapsinum and Curvularia lunata
Authors: KATILÉ SERIBA O. , PERUMAL RAMASAMY , ROONEY WILLIAM L. , PROM LOUIS K. , MAGILL CLINT W.
Published: September 2009

Differences in grain mould disease levels among different sorghum varieties grown in the same environment imply that host genes play a role in controlling disease severity. The fungi most often recovered from naturally infected sorghum grain, Fusarium thapsinum and Curvularia lunata, were used to inoculate a set of resistant and susceptible cultivars at anthesis in both field and glasshouse trials. In the field, 12 cultivars were inoculated with a mixture of F. thapsinum and C. lunata and, in the glasshouse, individual panicles from four selected cultivars were inoculated with spore suspensions of C. lunata, F. thapsinum, a mixture of the two or water to serve as a control. Based on grain mould severity ratings and germination tests on the seed from the field trial, Tx2911, Sureno, SC719‐11E and SC650‐11E displayed a high level of resistance to grain mould. To determine whether resistant and susceptible lines differed in response to the pathogens, PR‐10 mRNA levels were measured using real‐time reverse transcriptase‐polymerase chain reaction. PR‐10 is a protein with antifungal properties that has been associated with defence responses in sorghum and other plant species. In field tests, most, but not all, cultivars showed significant induction of normalized relative quantities of PR‐10 after dual inoculation with spores of both C. lunata and F. thapsinum. Under glasshouse‐controlled conditions, glumes of inoculated plants showed the clear induction of PR‐10 mRNA, and the response was greater in resistant (Tx2911 and Sureno) than in susceptible (RTx430 and SC170‐6‐17) cultivars. Inoculation with spores from a single mould‐inducing pathogen generally induced greater responses than when spores were combined. For RTx430, SC170‐6‐17 and Sureno, the response to C. lunata was greater, whereas Tx2911 showed a stronger response to F. thapsinum. The results indicate that the induction of PR‐10 in sorghum glumes may be a factor useful in breeding programmes designed to combine multiple factors for resistance.
Escape of farmed tilapiines into the wild and entry of wild forms in fishponds, and the possible interactions between wild and farmed tilapiines from a sample of smallholder farms in Central Uganda
Authors: Mwanja Matthew Tenywa , Mwanja Wilson Waiswa
Published: September 2009

Seven smallholder fishponds in central Uganda were studied between 2000 and 2001 to investigate the interaction of farmed tilapiines with their wild conspecifics. Emphasis was on the features that facilitate escape of fish and/or entry of fish into the farms and interactions between the farmed and the wild. These included number of species, source of seed, connection between pond and natural watercourses, purpose of the farm, destination of cultured fish and interaction between farmed and wild fish. Fishponds had no screens against entry of wild fish into the farm or escape of farmed fish into the wild and occurred within wetlands close to natural watercourses. Ponds stocked with one fish species were found to have multispecies with some individuals that were apparently intermediate morphs between the species. Fry produced within the growout fishponds was shared with other farmers within and outside the watersheds. This study showed that smallholder farms with little or no control of escape or entry of fish out and into the fishponds, and little or no management present circumstances that facilitate continued movement of tilapiines within and across watersheds in Ugandan waters. The study also indicated possible genetic interaction between farmed and their wild conspecifics through interactions within fishponds.
Evaluation of the effectiveness of an early peripheral burning strategy in controlling wild fires in north‐western Zimbabwe
Authors: Mapaure Isaac , Campbell Bruce M. , Gambiza James
Published: September 2009

A review of the occurrence of wild fires in Sengwa Wildlife Research Area (SWRA), Zimbabwe, is presented for the period 1965–1993. The effectiveness and desirability of early burning of peripheral areas introduced in 1979 are evaluated. More than 75% of wild fires occurred between July and October, 48.6% of which originated from communal lands. Early burning of peripheral areas led to significant reductions in extent of areas burnt, from annual mean areas of 115 km2 (1965–1978) to 11 km2 (1979–1993) because of effective control of fires, which originated from communal lands. Some areas did not burn at all after 1979, and the overall probability of burning dropped from 0.484 to 0.187. Whilst it may be desirable to keep fires out of SWRA in the short term, fuel build‐ups increase the fire hazard resulting in negative consequences on biodiversity in the long term. Consideration should be given to combine peripheral burning with low‐intensity prescribed burning of selected blocks to keep a semblance of natural fire regimes to ensure the maintenance of biodiversity while simultaneously reducing the fire‐hazard. An integrated fire management plan should be put in place for SWRA.
Home ranges and survival of Nahan’s Francolin Francolinus nahani in Budongo Forest, Uganda
Authors: Sande Eric , Dranzoa Christine , Wegge Per , Carroll John P.
Published: September 2009

