bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining the transgene containment level provided by chloroplast transformation
Authors: Ruf Stephanie , Karcher Daniel , Bock Ralph
Published: April 2007

Plastids (chloroplasts) are maternally inherited in most crops. Maternal inheritance excludes plastid genes and transgenes from pollen transmission. Therefore, plastid transformation is considered a superb tool for ensuring transgene containment and improving the biosafety of transgenic plants. Here, we have assessed the strictness of maternal inheritance and the extent to which plastid transformation technology confers an increase in transgene confinement. We describe an experimental system facilitating stringent selection for occasional paternal plastid transmission. In a large screen, we detected low-level paternal inheritance of transgenic plastids in tobacco. Whereas the frequency of transmission into the cotyledons of F
1
seedlings was ≈1.58 × 10
−5
(on 100% cross-fertilization), transmission into the shoot apical meristem was significantly lower (2.86 × 10
−6
). Our data demonstrate that plastid transformation provides an effective tool to increase the biosafety of transgenic plants. However, in cases where pollen transmission must be prevented altogether, stacking with other containment methods will be necessary to eliminate the residual outcrossing risk.
High-affinity single-domain binding proteins with a binary-code interface
Authors: Koide Akiko , Gilbreth Ryan N. , Esaki Kaori , Tereshko Valentina , Koide Shohei
Published: April 2007

High degrees of sequence and conformation complexity found in natural protein interaction interfaces are generally considered essential for achieving tight and specific interactions. However, it has been demonstrated that specific antibodies can be built by using an interface with a binary code consisting of only Tyr and Ser. This surprising result might be attributed to yet undefined properties of the antibody scaffold that uniquely enhance its capacity for target binding. In this work we tested the generality of the binary-code interface by engineering binding proteins based on a single-domain scaffold. We show that Tyr/Ser binary-code interfaces consisting of only 15–20 positions within a fibronectin type III domain (FN3; 95 residues) are capable of producing specific binding proteins (termed “monobodies”) with a low-nanomolar
K
d
. A 2.35-Å x-ray crystal structure of a monobody in complex with its target, maltose-binding protein, and mutation analysis revealed dominant contributions of Tyr residues to binding as well as striking molecular mimicry of a maltose-binding protein substrate, β-cyclodextrin, by the Tyr/Ser binary interface. This work suggests that an interaction interface with low chemical diversity but with significant conformational diversity is generally sufficient for tight and specific molecular recognition, providing fundamental insights into factors governing protein–protein interactions.
Insertion of group II intron retroelements after intrinsic transcriptional terminators
Authors: Robart Aaron R. , Seo Wooseok , Zimmerly Steven
Published: April 2007

Mobile DNAs use many mechanisms to minimize damage to their hosts. Here we show that a subclass of group II introns avoids host damage by inserting directly after transcriptional terminator motifs in bacterial genomes (stem-loops followed by Ts). This property contrasts with the site-specific behavior of most group II introns, which insert into homing site sequences. Reconstituted ribonucleo protein particles of the
Bacillus halodurans
intron
B.h
.I1 are shown to reverse-splice into DNA targets
in vitro
but require the DNA to be single-stranded and fold into a stem-loop analogous to the RNA structure that forms during transcription termination. Recognition of this DNA stem-loop motif accounts for
in vivo
target specificity. Insertion after terminators is a previously unrecognized strategy for a selfish DNA because it prevents interruption of coding sequences and restricts expression of the mobile DNA after integration.
Genesis of hexavalent chromium from natural sources in soil and groundwater
Authors: Oze Christopher , Bird Dennis K. , Fendorf Scott
Published: April 2007

Naturally occurring Cr(VI) has recently been reported in ground and surface waters. Rock strata rich in Cr(III)-bearing minerals, in particular chromite, are universally found in these areas that occur near convergent plate margins. Here we report experiments demonstrating accelerated dissolution of chromite and subsequent oxidation of Cr(III) to aqueous Cr(VI) in the presence of birnessite, a common manganese mineral, explaining the generation of Cr(VI) by a Cr(III)-bearing mineral considered geochemically inert. Our results demonstrate that Cr(III) within ultramafic- and serpentinite-derived soils/sediments can be oxidized and dissolved through natural processes, leading to hazardous levels of aqueous Cr(VI) in surface and groundwater.
Lung metastasis genes couple breast tumor size and metastatic spread
Authors: Minn Andy J. , Gupta Gaorav P. , Padua David , Bos Paula , Nguyen Don X. , Nuyten Dimitry , Kreike Bas , Zhang Yi , Wang Yixin , Ishwaran Hemant , Foekens John A. , van de Vijver Marc , Massagué Joan
Published: April 2007

The association between large tumor size and metastatic risk in a majority of clinical cancers has led to questions as to whether these observations are causally related or whether one is simply a marker for the other. This is partly due to an uncertainty about how metastasis-promoting gene expression changes can arise in primary tumors. We investigated this question through the analysis of a previously defined “lung metastasis gene-expression signature” (LMS) that mediates experimental breast cancer metastasis selectively to the lung and is expressed by primary human breast cancer with a high risk for developing lung metastasis. Experimentally, we demonstrate that the LMS promotes primary tumor growth that enriches for LMS
+
cells, and it allows for intravasation after reaching a critical tumor size. Clinically, this corresponds to LMS
+
tumors being larger at diagnosis compared with LMS
−
tumors and to a marked rise in the incidence of metastasis after LMS
+
tumors reach 2 cm. Patients with LMS-expressing primary tumors selectively fail in the lung compared with the bone or other visceral sites and have a worse overall survival. The mechanistic linkage between metastasis gene expression, accelerated tumor growth, and likelihood of metastatic recurrence provided by the LMS may help to explain observations of prognostic gene signatures in primary cancer and how tumor growth can both lead to metastasis and be a marker for cells destined to metastasize.
Ancient DNA reveals lack of postglacial habitat tracking in the arctic fox
Authors: Dalén Love , Nyström Veronica , Valdiosera Cristina , Germonpré Mietje , Sablin Mikhail , Turner Elaine , Angerbjörn Anders , Arsuaga Juan Luis , Götherström Anders
Published: April 2007

