bluuebunny/crossref_metadata_2025 huggingface dataset:
Issues of water supply and contemporary urban society: the case of Greater Amman, Jordan
Authors: Potter Robert B. , Darmame Khadija , Nortcliff Stephen
Published: October 2010

Over the last two decades, Jordan has suffered a chronic water crisis, and is the tenth most water-scarce nation on Earth. Such water stress has been well illustrated in the case of Greater Amman, the capital, which has grown dramatically from a population of around 2000 in the 1920s, to 2.17 million today. One of the distinctive characteristics of the water supply regime of Greater Amman is that since 1987 it has been based on a system of rationing, with households receiving water once a week for various durations. Amman is highly polarized socio-economically, and by means of household surveys, both quantitative and qualitative, conducted in high- and low-income divisions of the city, a detailed empirical evaluation of the storage and use of water, the strategies used by households to manage water and overall satisfaction with water supply issues is provided in this paper, looking specifically at issues of social equity. The analysis demonstrates the social and economic costs of water rationing and consequent management to be high, as well as emphasizing that issues of water quality are of central importance to all consumers regardless of their socio-economic status within the city.
Progressive development of water resources in the Middle East for sustainable water supply in a period of climate change
Authors: Issar Arie S. , Adar Eilon
Published: October 2010

The history of the Middle East has been influenced by past global climatic changes. Warm periods caused droughts, resulting in desertification, migration and war. Cold periods were humid and brought prosperity and agricultural settlement to the desert fringes. The forecast based on this correlation is that the present global warming will cause the drying up of the Middle East. As in the past, this negative impact should be mitigated by using the groundwater resources stored from past wetter times. This will involve deep drilling, pumping and modern irrigation methods within the framework of a new policy of ‘progressive development’, which will entail the use of currently undeveloped natural water resources beyond that of present water replenishment. While the use of the one-time groundwater reserves is taking place, a master long-term comprehensive progressive development plan for the Middle East will be prepared. This plan will include the step-by-step development of other water resources such as treated effluents, desalinated brackish groundwater and desalination of seawater.
Past, present and future precipitation in the Middle East: insights from models and observations
Authors: Black Emily , Brayshaw David J. , Rambeau Claire M. C.
Published: October 2010

Anthropogenic changes in precipitation pose a serious threat to society—particularly in regions such as the Middle East that already face serious water shortages. However, climate model projections of regional precipitation remain highly uncertain. Moreover, standard resolution climate models have particular difficulty representing precipitation in the Middle East, which is modulated by complex topography, inland water bodies and proximity to the Mediterranean Sea. Here we compare precipitation changes over the twenty-first century against both millennial variability during the Holocene and interannual variability in the present day. In order to assess the climate model and to make consistent comparisons, this study uses new regional climate model simulations of the past, present and future in conjunction with proxy and historical observations. We show that the pattern of precipitation change within Europe and the Middle East projected by the end of the twenty-first century has some similarities to that which occurred during the Holocene. In both cases, a poleward shift of the North Atlantic storm track and a weakening of the Mediterranean storm track appear to cause decreased winter rainfall in southern Europe and the Middle East and increased rainfall further north. In contrast, on an interannual time scale, anomalously dry seasons in the Middle East are associated with a strengthening and focusing of the storm track in the north Mediterranean and hence wet conditions throughout southern Europe.
Response to Yokoyama et al.: Past and current tendency for facial flushing after a small dose of alcohol is a marker for increased risk of upper aerodigestive tract cancer in Japanese drinkers
Authors: Matsuo Keitaro , Oze Isao , Tanaka Hideo
Published: October 2010

(Cancer Sci 2010; 101: 2499–2500)
Mammaglobin RT‐qPCR for breast cancer metastasis detection in sentinel lymph nodes
Authors: Span Paul N. , Van Laarhoven Hanneke W. , Sweep Fred C. G. J.
Published: October 2010

(Cancer Sci 2010; 101: 2501)
Combined androgen blockade for prostate cancer: Review of efficacy, safety and cost‐effectiveness
Authors: Akaza Hideyuki
Published: October 2010

A standard treatment for advanced prostate cancer is androgen deprivation by surgical or medical castration. In theory, however, combined androgen blockade (CAB) with an antiandrogen plus castration should be more effective because castration alone does not completely eliminate androgens in the prostate. Therefore, a number of randomized clinical trials (RCT) were conducted in the 1990s to investigate the efficacy of CAB with an antiandrogen (nilutamide or flutamide) plus castration; however, there were both positive and negative results for the efficacy of CAB. The lack of data on safety, quality of life (QOL) and cost‐effectiveness has been a hindrance to the adoption of CAB for the treatment of prostate cancer. Nevertheless, discussion on CAB for the treatment of prostate cancer has continued for over 20 years, which suggests that there remains some hope for this regimen. In the 2000s, clinical research on CAB with the antiandrogen bicalutamide commenced. CAB using this new antiandrogen was found to prolong overall survival (OS) in patients with prostate cancer, with favorable safety profiles and cost‐effectiveness, without deteriorating QOL. In this article, we discuss the feasibility of CAB with bicalutamide for the treatment of prostate cancer by reviewing the theoretical background of CAB and then the results of RCT conducted in the 1990s when the usefulness of CAB was assessed. (Cancer Sci 2011; 102: 51–56)
Long interspersed nuclear element‐1 hypomethylation is a potential biomarker for the prediction of response to oral fluoropyrimidines in microsatellite stable and CpG island methylator phenotype‐negative colorectal cancer
Authors: Kawakami Kazuyuki , Matsunoki Aika , Kaneko Mami , Saito Kenichiro , Watanabe Go , Minamoto Toshinari
Published: October 2010