We studied home ranges, habitat use and survival of radio‐tagged Nahan’s Francolin in Budongo Forest Reserve, Uganda during July 1998–December 1999. We studied Nahan’s Francolin in an unlogged nature reserve, in a compartment logged in 1947–1952 and in a compartment logged twice, in 1963–1964 and 1996–1997. Mean home range was 14.22 ± 1.35 ha (n = 17). The home range was significantly larger in the nature reserve than in the recently logged compartment. Birds spent more time during the day in areas with high understorey vegetation density but preferred to roost and nest between buttresses of large trees. Understorey vegetation density and canopy openness were significantly greater in the logged forest than in the nature reserve. Annual survival of adult Nahan’s Francolins was 20.09 ± 7.33% (n = 23). Our results suggest that the maintenance of large trees and areas with high understorey vegetation density are both important for Nahan’s Francolin.
Natural regeneration and population dynamics of the tree Afzelia quanzensis in woodlands in Southern Africa
Authors: Gerhardt Karin , Todd Colleen
Published: September 2009

The logging of tree species of high commercial value is increasing throughout the African continent, yet the ecology of these species is generally poorly known. We studied the regeneration pattern and size class distribution of Afzelia quanzensis populations in northern South Africa over a 5‐year period. Recruitment was low as the annual seedling mortality was >65%. Seedlings were located under the canopy and were affected by drought and browsing. The adults were scattered or were in a clump‐dispersed pattern, which would result in higher recruitment of offspring near parents. Individuals of 0–10 cm diameter at breast height (DBH) were few, while there were 32 trees ha−1 at >10 cm DBH with an annual mortality of 0.8%. Annual diameter increments varied between 0.06 and 0.28 cm. It appears that the transition from the sapling into the juvenile stage could be a bottleneck in the regeneration of the species. A longer study, including more rainfall cycles, may reveal other patterns as dry and wet years have different impacts on dynamics.
An assessment of the puku (Kobus vardoniiLivingstone 1857) population at Lake Rukwa, Tanzania
Authors: Waltert Matthias , Chuwa Mark , Kiffner Christian
Published: September 2009

The population of puku,Kobus vardonii, at Lake Rukwa, one of only two in Tanzania, is poorly known. A multi‐species dry season game count carried out in Rukwa Game Reserve (RGR) in 2004 estimated a population size of 1729, but was associated with a high margin of error [coefficient of variation (CV) 0.88]. To increase the precision for the local puku population estimate, we conducted a zig‐zag line transect survey restricted only to areas occupied by puku in the dry season of 2006. This survey technique produced an estimate of 776 individuals and the CV was considerably reduced to 0.29. Puku herd size was comparable with the studies carried out in the Kilombero valley, Tanzania and in Kasanka National Park, Zambia, thus broadly confirming the herding ecology of this species. We found that pukus were restricted to the central parts of the floodplains, suggesting an avoidance of habitats used by pastoralists at the edge of RGR. Compared with the estimates of the puku population made in the 1980s, the puku population has declined. We recommend regular monitoring and enforcement of the current management plan to conserve the local puku population.
Rotterdam score predicts early mortality in Budd‐Chiari syndrome, and surgical shunting prolongs transplant‐free survival
Authors: MONTANO‐LOZA A. J. , TANDON P. , KNETEMAN N. , BAILEY R. , BAIN V. G.
Published: September 2009

Background  Budd–Chiari syndrome carries significant mortality, but factors predicting this outcome are uncertain.

Aim  To determine factors associated with 3‐month mortality and compare outcomes after surgical shunting or liver transplantation.

Methods  From 1985 to 2008, 51 patients with Budd–Chiari syndrome were identified.

Results  By logistic regression analysis, features associated with higher risk of 3‐month mortality were Rotterdam class III, Clichy >6.6, model for end‐stage liver disease (MELD) >20 and Child–Pugh C. Rotterdam class III had the best performance to discriminate 3‐month mortality with sensitivity of 0.89 and specificity of 0.63, whereas Clichy >6.60 had sensitivity of 0.78 and specificity of 0.69; MELD >20 had sensitivity of 0.78 and specificity of 0.75 and Child–Pugh C had sensitivity of 0.67 and specificity of 0.72. Eighteen patients underwent surgical shunts and 14 received liver transplantation with no significant differences in survival (median survival 10 ± 3 vs. 8 ± 2 years; log‐rank, P = 0.9).