We investigated the clinical value of methylation of long interspersed nuclear element‐1 (LINE‐1) for the prognosis of colorectal cancer (CRC) and for the survival benefit from adjuvant chemotherapy with oral fluoropyrimidines. LINE‐1 methylation in tumor DNA was measured by quantitative methylation‐specific PCR in 155 samples of stage II and stage III CRC. The presence of microsatellite instability and CpG island methylator phenotype (CIMP) were assessed and 131 microsatellite stable/CIMP− cases were selected for survival analysis, of which 77 patients had received postoperative adjuvant chemotherapy with oral fluoropyrimidines. The CRC cell lines were used to investigate possible mechanistic links between LINE‐1 methylation and effects of 5‐fluorouracil (5‐FU). High LINE‐1 methylation was a marker for better prognosis in patients treated by surgery alone. Patients with low LINE‐1 methylation who were treated with adjuvant chemotherapy survived longer than those treated by surgery alone, suggestive of a survival benefit from the use of oral fluoropyrimidines. In contrast, a survival benefit from chemotherapy was not observed for patients with high LINE‐1 methylation. The CRC cell lines treated with 5‐FU showed increased expression of LINE‐1 mRNA. This was associated with upregulation of the phospho‐histone H2A.X in cells with low LINE‐1 methylation, but not in cells with high LINE‐1 methylation. The 5‐FU‐mediated induction of phospho‐histone H2A.X, a marker of DNA damage, was inhibited by knockdown of LINE‐1. These results suggest that LINE‐1 methylation is a novel predictive marker for survival benefit from adjuvant chemotherapy with oral fluoropyrimidines in CRC patients. This finding could be important for achieving personalized chemotherapy. (Cancer Sci 2011; 102: 166–174)
Addiction research centres and the nurturing of creativity. The Centre for Alcohol and Drug Research: social science alcohol and drug research in Denmark
Authors: Pedersen Mads U. , Elmeland Karen , Frank Vibeke A.
Published: October 2010

Aims  The purpose of this paper is to introduce the social science alcohol and drug research undertaken by the Centre for Alcohol and Drug Research (CRF) and at the same time offer an insight into the development in Danish alcohol and drug research throughout the past 15–20 years.

Method  A review of articles, books and reports published by researcher from CRF from the mid‐1990s until today and an analysis of the policy‐making in the Danish substance use and misuse area.

Results  CRF is a result of the discussions surrounding social, health and allocation policy questions since the mid‐1980s. Among other things, these discussions led to the formal establishment of the Centre in 1991 under the Aarhus University, the Faculty of Social Science. Since 2001 the Centre has received a permanent basic allocation, which has made it possible to appoint tenured senior researchers; to work under a more long‐term research strategy; to function as a milieu for educating PhD students; and to diversify from commissioned research tasks to initiating projects involving more fundamental research. Research at the Centre is today pivoted around four core areas: consumption, policy, prevention and treatment.

Conclusion  The emergence, continuation, financing and character of the research taking place at CRF can be linked closely to the specific Danish drug and alcohol discourse and to the division of the responsibility for alcohol and drug research into separate Ministries.
Risky single‐occasion drinking: bingeing is not bingeing
Authors: Gmel Gerhard , Kuntsche Emmanuel , Rehm Jürgen
Published: October 2010

Aims  To review the concept of binge drinking as a measure of risky single occasion drinking (RSOD), to illustrate its differential impact on selected health outcomes and to identify research gaps.

Methods  Narrative literature review with focus on conceptual and methodological differences, trajectories of RSOD and effects of RSOD on fetal outcomes, coronary heart disease (CHD) and injuries.

Results  Effects ascribed commonly to RSOD may often be the effects of an undifferentiated mixture of risky single occasions and regular heavy volume drinking, constituted by frequent, successive RSOD. This leads to the problem that additional risks due to RSOD are mis‐specified and remain unidentified or underestimated in some cases, such as for injuries or CHD, but are probably overstated for some chronic consequences or for effects of maternal drinking on newborns.

Conclusion  A stronger focus should be placed upon methods that can differentiate the effects of RSOD from those due to frequent occasions of heavy drinking that result in heavy volume drinking.
Deferasirox administration for the treatment of non‐transfusional iron overload in patients with thalassaemia intermedia
Authors: Ladis Vassilis , Berdousi Helen , Gotsis Efstathios , Kattamis Antonis
Published: October 2010

Abnormal iron regulation in patients with thalassaemia intermedia may lead to iron overload even in the absence of transfusions. There are limited data on iron chelator use in patients with thalassaemia intermedia and no guidelines exist for the management of iron overload. We present data from 11 patients with thalassaemia intermedia treated with deferasirox (Exjade®, 10–20 mg/kg/d) for 24 months. Liver iron concentration and serum ferritin levels significantly decreased over the first 12 months (P = 0·005) and continued to decrease over the remainder of the study (P = 0·005). This small‐scale study indicated that deferasirox may be suitable for controlling iron levels in patients with thalassaemia intermedia.
Autologous 111In‐labelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy: a report from the United Kingdom ITP Registry
Authors: Sarpatwari Ameet , Provan Drew , Erqou Sebhat , Sobnack Ravin , David Tai Foong Way , Newland Adrian C.
Published: October 2010

While splenectomy is an effective therapy for primary immune thrombocytopenia (ITP), possible complications and observed non‐complete response (CR) in one‐third of patients demonstrate the need for further research into potential pre‐surgical predictors of outcomes. Past investigations into platelet sequestration studies, a hypothesized predictive test, have adopted heterogeneous methods and varied widely with regard to power. By studying patients with primary ITP who underwent autologous 111In‐labelled platelet sequestration studies at Barts and The London NHS Trust between 1994 and 2008, we evaluated the effectiveness of sequestration site in predicting short, medium, and long‐term CR (platelet count >100 × 109/l) to splenectomy through multivariate (gender, age at splenectomy, and mean platelet lifespan) logistic regression modelling. In total, 256 patients with primary ITP underwent scans; 91 (35·5%) proceeded to splenectomy. Logistic regression revealed significant adjusted odds ratios for CR of 7·47 (95% confidence interval [CI], 1·89–29·43) at 1–3 months post‐splenectomy, 4·85 (95% CI, 1·04–22·54) at 6–12 months post‐splenectomy, and 5·39 (95% CI, 1·34–21·65) at last follow‐up (median: 3·8 years [range: 0·5–13·1 years]) in patients with purely or predominantly splenic versus mixed or hepatic sequestration. These findings demonstrate the utility of autologous 111In‐labelled platelet sequestration studies as an adjunct predictive instrument prior to splenectomy.
Local adaptations of life‐history traits of a Drosophila parasitoid, Leptopilina boulardi: does climate drive evolution?
Authors: MOIROUX JOFFREY , LANN CÉCILE LE , SEYAHOOEI MAJEED A. , VERNON PHILIPPE , PIERRE JEAN‐SÉBASTIEN , VAN BAAREN JOAN , VAN ALPHEN JACQUES J. M.
Published: October 2010

1. Climate is an important source of selection on life histories, and local adaptations to climate have been described in several cline studies. Temperature is the main climatic factor that has been considered as an agent of selection, whereas other factors may vary with it, such as precipitation.

2. We compared life‐history traits of five populations of Leptopilina boulardi, a Drosophila parasitoid, originating from contrasting climates. Referring to cline studies, we hypothesised shorter lifespan, earlier reproduction, and lower lipid content in populations from the hottest and driest areas if life histories have been selected in response to temperature and/or humidity.

3. Our results are opposite to these predictions. Females from humid and mild climates invested more in early reproduction and lived for fewer days than females from dry and hot areas, which were synovigenic (i.e. they matured additional eggs during adult life) and able to synthesise lipids during adult life.

4. We suggest that life histories are more adapted to host distribution than to climatic factors. Drosophila patches are more abundant in the humid area, allowing the parasitoids to spend less energy and time finding hosts. This may result in selection for early reproduction traded‐off against longevity. In the hot and dry climate, females have to fly large distances to find host patches. Synovigeny, a long lifespan, lipogenesis, and high dispersal ability may be adaptive there. This is the first time that between‐population differences in the ability to synthesise lipids have been described in parasitoids.
The use of oviposition‐induced plant cues by Trichogramma egg parasitoids
Authors: PASHALIDOU FOTEINI G. , HUIGENS MARTINUS E. , DICKE MARCEL , FATOUROS NINA E.
Published: October 2010

1. Female parasitoids have evolved various foraging strategies in order to find suitable hosts. Egg parasitoids have been shown to exploit plant cues induced by the deposition of host eggs.

2. The tiny wasp Trichogramma brassicae uses oviposition‐induced cues from Brussels sprouts to locate eggs of the cabbage white butterflies Pieris brassicae and Pieris rapae that differ in their egg‐laying behaviour. These plant cues are elicited by male‐derived anti‐aphrodisiac pheromones in the accessory reproductive gland (ARG) secretions of mated female butterflies. However, the closely related generalist species Trichogramma evanescens does not respond to Brussels sprout cues induced by the deposition of P. brassicae egg clutches.

3. Here we showed in two‐choice bioassays that T. evanescens wasps respond to Brussels sprout cues induced by (i) the deposition of single eggs by P. rapae, and (ii) the application of ARG secretions from either mated P. rapae females, or from virgin female butterflies in combination with P. rapae's anti‐aphrodisiac compound indole. The wasps only associatively learned to respond to Brussels sprout cues after applying indole alone by linking those cues with the presence of P. rapae eggs.

4. Our results indicate that Trichogramma wasps more commonly exploit oviposition‐induced plant cues to locate their host eggs. Generalist wasps show less specificity in their response than specialists and employ associative learning.
Bridging the gap between ‘planning’ and ‘doing’ for biodiversity conservation in freshwaters
Authors: BARMUTA LEON A. , LINKE SIMON , TURAK EREN
Published: October 2010

1. Systematic conservation planning has been applied to terrestrial and marine systems for over a decade, but only recently been used for freshwaters. Of the various methods proposed, those that explicitly include the costs of, opportunities for and constraints on conservation actions are the most defensible because they allow transparent, rational decisions to be made about conservation priorities.