Conclusions  Rotterdam score is the best discrimination index for 3‐month mortality in Budd–Chiari syndrome and should be used preferentially to determine treatment urgency. Surgical shunts constitute an important therapeutic modality that may help save liver grafts and prolong transplantation‐free survival in a selected group of patients with Budd–Chiari syndrome.
Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype
Authors: Scholz Ina , Oberwittler Heike , Riedel Klaus‐Dieter , Burhenne Jürgen , Weiss Johanna , Haefeli Walter E. , Mikus Gerd
Published: September 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Pharmacokinetic variability of voriconazole is largely caused by CYP3A4‐ and CYP2C19‐mediated metabolism.

• Oral bioavailability of voriconazole has been claimed to be almost 100%, thus facilitating a change from intravenous to oral application without dose adjustment.

WHAT THIS STUDY ADDS

• For the first time voriconazole exposure after intravenous and oral administration in relation to CYP2C19 activity is reported.

• In addition, the predominant metabolic pathway is the hydroxylation that seems to be influenced by the CYP2C19 genotype.

• Enterohepatic circulation of both hydroxylated metabolites must be anticipated.

AIMSThe aim was to determine the pharmacokinetics of voriconazole after a single oral dose in comparison with intravenous (i.v.) administration in healthy individuals stratified according to the cytochrome P450 (CYP) 2C19 genotype. In addition, the possible metabolic pathways and their modulation according to CYP2C19 genotype were investigated after oral and i.v. administration of voriconazole.

METHODSIn a single‐centre, open‐label, two‐period crossover study 20 participants received single doses of 400 mg voriconazole orally and 400 mg voriconazole intravenously in randomized order. Blood and urine samples were collected up to 96 h post dose and the voriconazole and three major metabolites were quantified by high‐performance liquid chromatography coupled to mass spectroscopy.

RESULTSAbsolute oral bioavailability of voriconazole was 82.6% (74.1, 91.0). It ranged from 94.4% (78.8, 109.9) in CYP2C19 poor metabolizers to 75.2% (62.9, 87.4) in extensive metabolizers. In contrast to voriconazole and its N‐oxide, the plasma concentrations of both hydroxylated metabolites showed a large second peak after 24 h. Independent of the route of administration, voriconazole partial metabolic hydroxylation after i.v. administration was eightfold higher compared with N‐oxidation [48.8 ml min−1(30.5, 67.1)vs.6.1 ml min−1(4.1, 8.0)]. The formation of the metabolites was related to CYP2C19 activity.

CONCLUSIONSIndependent of the route of administration, voriconazole exposure was three times higher in CYP2C19 poor metabolizers compared with extensive metabolizers. Voriconazole has a high bioavailability with no large differences between the CYP2C19 genotypes. The hydroxylation pathway of voriconazole elimination exceeded the N‐oxidation, both influenced by the CYP2C19 genotype.
Validation and validity of diagnoses in the General Practice Research Database: a systematic review
Authors: Herrett Emily , Thomas Sara L. , Schoonen W. Marieke , Smeeth Liam , Hall Andrew J.
Published: September 2009

AIMS To investigate the range of methods used to validate diagnoses in the General Practice Research Database (GPRD), to summarize findings and to assess the quality of these validations.

METHODS A systematic literature review was performed by searching PubMed and Embase for publications using GPRD data published between 1987 and April 2008. Additional publications were identified from conference proceedings, back issues of relevant journals, bibliographies of retrieved publications and relevant websites. Publications that reported attempts to validate disease diagnoses recorded in the GPRD were included.

RESULTS We identified 212 publications, often validating more than one diagnosis. In total, 357 validations investigating 183 different diagnoses met our inclusion criteria. Of these, 303 (85%) utilized data from outside the GPRD to validate diagnoses. The remainder utilized only data recorded in the database. The median proportion of cases with a confirmed diagnosis was 89% (range 24–100%). Details of validation methods and results were often incomplete.

CONCLUSIONS A number of methods have been used to assess validity. Overall, estimates of validity were high. However, the quality of reporting of the validations was often inadequate to permit a clear interpretation. Not all methods provided a quantitative estimate of validity and most methods considered only the positive predictive value of a set of diagnostic codes in a highly selected group of cases. We make recommendations for methodology and reporting to strengthen further the use of the GPRD in research.
Radiopacifiers do not induce genetic damage in murine fibroblasts: an in vitro study
Authors: Ribeiro D. A. , Carlin V. , Fracalossi A. C. C. , Oyama L. M.
Published: September 2009

Aim  To evaluate whether several radiopacifiers are able to induce genetic damage in a laboratory cell culture study.

Methodology  Murine fibroblasts were exposed to barium sulphate, bismuth oxide or zirconium oxide, at final concentrations ranging from 10 to 1 000 μg mL−1 for 1 h at 37 °C. The negative control group was treated with a vehicle control [phosphate buffered solution (PBS)] for 1 h at 37 °C and the positive control group was treated with hydrogen peroxide (at 10 μM) for 5 min on ice. Genotoxicity data were assessed by the single‐cell gel (comet) assay.