2. Applying these procedures to freshwater systems presents a number of challenges, including accounting for lateral, longitudinal and vertical connections, and the dynamism and resilience of freshwaters in space and time. Recent research on freshwater conservation planning contains an array of methods to address these issues.

3. The first step in bridging the implementation gap will be to communicate that conserving aquatic biodiversity often will not be achieved by merely ‘locking up’ catchments and that many human uses can coexist with biodiversity conservation.

4. To bridge the gap between research and implementation, terrestrial experience suggests that genuinely collaborative involvement with stakeholders and managers needs to be part of the planning process. Otherwise, even the most transparently optimised conservation plan will be ignored.

5. Case studies explored by the advocates of social learning and ‘resilience thinking’ provide frameworks for creative engagement between the ecological and social sciences. There is probably scope to modify existing catchment management networks to incorporate aquatic biodiversity conservation.
Dynamics of Plateau Bursting Depending on the Location of its Equilibrium
Authors: Osinga H. M. , Tsaneva‐Atanasova K. T.
Published: October 2010

We present a mathematical analysis of the dynamics that underlies plateau bursting in models of endocrine cells under variation of the location of the (unstable) equilibrium around which these bursting patterns are organised. We focus primarily on the less well‐studied case of pseudo‐plateau bursting, but also consider the square‐wave case. The behaviour of such models is explained using the theory for systems with multiple time scales and it is well known that the underlying so‐called fast subsystem organises their dynamics. However, such results are valid only in a sufficiently small neighbourhood of the singular limit that defines the fast subsystem. Hence, the slow variable (intracellular calcium concentration) must be very slow, which is actually not the case for pseudo‐plateau bursting. Furthermore, the theoretical predictions are also only valid for parameter values such that the equilibrium is close to a homoclinic bifurcation occuring in the fast subsystem. In the present study, we use numerical explorations to discuss what happens outside this theoretically known neighbourhood of parameter space. In particular, we consider what happens as the equilibrium moves outside a small neighbourhood of the homoclinic bifurcation that occurs in the fast subsystem, and relatively fast speeds are allowed for the slow variable which is controlled by a relatively large value of a parameter ε. The results obtained complement our earlier work [Tsaneva‐Atanasova et al. (2010) J Theor Biol264, 1133–1146], which focussed on how the bursting patterns vary with the rate of change ε of the slow variable: we fix ε and move the equilibrium over the full range of the bursting regime. Our findings show that the transitions between different bursting patterns are rather similar for square‐wave and pseudo‐plateau bursting, provided that the value of ε for the pseudo‐plateau‐bursting model is chosen so that it is much larger than for the square‐wave bursting model. Furthermore, the two families of tonic spiking and plateau bursting, which are generally viewed as two separately generated families, are actually connected into a single family in the two‐parameter plane through branches of unstable periodic orbits.
Extended treatment duration for treatment naïve chronic hepatitis C genotype 1 late viral responders: a meta‐analysis comparing 48 weeks vs 72 weeks of pegylated interferon and ribavirin
Authors: Parikh M. , Singh A. , Sood G.
Published: October 2010

Summary.  Patients with genotype I chronic hepatitis C virus (HCV) infection with late virological response to therapy have low sustained viral response (SVR) with standard 48 weeks of therapy and may benefit from extended therapy. We performed a systematic review and meta‐analysis of five studies to compare the outcome of 48 weeks vs 72 weeks treatment in treatment naïve chronic hepatitis C genotype I patients with late virological response. The end of treatment response with extended 72 weeks of treatment compared to standard 48 weeks of treatment was similar 48% and 56%, respectively, with pooled odds ratio (OR) (0.85; 95% CI 0.52–1.37). However, the SVR rates were higher with 72 weeks of treatment compared to 48 weeks treatment 32%vs 25% with pooled OR of 1.67 in favour of extended duration therapy (95% CI 1.16–2.40). This was because of lower relapse rates with extended duration therapy (35%vs 55%) with OR of 0.39 in favour of 72 weeks therapy (95% CI 0.25–0.61). There was no heterogeneity. No publication bias was noted as assessed by Egger’s test. Extending the treatment duration from 48 to 72 weeks in genotype 1 infected patients with late virological response improves SVR. Thus, therapy extension in genotype 1 late viral responders (LVR) may be a consideration to improve treatment response; however, the proportion of patients with LVR that might benefit from 72‐week therapy appears to be small.
Regulation of the phototrophic iron oxidation (pio) genes in Rhodopseudomonas palustris TIE‐1 is mediated by the global regulator, FixK
Authors: Bose Arpita , Newman Dianne K.
Published: October 2010

The pioABC operon is required for phototrophic iron oxidative (photoferrotrophic) growth by the α‐proteobacterium Rhodopseudomonas palustris TIE‐1. Expression analysis of this operon showed that it was transcribed and translated during anaerobic growth, upregulation being observed only under photoferrotrophic conditions. Very low levels of transcription were observed during aerobic growth, suggesting expression was induced by anoxia. The presence of two canonical FixK boxes upstream of the identified pioABC transcription start site implicated FixK as a likely regulator. To test this possibility, a ΔfixK mutant of R. palustris TIE‐1 was assessed for pioABC expression. pioABC expression decreased dramatically in ΔfixK versus WT during photoferrotrophic growth, implying that FixK positively regulates its expression; coincidently, the onset of iron oxidation was prolonged in this mutant. In contrast, pioABC expression increased in ΔfixK under all non‐photoferrotrophic conditions tested, suggesting the presence of additional levels of regulation. Purified FixK directly bound only the proximal FixK box in gel mobility‐shift assays. Mutant expression analysis revealed that FixK regulates anaerobic phototrophic expression of other target genes with FixK binding sites in their promoters. This study shows that FixK regulates key iron metabolism genes in an α‐proteobacterium, pointing to a departure from the canonical Fur/Irr mode of regulation.
Functional and structural characterization of a novel mannosyl‐3‐phosphoglycerate synthase from Rubrobacter xylanophilus reveals its dual substrate specificity
Authors: Empadinhas Nuno , Pereira Pedro José Barbosa , Albuquerque Luciana , Costa Joana , Sá‐Moura Bebiana , Marques Alexandra T. , Macedo‐Ribeiro Sandra , da Costa Milton S.
Published: October 2010

Rubrobacter xylanophilus is the only actinobacterium known to accumulate the organic solute mannosylglycerate (MG); moreover, the accumulation of MG is constitutive. The key enzyme for MG synthesis, catalysing the conversion of GDP‐mannose (GDP‐Man) and D‐3‐phosphoglycerate (3‐PGA) into the phosphorylated intermediate mannosyl‐3‐phosphoglycerate and GDP, was purified from R. xylanophilus cell extracts and the corresponding gene was expressed in E. coli. Despite the related solute glucosylglycerate (GG) having never been detected in R. xylanophilus, the cell extracts and the pure recombinant mannosyl‐3‐phosphoglycerate synthase (MpgS) could also synthesize glucosyl‐3‐phosphoglycerate (GPG), the precursor of GG, in agreement with the higher homology of the novel MpgS towards GPG‐synthesizing mycobacterial glucosyl‐3‐phosphoglycerate synthases (GpgS) than towards MpgSs from hyper/thermophiles, known to accumulate MG under salt or thermal stress. To understand the specificity and substrate ambiguity of this novel enzyme, we determined the crystal structure of the unliganded MpgS and of its complexes with the nucleotide and sugar donors, at 2.2, 2.8 and 2.5 Å resolution respectively. The first three‐dimensional structures of a protein from this extremely gamma‐radiation‐resistant thermophile here reported show that MpgS (GT81 family) contains a GT‐A like fold and clearly explain its nucleotide and sugar‐donor specificity. In the GDP–Man complex, a flexible loop (254RQNRHQ259), located close to the active site moves towards the incoming sugar moiety, providing the ligands for both magnesium ion co‐ordination and sugar binding. A triple mutant of R. xylanophilus MpgS, mimicking the 206PLAGE210 loop stabilizing hydrogen bond network observed for mycobacterial GpgSs, reduces significantly the affinity to GDP–Man, implicating this loop in the sugar‐donor discrimination.
YeeV is an Escherichia coli toxin that inhibits cell division by targeting the cytoskeleton proteins, FtsZ and MreB
Authors: Tan Qian , Awano Naoki , Inouye Masayori
Published: October 2010

Toxin–antitoxin (TA) systems of free‐living bacteria have recently demonstrated that these toxins inhibit cell growth by targeting essential functions of cellular metabolism. Here we show that YeeV toxin inhibits cell division, leads to a change in morphology and lysis of Escherichia coli cells. YeeV interacts with two essential cytoskeleton proteins, FtsZ and MreB. Purified YeeV inhibits both the GTPase activity and the GTP‐dependent polymerization of FtsZ. YeeV also inhibits ATP‐dependent polymerization of MreB. Truncated C‐terminal deletions of YeeV result in elongation of cells, and a deletion of the first 15 amino acids from the N‐terminus of YeeV caused lemon‐shaped cell formation. The YeeV toxin is distinct from other well‐studied toxins: it directs the binding of two cytoskeletal proteins and inhibits FtsZ and MreB simultaneously.
A domino effect in drug action: from metabolic assault towards parasite differentiation
Authors: Haanstra Jurgen R. , Kerkhoven Eduard J. , van Tuijl Arjen , Blits Marjolein , Wurst Martin , van Nuland Rick , Albert Marie‐Astrid , Michels Paul A. M. , Bouwman Jildau , Clayton Christine , Westerhoff Hans V. , Bakker Barbara M.
Published: October 2010

Awareness is growing that drug target validation should involve systems analysis of cellular networks. There is less appreciation, though, that the composition of networks may change in response to drugs. If the response is homeostatic (e.g. through upregulation of the target protein), this may neutralize the inhibitory effect. In this scenario the effect on cell growth and survival would be less than anticipated based on affinity of the drug for its target. Glycolysis is the sole free‐energy source for the deadly parasite Trypanosoma brucei and is therefore a possible target pathway for anti‐trypanosomal drugs. Plasma‐membrane glucose transport exerts high control over trypanosome glycolysis and hence the transporter is a promising drug target. Here we show that at high inhibitor concentrations, inhibition of trypanosome glucose transport causes cell death. Most interestingly, sublethal concentrations initiate a domino effect in which network adaptations enhance inhibition. This happens via (i) metabolic control exerted by the target protein, (ii) decreases in mRNAs encoding the target protein and other proteins in the same pathway, and (iii) partial differentiation of the cells leading to (low) expression of immunogenic insect‐stage coat proteins. We discuss how these ‘anti‐homeostatic’ responses together may facilitate killing of parasites at an acceptable drug dosage.
A molecular mechanism that stabilizes cooperative secretions in Pseudomonas aeruginosa
Authors: Xavier Joao B. , Kim Wook , Foster Kevin R.
Published: October 2010