Results  All the tested compounds did not induce DNA breakage as depicted by the mean tail moment in all the concentrations analysed.

Conclusion  Exposure to the tested radiopacifiers may not be a factor that increases the level of DNA lesions in mammalian cells as detected by a single‐cell gel (comet) assay.
Fracture resistance of thin‐walled roots restored with different post systems
Authors: Kıvanç B. H. , Alaçam T. , Ulusoy Ö. İ. A. , Genç Ö. , Görgül G.
Published: September 2009

Aim  To compare the fracture resistance of thin‐walled roots after restoration with different types of post systems.

Methodology  One hundred and sixty‐five decoronated maxillary central incisors were root filled and randomly assigned to three groups with respect to the remaining dentine thickness of root (1.0 mm, 1.5 mm, 2.0 mm). Each group was randomly divided into five equal subgroups. The subgroups were restored with one of the following post systems: polyethylene woven fibre (R), composite resin cured by light‐transmitting post + glass fibre post (L), electrical glass fibre post (E), composite corono‐radicular restoration (C) and cast metal post (M). Standard cores were constructed using composite resin in the first four groups. The samples were subjected to a gradually increasing force (1 mm min−1). The force required to fracture was recorded. The data was analysed with anova and Tukey test (P = 0.05).

Results  The cast metal post group had the highest fracture strength (P < 0.001). There was no significant difference in fracture resistance between the other four groups. Fracture resistance was affected largely by the remaining dentine thickness in fibre post groups; however, the difference was not significant. On the contrary in the cast metal post group load failure was inversely influenced by axio‐proximal dimension of dentine walls.

Conclusion  The cast post group had a higher fracture strength than resin groups. The force required to fracture the roots was similar for all fibre post systems and for all dentine thicknesses.
Effect of acid‐etching procedure on selected physical properties of mineral trioxide aggregate
Authors: Kayahan M. B. , Nekoofar M. H. , Kazandağ M. , Canpolat C. , Malkondu O. , Kaptan F. , Dummer P. M. H.
Published: September 2009

Aim  To evaluate the effect of acid‐etch procedures on the compressive strength and surface microhardness of tooth‐coloured mineral trioxide aggregate (MTA).

Methodology  White ProRoot MTA (Dentsply Tulsa Dental) was mixed and packed into cylindrical tubes of 4 mm in diameter and 6 mm in height. Three groups, each of 15 specimens were subjected to an acid‐etch procedure either 4, 24 or 96 h after mixing. The compressive strength was measured and compared with unetched control groups. Differences between groups were analysed using the Kruskall–Wallis test. A further batch of cylindrical specimens of 6 mm in diameter and 12 mm in height were prepared for testing surface microhardness. Three groups of 15 specimens were subjected to the acid‐etch procedure at either 4, 24 or 96 h following mixing. Data were subjected to one‐way anova. Changes in the surface microstructure before and after the acid‐etch procedures were analysed using a scanning electron microscope (SEM).

Results  There was a general trend for the compressive strength and surface microhardness of specimens to increase with time. In terms of compressive strength, the increase was significant between 4 h and the other time periods for both experimental and control groups (P < 0.0001); however, there was no significant difference between 24 and 96 h. The increase in surface microhardness was significant between 4, 24 and 96 h (P < 0.0001). In addition, there was a significant difference between experimental and control groups at all time periods (P < 0.0001). SEM examination revealed morphological differences between the intact and the etched MTA surfaces.

Conclusions  Acid‐etch procedures affected the compressive strength and surface microhardness of ProRoot MTA. This indicates that it may be better to postpone restorative procedures for at least 96 h after mixing MTA. Etching created surface changes that might have the potential to enhance bonding of resinous materials.
Considering ecological dynamics in resource selection functions
Authors: McLoughlin Philip D. , Morris Douglas W. , Fortin Daniel , Vander Wal Eric , Contasti Adrienne L.
Published: September 2009

1. Describing distribution and abundance is requisite to exploring interactions between organisms and their environment. Recently, the resource selection function (RSF) has emerged to replace many of the statistical procedures used to quantify resource selection by animals.

2. A RSF is defined by characteristics measured on resource units such that its value for a unit is proportional to the probability of that unit being used by an organism. It is solved using a variety of techniques, particularly the binomial generalized linear model.

3. Observing dynamics in a RSF – obtaining substantially different functions at different times or places for the same species – alerts us to the varying ecological processes that underlie resource selection.

4. We believe that there is a need for us to reacquaint ourselves with ecological theory when interpreting RSF models. We outline a suite of factors likely to govern ecologically based variation in a RSF. In particular, we draw attention to competition and density‐dependent habitat selection, the role of predation, longitudinal changes in resource availability and functional responses in resource use.