Bacterial populations frequently act as a collective by secreting a wide range of compounds necessary for cell–cell communication, host colonization and virulence. How such behaviours avoid exploitation by spontaneous ‘cheater’ mutants that use but do not contribute to secretions remains unclear. We investigate this question using Pseudomonas aeruginosa swarming, a collective surface motility requiring massive secretions of rhamnolipid biosurfactants. We first show that swarming is immune to the evolution of rhlA‐‘cheaters’. We then demonstrate that P. aeruginosa resists cheating through metabolic prudence: wild‐type cells secrete biosurfactants only when the cost of their production and impact on individual fitness is low, therefore preventing non‐secreting strains from gaining an evolutionary advantage. Metabolic prudence works because the carbon‐rich biosurfactants are only produced when growth is limited by another growth limiting nutrient, the nitrogen source. By genetically manipulating a strain to produce the biosurfactants constitutively we show that swarming becomes cheatable: a non‐producing strain rapidly outcompetes and replaces this obligate cooperator. We argue that metabolic prudence, which may first evolve as a direct response to cheating or simply to optimize growth, can explain the maintenance of massive secretions in many bacteria. More generally, prudent regulation is a mechanism to stabilize cooperation.
Separating parental environment from seed size effects on next generation growth and development in Arabidopsis
Authors: ELWELL ANGELA L. , GRONWALL DAVID S. , MILLER NATHAN D. , SPALDING EDGAR P. , DURHAM BROOKS TESSA L.
Published: October 2010

Plant growth and development is profoundly influenced by environmental conditions that laboratory experimentation typically attempts to control. However, growth conditions are not uniform between or even within laboratories and the extent to which these differences influence plant growth and development is unknown. Experiments with wild‐type Arabidopsis thaliana were designed to quantify the influences of parental environment and seed size on growth and development in the next generation. A single lot of seed was planted in six environmental chambers and grown to maturity. The seed produced was mechanically sieved into small and large size classes then grown in a common environment and subjected to a set of assays spanning the life cycle. Analysis of variance demonstrated that seed size effects were particularly significant early in development, affecting primary root growth and gravitropism, but also flowering time. Parental environment affected progeny germination time, flowering and weight of seed the progeny produced. In some cases, the parental environment affected the magnitude of (interacted with) the observed seed size effects. These data indicate that life history circumstances of the parental generation can affect growth and development throughout the life cycle of the next generation to an extent that should be considered when performing genetic studies.
Minimum hydraulic safety leads to maximum water‐use efficiency in a forage grass
Authors: HOLLOWAY‐PHILLIPS MEISHA‐MARIKA , BRODRIBB TIMOTHY J.
Published: October 2010

Understanding how water‐use regulation relates to biomass accumulation is imperative for improving crop production in water‐limited environments. Here, we examine how the vulnerability of xylem to water stress‐induced cavitation and the coordination between water transport capacity and assimilation (A) influences diurnal water‐use efficiency (WUE) and dry‐matter production in Lolium perenne L. – a commercial forage grass. Plants were exposed to a range of water stresses, causing up to 90% leaf death, by withholding water and then rewatering to observe the recovery process. Leaf hydraulic conductance (Kleaf) declined to 50% of maximum at a leaf water potential (ψleaf) of −1 MPa, whereas complete stomatal closure occurred well after this point, at −2.35 MPa, providing no protection against hydraulic dysfunction. Instantaneous A remained maximal until >70% of hydraulic conductivity had been lost. Post‐stress rewatering showed that 95% loss of Kleaf could be incurred before the recovery of gas exchange exceeded 1 d, with a rapid transition to leaf death after this point. Plants exposed to sustained soil water deficits through restricted nightly watering regimes did not suffer cumulative losses in Kleaf; instead, ψleaf and gas exchange recovered diurnally. The effect was improved WUE during the day and optimal ψleaf during the night for the maintenance of growth.
Regulation of xenogeneic porcine pancreatic islets
Authors: Arcidiacono Judith A. , Evdokimov Evgenij , Lee Mark H. , Jones Jeff , Rudenko Larisa , Schneider Bruce , Snoy Phillip J. , Wei Cheng‐Hong , Wensky Allen K. , Wonnacott Keith
Published: October 2010

Arcidiacono JA, Evdokimov E, Lee MH, Jones J, Rudenko L, Schneider B, Snoy PJ, Wei C‐H, Wensky AK, Wonnacott K. Regulation of xenogeneic porcine pancreatic islets. Xenotransplantation 2010; 17: 329–337. © 2010 John Wiley & Sons A/S.

Abstract:  The use of xenogeneic porcine pancreatic islets has been shown to be a potentially promising alternative to using human allogeneic islets to treat insulin‐dependent type 1 diabetes (T1D). This article provides an overview of the existing FDA regulatory framework that would be applied to the regulation of clinical trials utilizing xenogeneic porcine pancreatic islets to treat T1D.
Transplantation of mouse embryonic stem cells induces hematopoietic and tissue chimerism in rats
Authors: Baertschiger Reto M. , Gonelle‐Gispert Carmen , Morel Philippe , Sgroi Antonino , Serre‐Beinier Veronique , Stouffs Michael , Jaconi Marisa E. , Bühler Leo H.
Published: October 2010

Baertschiger RM, Gonelle‐Gispert C, Morel P, Sgroi A, Serre‐Beinier V, Stouffs M, Jaconi ME, Bühler LH. Transplantation of mouse embryonic stem cells induces hematopoietic and tissue chimerism in rats. Xenotransplantation 2010; 17: 362–369. © 2010 John Wiley & Sons A/S.