5. How best to incorporate governing factors in a RSF is currently in a state of development; however, we see promise in the inclusion of random as well as fixed effects in resource selection models, and matched case–control logistic regression.

6. Investigating the basis of ecological dynamics in a RSF will allow us to develop more robust models when applied to forecasting the spatial distribution of animals. It may also further our understanding of the relative importance of ecological interactions on the distribution and abundance of species.
Model based precision structural measurements on barely resolved objects
Authors: BADDELEY D. , WEILAND Y. , BATRAM C. , BIRK U. , CREMER C.
Published: September 2009

A model based method for the accurate quantification of the 3D structure of fluorescently labelled cellular objects similar in size to the optical resolution limit is presented. This method is applied to both simulated confocal images of chromatin structures and to real confocal data obtained on a Fluorescence in situ Hybridization (FISH) labelled gene domain. The model assumes that the object is composed of a small number of discrete points which are convolved with the microscope point spread function to give the image. Fitting this model to image data results in a method to assess object structure which is accurate, shows a low bias, and does not require user intervention or the potentially subjective setting of a threshold.
Signalling Pathway Alterations in Pituitary Adenomas: Involvement of Gsα, cAMP and Mitogen‐Activated Protein Kinases
Authors: Pertuit M. , Barlier A. , Enjalbert A. , Gérard C.
Published: September 2009

Despite extensive research on sporadic pituitary adenomas, it is not yet possible to assign one protein alteration to one specific type of pituitary adenomas. Nevertheless, alterations of the cAMP pathway appear to be molecular hallmarks of most growth hormone (GH)‐secreting adenomas. However, these alterations do not confer specific phenotypes to patients carrying these alterations. In this review, we summarise the literature regarding signalling alterations observed in GH‐secreting adenomas. We focus on Gsα alterations and their possible cross‐talk with the extracellular signal‐related kinase (ERK)1/2 pathway. In the light of results obtained on human somatotroph adenoma cells in primary culture and on models of murine somatotroph cell lines, we postulate a crucial role for ERK1/2 in GH‐secreting adenomas downstream of cAMP pathway alterations that might impact the tumoural phenotype.
Ghrelin Potentiates Miniature Excitatory Postsynaptic Currents in Supraoptic Magnocellular Neurones
Authors: Yokoyama T. , Saito T. , Ohbuchi T. , Suzuki H. , Otsubo H. , Okamoto T. , Fujihara H. , Nagatomo T. , Ueta Y.
Published: September 2009

Ghrelin is an orexigenic peptide discovered in the stomach as a ligand of the orphan G‐protein coupled receptor, and participates in the regulation of growth hormone (GH) release. Previous studies have demonstrated that ghrelin suppressed water intake and stimulated the secretion of arginine vasopressin in rats. We examined the effect of ghrelin on the excitatory synaptic inputs to the magnocellular neurosecretory cells (MNCs) in the supraoptic nucleus (SON) using whole‐cell patch‐clamp recordings in in vitro rat and mouse brain slice preparations. The application of ghrelin (10−7∼10−6 m) caused a significant increase in the frequency of the miniature excitatory postsynaptic currents (mEPSCs) in a dose‐related manner without affecting the amplitude. The increased frequency of the spontaneous EPSCs persisted in the presence of tetrodotoxin (1 μM). Des‐n‐octanoyl ghrelin (10−6 m) did not have a significant effect on the mEPSCs. The ghrelin‐induced potentiation of the mEPSCs was significantly suppressed by previous exposure to the transient receptor potential vanilloid (TRPV) blocker, ruthenium red (10 μM) and GH secretagougue type 1a receptor selective antagonist, BIM28163 (10 μm). The effects of ghrelin on the supraoptic MNCs in trpv1 knockout mice were significantly attenuated compared to those in wild‐type mice counterparts. These results suggest that ghrelin participates in the regulation of synaptic inputs to the MNCs in the SON via interaction with the GH secretagogue type 1a receptor, and that the TRPV1 channel may be involved in ghrelin‐induced potentiation of mEPSCs to the MNCs in the SON.
An Association Between Stress‐Induced Disruption of the Hypothalamic‐Pituitary‐Adrenal Axis and Disordered Glucose Metabolism in an Animal Model of Post‐Traumatic Stress Disorder
Authors: Cohen H. , Kozlovsky N. , Savion N. , Matar M. A. , Loewenthal U. , Loewenthal N. , Zohar J. , Kaplan Z.
Published: September 2009

Retrospective clinical reports suggesting that traumatic stress populations display an increased propensity for glucose metabolism disorders were examined in a controlled prospective animal model. Stress‐induced behavioural and hypothalamic‐pituitary‐adrenal (HPA) axis response patterns were correlated to central and peripheral parameters of glucose metabolism and signalling, and to body measurements in Sprague–Dawley rats exposed to predator scent stress. Forty days post‐exposure, fasting blood glucose and insulin levels, oral glucose tolerance test, body weight and white adipose tissue mass, systemic corticosterone levels and brain expression of insulin receptor (IR) and insulin‐sensitive glucose transporter 4 (GLUT4) protein levels were evaluated. In a second experiment inbred strains with hyper‐ (Fischer) and hypo‐ (Lewis) reactive HPA axes were employed to assess the association of metabolic data with behavioural phenomenology versus HPA axis response profile. For data analysis, animals were classified according to their individual behavioural response patterns (assessed at day 7) into extreme, partial and minimal response groups. The exposed Sprague–Dawley rats fulfilling criteria for extreme behavioural response (EBR) (20.55%) also exhibited significant increases in body weight, abdominal circumference and abdominal white adipose tissue mass; a hyperglycaemic oral glucose tolerance test; and fasting hyperglycaemia, hyperinsulinaemia and hypercorticosteronemia, whereas minimal responders (MBR) and control animals displayed no such disturbances. Hippocampal and hypothalamic expression of IR and GLUT4 protein were significantly lower in EBR than in MBR and control rats. The inbred strains showed no metabolic differences at baseline. Exposed Fischer rats displayed hyperglycaemia and hyperinsulinaemia, whereas Lewis rats did not. A significant protracted disorder of glucose metabolism was induced by exposure to a stress paradigm. This metabolic response was associated with the characteristic pattern of HPA axis (corticosterone) response, which underlies the behavioural response to stress.
Dopamine Agonist Signalling in the Hypothalamus of Female Rats is Independent of Calcium‐Dependent Kinases
Authors: Balasubramanian B. , Mani S. K.
Published: September 2009

We have previously demonstrated that dopamine agonist, SKF38396 (SKF), can substitute for progesterone in the facilitation of female reproductive behaviour in oestradiol benzoate‐primed female rats and mice. We also reported that both progesterone‐ and SKF‐initiated signalling were mediated by the cAMP‐dependent protein kinase A signal transduction cascade. As the rapid effects of progesterone are also mediated by calcium‐dependent kinases, calcium‐ and calmodulin‐dependent kinase (CaMKII) and protein kinase (PKC), we sought to determine whether SKF‐initiated signalling also recruited calcium as a second messenger. We measured the changes in the activation of CaMKII and PKC in the ventromedial nucleus (VMN) of the hypothalamus and preoptic area (POA) of the rat brain, which are the two regions implicated in the regulation of female reproductive behaviour in rodents. We measured the basal activities representing the activation of the kinases by in vivo treatments, as well as the total kinase activities assayed in the presence of exogenous cofactors in vitro. We report that, in contrast to progesterone‐initiated signalling, there was no recruitment of calcium by SKF in the hypothalamus, as shown by the absence of changes in CaMKII activities in the VMN and POA. Furthermore, SKF‐treatment resulted in a rapid increase in calcium‐independent basal PKC activity in the VMN but not the POA. These rapid changes were not the result of changes in PKC protein levels or phosphorylation status. These data indicate that progesterone‐ and SKF‐recruit distinct signalling molecules within the same regions of the brain to activate region‐specific signal transduction pathways.
Impact of obesity, steatosis and insulin resistance on progression and response to therapy of hepatitis C
Authors: Negro F. , Clément S.
Published: September 2009

Summary.  Clinical progression of chronic hepatitis C depends on several cofactors, which also have a negative affect on the rate of response to interferon‐α‐based therapy. Given the current worldwide prevalence of the metabolic syndrome, the impact of obesity and insulin resistance, and of their histopathological correlate, hepatic steatosis, on the natural history and management of chronic hepatitis C is undoubtedly very important. We will review some of the current knowledge on the clinical consequences of overweight/obesity, steatosis and insulin resistance on chronic hepatitis C, and discuss how this issue may be dealt with in clinical practice.
Genomic reaction norms: using integrative biology to understand molecular mechanisms of phenotypic plasticity
Authors: AUBIN‐HORTH NADIA , RENN SUSAN C. P.
Published: September 2009