Abstract:  Embryonic stem cells (ESC) can differentiate into all cell lineages, and ESC‐like cells were shown to induce hematopoietic chimerism and tolerance in allogeneic models. The aim of our study was to test the capacity of mouse ESC (mESC) to engraft in rats in a xenotransplantation setting. Forty‐six rats were transplanted intravenously with 1 million mESC, without immunosuppression (group 1, n = 23) or with cyclosporine (group 2, n = 23). Three months after mESC transplantation, skin grafts were performed from allogeneic, xenogeneic identical to mESC, or xenogeneic third party donors. At day 27 post‐transplant, we detected circulating mouse cells in the blood of 4/23 and 5/23 animals of group 1 and group 2, respectively. Chimerism was confirmed by PCR. We also identified long‐term surviving murine cells within livers of chimeric animals. Skin grafts showed no difference in survival between allogeneic and xenogeneic donors. Transplantation of xenogeneic mouse ESC induced short‐term chimerism in the blood and persistent tissue chimerism in the liver of recipient rats, but did not induce tolerance to skin grafts. Improved immunosuppressive protocols should be tested to prolong chimerism and allow tolerance.
Korean attitudes to Xenotransplantation: a survey conducted in 20091
Authors: Mo Hyojung , Kwon Ivo
Published: October 2010

Mo H, Kwon I. Korean attitudes to Xenotransplantation: a survey conducted in 2009. Xenotransplantation 2010; 17: 391–395. © 2010 John Wiley & Sons A/S.

Abstract: Background:  Xenotransplantation research has been being actively conducted in Korea. However, there are numbers of socio‐ethical issues involved in this research, and it is necessary to know public attitudes toward the research, inducing “public consensus” for the sound development of the technology.

Materials and methods:  A telephone survey consisting of 10 questionnaire items was conducted to investigate the attitudes of Koreans on social and ethical issues related to xenotransplantation. Participants were randomly selected in proportion to the 2009 Korean population census. The response rate was 22.3%. Finally, 500 sets of data were collected and analyzed with SPSS® 12. A statistical analysis was performed using the chi‐square test.

Results:  In the first phase of the study, 69.8% of the respondents were positive about xenotransplantation while 29.0% were negative. However, after being informed of the specific benefit and risk, 58.4% of the respondents stated that xenotransplantation research should be continued, while 38.6% of them indicated that these studies should be prohibited; 63.0% of the respondents agreed with lifelong surveillance after xenotransplantation, while 34.0% disagreed. To avoid triggering immune response in the transplantees, 63.0% of the respondents also approved of the necessity of genetic modification of pigs. If xenotransplantation proves to be safe, 56.8% of the respondents said that they would accept it if necessary; 69.8% of the respondents would recommend it for their family members and friends as a therapeutic option if they are in need. Men were more positive than women about the necessity of animal experimentation for xenotransplantation research, the necessity of lifelong surveillance, and the necessity of genetic modification of pigs. There was no significant difference between the religious and non‐religious group except about the issue of lifelong surveillance.

Conclusion:  Korean people have relatively positive attitudes toward xenotransplantation research and animal experiments regarding xenotransplantation.
The fate of human platelets perfused through the pig liver: implications for xenotransplantation
Authors: Burlak Christopher , Paris Leela L. , Chihara Ray K. , Sidner Richard A. , Reyes Luz M. , Downey Susan M. , Tector A. Joseph
Published: October 2010

Burlak C, Paris LL, Chihara RK, Sidner RA, Reyes LM, Downey SM, Tector AJ. The fate of human platelets perfused through the pig liver: implications for xenotransplantation. Xenotransplantation 2010; 17: 350–361. © 2010 John Wiley & Sons A/S.

Abstract: Background:  Pig liver xenotransplantation could offset the shortage of livers available for orthotopic liver transplantation. Studies in pig and baboon liver xenografts revealed the main obstacle to be a lethal thrombocytopenia that occurred within minutes to hours of transplantation.

Methods:  We have created a model of xenotransplantation‐induced thrombocytopenia using ex vivo pig liver perfusion with human platelets. Thrombocytopenia was examined using fluorescently labeled platelets during the ex vivo perfusion and coculture with primary liver sinusoidal endothelial cells (LSEC).

Results:  Ex vivo liver perfusion revealed that 93% of human platelets were removed from circulation after 15 min. Endothelial cells and platelets were not activated based on tissue factor release into the perfusate. Biopsies from the ex vivo perfusion at 15 and 30 min and in vitro analysis indicated that human platelets are phagocytosed by pig LSEC and degraded in phagosomes. Sixty to 120 min after the addition of platelets to the ex vivo perfusion system, we observed platelet fragments and degraded platelets in hepatocytes. Platelet phagocytosis was not mediated by opsonization as Fc blocking had no effect on platelet phagocytosis. In vitro uptake of human platelets by primary LSEC cultures peaked at 15 min followed by a greater than 55% decrease in platelet fluorescence after 3 h. Primary pig LSEC phagosomes containing human platelets were colocalized with lysosomes positive for lysosome‐associated membrane protein‐1 (LAMP1), indicating the formation of mature phagosomes within pig LSEC.