Phenotypic plasticity is the development of different phenotypes from a single genotype, depending on the environment. Such plasticity is a pervasive feature of life, is observed for various traits and is often argued to be the result of natural selection. A thorough study of phenotypic plasticity should thus include an ecological and an evolutionary perspective. Recent advances in large‐scale gene expression technology make it possible to also study plasticity from a molecular perspective, and the addition of these data will help answer long‐standing questions about this widespread phenomenon. In this review, we present examples of integrative studies that illustrate the molecular and cellular mechanisms underlying plastic traits, and show how new techniques will grow in importance in the study of these plastic molecular processes. These techniques include: (i) heterologous hybridization to DNA microarrays; (ii) next generation sequencing technologies applied to transcriptomics; (iii) techniques for studying the function of noncoding small RNAs; and (iv) proteomic tools. We also present recent studies on genetic model systems that uncover how environmental cues triggering different plastic responses are sensed and integrated by the organism. Finally, we describe recent work on changes in gene expression in response to an environmental cue that persist after the cue is removed. Such long‐term responses are made possible by epigenetic molecular mechanisms, including DNA methylation. The results of these current studies help us outline future avenues for the study of plasticity.
How do reproductive skew and founder group size affect genetic diversity in reintroduced populations?
Authors: MILLER K. A. , NELSON N. J. , SMITH H. G. , MOORE J. A.
Published: September 2009

Reduced genetic diversity can result in short‐term decreases in fitness and reduced adaptive potential, which may lead to an increased extinction risk. Therefore, maintaining genetic variation is important for the short‐ and long‐term success of reintroduced populations. Here, we evaluate how founder group size and variance in male reproductive success influence the long‐term maintenance of genetic diversity after reintroduction. We used microsatellite data to quantify the loss of heterozygosity and allelic diversity in the founder groups from three reintroductions of tuatara (Sphenodon), the sole living representatives of the reptilian order Rhynchocephalia. We then estimated the maintenance of genetic diversity over 400 years (∼10 generations) using population viability analyses. Reproduction of tuatara is highly skewed, with as few as 30% of males mating across years. Predicted losses of heterozygosity over 10 generations were low (1–14%), and populations founded with more animals retained a greater proportion of the heterozygosity and allelic diversity of their source populations and founder groups. Greater male reproductive skew led to greater predicted losses of genetic diversity over 10 generations, but only accelerated the loss of genetic diversity at small population size (<250 animals). A reduction in reproductive skew at low density may facilitate the maintenance of genetic diversity in small reintroduced populations. If reproductive skew is high and density‐independent, larger founder groups could be released to achieve genetic goals for management.
HiddenWolbachiadiversity in field populations of the European cherry fruit fly,Rhagoletis cerasi(Diptera, Tephritidae)
Authors: ARTHOFER WOLFGANG , RIEGLER MARKUS , SCHNEIDER DANIELA , KRAMMER MARTIN , MILLER WOLFGANG J. , STAUFFER CHRISTIAN
Published: September 2009

The European cherry fruit flyRhagoletis cerasihas been a field model for cytoplasmic incompatibility since the mid 1970s. TwoWolbachiastrains were detected in this tephritid species andwCer2 was described as the CI inducing agent dividing European populations into two unidirectional incompatible groups, i.e. southern females produce viable offspring with northern males, whereas the reciprocal cross results in incompatibility. We detected three newWolbachiastrains by sequencing a multitude of plasmids derived fromWolbachiasurface protein gene (wsp) polymerase chain reaction (PCR) products. Strain‐specific primers were developed allowing individual diagnosis without need for cloning. Hybridization of specific PCR products with awspoligonucleotide enhanced the detection limit significantly and revealed the presence of low‐titre infections in some strains, in different ontogenetic stages and in adults of different age. We then performed a survey of strain prevalence and infection frequency in eight European regions.wCer1 was fixed in all populations, whereaswCer2 was detected only in the South.wCer3 frequency was the lowest without a clear distribution pattern. The abundance ofwCer4 was homogenous across Europe. LikewCer2,wCer5 showed significant differences in spatial distribution. Our new findings of previously undetected and recombinantWolbachiastrains inR. cerasireveal a major caveat to the research community not to overlook hiddenWolbachiadiversity in field populations. Low‐titres and geographical variability inWolbachiadiversity are expected to influence the outcome ofWolbachiapopulation dynamics andWolbachia‐based insect population control and may create invasion barriers for expanding and artificially introducedWolbachiastrains.
Molecular road ecology: exploring the potential of genetics for investigating transportation impacts on wildlife
Authors: BALKENHOL NIKO , WAITS LISETTE P.
Published: September 2009

Transportation infrastructures such as roads, railroads and canals can have major environmental impacts. Ecological road effects include the destruction and fragmentation of habitat, the interruption of ecological processes and increased erosion and pollution. Growing concern about these ecological road effects has led to the emergence of a new scientific discipline called road ecology. The goal of road ecology is to provide planners with scientific advice on how to avoid, minimize or mitigate negative environmental impacts of transportation. In this review, we explore the potential of molecular genetics to contribute to road ecology. First, we summarize general findings from road ecology and review studies that investigate road effects using genetic data. These studies generally focus only on barrier effects of roads on local genetic diversity and structure and only use a fraction of available molecular approaches. Thus, we propose additional molecular applications that can be used to evaluate road effects across multiple scales and dimensions of the biodiversity hierarchy. Finally, we make recommendations for future research questions and study designs that would advance molecular road ecology. Our review demonstrates that molecular approaches can substantially contribute to road ecology research and that interdisciplinary, long‐term collaborations will be particularly important for realizing the full potential of molecular road ecology.
To see in different seas: spatial variation in the rhodopsin gene of the sand goby (Pomatoschistus minutus)
Authors: LARMUSEAU MAARTEN H. D. , RAEYMAEKERS JOOST A. M. , RUDDICK KEVIN G. , VAN HOUDT JEROEN K. J. , VOLCKAERT FILIP A. M.
Published: September 2009

Aquatic organisms living in a range of photic environments require specific mechanisms to tune their visual pigments. Maximum absorbance (λmax) of retinal rods in populations of the marine demersal sand goby, (Pomatoschistus minutus; Gobiidae, Teleostei) correlates with the local optic environment. It has been shown that this is not regulated through a physiological response by exchanging the rhodopsin chromophore. To test for evolutionary adaptation, the sequence of the rhodopsin (RH1) gene was analysed in 165 Pomatoschistus minutus individuals from seven populations across its distribution range. Analysis showed a high level of intraspecific polymorphism at the RH1 gene, including nonsynonymous mutations on amino acids, known as spectral tuning sites. Population differentiation at these sites was in agreement with the observed differentiation in λmax values. Analyses of dN/dS substitution rate ratios and likelihood ratio tests under site‐specific models detected a significant signal of positive Darwinian selection on the RH1 gene. A strong discrepancy in differentiation was noticed between RH1 gene variation and the presumably neutral microsatellites and mitochondrial data. Samples did not cluster according to geographical or historical proximity with regards to RH1, but according to the general photic conditions of the habitat environment of the sand goby. This study highlights the usefulness of sensory genes, like rhodopsin, for studying the characteristics of local adaptation in marine nonmodel organisms.
Do arms races punctuate evolutionary stasis? Unified insights from phylogeny, phylogeography and microevolutionary processes
Authors: TOJU HIROKAZU , SOTA TEIJI
Published: September 2009

One of the major controversies in evolutionary biology concerns the processes underlying macroevolutionary patterns in which prolonged stasis is disrupted by rapid, short‐term evolution that leads species to new adaptive zones. Recent advances in the understanding of contemporary evolution have suggested that such rapid evolution can occur in the wild as a result of environmental changes. Here, we examined a novel hypothesis that evolutionary stasis is punctuated by co‐evolutionary arms races, which continuously alter adaptive peaks and landscapes. Based on the phylogeny of long‐mouthed weevils in the genus Curculio, likelihood ratio tests showed that the macroevolutionary pattern of the weevils coincides with the punctuational evolution model. A coalescent analysis of a species, Curculio camelliae, the mouthpart of which has diverged considerably among populations because of an arms race with its host plant, further suggested that major evolutionary shifts had occurred within 7000 generations. Through a microevolutionary analysis of the species, we also found that natural selection acting through co‐evolutionary interactions is potentially strong enough to drive rapid evolutionary shifts between adaptive zones. Overall, we posit that co‐evolution is an important factor driving the history of organismal evolution.
Leaf hydraulics and drought stress: response, recovery and survivorship in four woody temperate plant species
Authors: BLACKMAN CHRISTOPHER J. , BRODRIBB TIMOTHY J. , JORDAN GREGORY J.
Published: September 2009

Efficient conduction of water inside leaves is essential for leaf function, yet the hydraulic‐mediated impact of drought on gas exchange remains poorly understood. Here we examine the decline and subsequent recovery of leaf water potential (Ψleaf), leaf hydraulic conductance (Kleaf), and midday transpiration (E) in four temperate woody species exposed to controlled drought conditions ranging from mild to lethal. During drought the vulnerability of Kleaf to declining Ψleaf varied greatly among the species sampled. Following drought, plants were rewatered and the rate of E and Kleaf recovery was found to be strongly dependent on the severity of the drought imposed. Gas exchange recovery was strongly correlated with the relatively slow recovery of Kleaf for three of the four species, indicating conformity to a hydraulic‐stomatal limitation model of plant recovery. However, there was also a shift in the sensitivity of stomata to Ψleaf suggesting that the plant hormone abscisic acid may be involved in limiting the rate of stomatal reopening. The level of drought tolerance varied among the four species and was correlated with leaf hydraulic vulnerability. These results suggest that species‐specific variation in hydraulic properties plays a fundamental role in steering the dynamic response of plants during recovery.