Conclusions:  Our observation of pig LSEC phagocytosis of human platelets describes a novel mechanism of large‐particle uptake in the liver. The creation of a model system to study xenotransplantation‐induced thrombocytopenia makes possible the investigation into mechanisms that mediate platelet loss.
Creation of a prevascularized site for cell transplantation in rats
Authors: Stiegler Philipp , Matzi Veronika , Pierer Eve , Hauser Oliver , Schaffellner Silvia , Renner Heiko , Greilberger Joachim , Aigner Reingard , Maier Alfred , Lackner Carolin , Iberer Florian , Smolle‐Jüttner Freyja‐Maria , Tscheliessnigg Karlheinz , Stadlbauer Vanessa
Published: October 2010

Stiegler P, Matzi V, Pierer E, Hauser O, Schaffellner S, Renner H, Greilberger J, Aigner R, Maier A, Lackner C, Iberer F, Smolle‐Jüttner F‐M, Tscheliessnigg K, Stadlbauer V. Creation of a prevascularized site for cell transplantation in rats. Xenotransplantation 2010; 17: 379–390. © 2010 John Wiley & Sons A/S.

Abstract: Introduction:  Transplanted cells, especially islet cells, are likely to become apoptotic due to local hypoxia leading to graft dysfunction. Isolated pancreatic islet cells depend on the diffusion of oxygen from the surrounding tissue; therefore, access to sufficient oxygen supply is beneficial, particularly when microcapsules are used for immunoisolation in xenotransplantation. The aim of this study was to create a prevascularized site for cell transplantation in rats and test its effectiveness with microencapsulated HEK293 cells.

Methods:  The combination of implantation of a foam dressing, vacuum‐assisted wound closure (foam+VAC) and hyperbaric oxygenation (HBO) was used in 40 Sprague‐Dawley rats. Blood flow and vascular endothelial growth factor (VEGF) levels were determined. Sodium cellulose sulphate (SCS)‐microencapsulated HEK293 cells were xenotransplanted into the foam dressing in rats pre‐treated with HBO, and angiogenesis and apoptosis were assessed.

Results:  Vessel ingrowth and VEGF levels increased depending on the duration of HBO treatment. The area containing the foam was perfused significantly better in the experimental groups when compared to controls. Only a small amount of apoptosis occurs in SCS‐microencapsulated HEK293 cells after xenotransplantation.

Conclusion:  As ischemia‐damaged cells are likely to undergo cell death or loose functionality due to hypoxia, therefore leading to graft dysfunction, the combination foam+VAC and HBO might be a promising method to create a prevascularized site to achieve better results in xenogeneic cell transplantation.
The immunology of corneal xenotransplantation: a review of the literature
Authors: Hara Hidetaka , Cooper David K. C.
Published: October 2010

Hara H, Cooper DKC. The immunology of corneal xenotransplantation: a review of the literature. Xenotransplantation 2010; 17: 338–349. © 2010 John Wiley & Sons A/S.

Abstract: As the worldwide demand for human donor corneas far exceeds supply, there is a need for a new source of corneas for clinical transplantation. Genetically engineered pigs may prove to be that new source, particularly as current evidence indicates that the anatomical and biomechanical properties of human and pig corneas are similar. Experience with clinical and experimental corneal xenotransplantation has been comprehensively reviewed and is summarized. Studies in small and large animal models have documented that both humoral and cellular immune responses play roles in xenograft rejection. Recent progress in the genetic manipulation of pigs has led to the prospect that clinical corneal xenotransplantation, in the absence of exogenous immunosuppressive therapy, may become successful in the foreseeable future.
Phylogeography of the mud crab (Scylla serrata) in the Indo‐West Pacific reappraised from mitochondrial molecular and oceanographic clues: transoceanic dispersal and coastal sequential colonization
Authors: He Lijun , Zhang Aibing , Zhu Chaodong , Weese David , Qiao Zhenguo
Published: October 2010

The widespread mud crab, Scylla serrata, of the Indo‐West Pacific is an excellent model species to demonstrate how the colonization history of a species can be influenced by complex oceanographic conditions. Through the combination of ecological data (fossil records and paleo‐oceanographic conditions) and molecular data (coalescent simulations, network analysis, and nucleotide diversity tests), the phylogeographic history of S. serrata was re‐analyzed. Based on the analysis of mtDNA cytochrome oxidase I sequences, two major clades were identified for S. serrata, including a widespread clade (Clade I) with three disjunct geographic clusters (IA, IB and IC) and an endemic Northwest Australian clade (Clade II). Moreover, a significant phylogeographic structure corresponding to four subpopulations was revealed: Northwest Australia, West Indian Ocean, Red Sea‐South China Sea and West Pacific. A colonization history of a Northwest Australia origin for S. serrata followed by westward transmarine dispersal across the Indian Ocean for Clade I and sequential colonization from the West Indian Ocean to Red Sea‐South China Sea and West Pacific was corroborated. The Pleistocene fluctuations of paleo‐oceanographic conditions including surface circulations and physical topography in the Indo‐West Pacific might be responsible for the wide distribution, colonization history and genetic divergence of this species.