How species respond to an increased availability of habitat, for example at the end of the last glaciation, has been well established. In contrast, little is known about the opposite process, when the amount of habitat decreases. The hypothesis of habitat tracking predicts that species should be able to track both increases and decreases in habitat availability. The alternative hypothesis is that populations outside refugia become extinct during periods of unsuitable climate. To test these hypotheses, we used ancient DNA techniques to examine genetic variation in the arctic fox (Alopex lagopus) through an expansion/contraction cycle. The results show that the arctic fox in midlatitude Europe became extinct at the end of the Pleistocene and did not track the habitat when it shifted to the north. Instead, a high genetic similarity between the extant populations in Scandinavia and Siberia suggests an eastern origin for the Scandinavian population at the end of the last glaciation. These results provide new insights into how species respond to climate change, since they suggest that populations are unable to track decreases in habitat avaliability. This implies that arctic species may be particularly vulnerable to increases in global temperatures.
Analysis ofPALB2/FANCN-associated breast cancer families
Authors: Tischkowitz Marc , Xia Bing , Sabbaghian Nelly , Reis-Filho Jorge S. , Hamel Nancy , Li Guilan , van Beers Erik H. , Li Lili , Khalil Tayma , Quenneville Louise A. , Omeroglu Atilla , Poll Aletta , Lepage Pierre , Wong Nora , Nederlof Petra M. , Ashworth Alan , Tonin Patricia N. , Narod Steven A. , Livingston David M. , Foulkes William D.
Published: April 2007

No more than ≈30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such asBRCA1,BRCA2,TP53,CHEK2,ATM, andFANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship withBRCA2,PALB2was sequenced in affected probands from 68BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. The average BRCAPRO score was 0.58. A truncating mutation (229delT) was identified in one family with a strong history of breast cancer (seven breast cancers in three female mutation carriers). This mutation and its associated breast cancers were characterized with another recently reported but unstudied mutation (2521delA) that is also associated with a strong family history of breast cancer. There was no loss of heterozygosity in tumors with either mutation. Moreover, comparative genomic hybridization analysis showed major similarities to that ofBRCA2tumors but with some notable differences, especially loss of 18q, a change that was previously unknown inBRCA2tumors and less common in sporadic breast cancer. This study supports recent observations thatPALB2mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least somePALB2mutations are associated with a substantially increased risk for the disease.
Direct and adaptor-mediated substrate recognition by an essential AAA+ protease
Authors: Chien Peter , Perchuk Barrett S. , Laub Michael T. , Sauer Robert T. , Baker Tania A.
Published: April 2007

Regulated proteolysis is required to execute many cellular programs. In
Caulobacter crescentus
, timely degradation of the master regulator CtrA by ClpXP protease is essential for cell-cycle progression and requires the colocalization of CtrA and RcdA. Here, we establish a biochemical framework to understand regulated proteolysis in
C. crescentus
and show that RcdA is not an adaptor for CtrA degradation. CtrA is rapidly degraded without RcdA and is recognized with an affinity comparable with the best ClpXP substrates. In contrast, SspBα, the α-proteobacterial homolog of SspB, functions as an adaptor to enhance degradation of specific substrates. Cargo-free SspBα is also itself a substrate of ClpXP-mediated proteolysis. Thus, our analysis (
i
) reveals the consequences of both direct and adaptor-stimulated recognition in mediating substrate specificity
in vitro
, (
ii
) reveals a potential regulatory role of controlled adaptor stability, and (
iii
) suggests that cell-cycle regulation of CtrA stability depends on repression of its intrinsic degradation rather than adaptor-mediated enhancement.
Enhanced EGFP-chromophore-assisted laser inactivation using deficient cells rescued with functional EGFP-fusion proteins
Authors: Vitriol Eric A. , Uetrecht Andrea C. , Shen Feimo , Jacobson Ken , Bear James E.
Published: April 2007

Chromophore-assisted laser inactivation (CALI) is a light-mediated technique that offers precise spatiotemporal control of protein inactivation, enabling better understanding of the protein's role in cell function. EGFP has been used effectively as a CALI chromophore, and its cotranslational attachment to the target protein avoids having to use exogenously added labeling reagents. A potential drawback to EGFP-CALI is that the CALI phenotype can be obscured by the endogenous, unlabeled protein that is not susceptible to light inactivation. Performing EGFP-CALI experiments in deficient cells rescued with functional EGFP-fusion proteins permits more complete loss of function to be achieved. Here, we present a modified lentiviral system for rapid and efficient generation of knockdown cell lines complemented with physiological levels of EGFP-fusion proteins. We demonstrate that CALI of EGFP-CapZβ increases uncapped actin filaments, resulting in enhanced filament growth and the formation of numerous protrusive structures. We show that these effects are completely dependent upon knocking down the endogenous protein. We also demonstrate that CALI of EGFP-Mena in Mena/VASP-deficient cells stabilizes lamellipodial protrusions.
Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase
Authors: Acconcia Filippo , Barnes Christopher J. , Singh Rajesh R. , Talukder Amjad H. , Kumar Rakesh
Published: April 2007

Integrin-linked kinase (ILK) is a phosphorylated protein that regulates physiological processes that overlap with those regulated by p21-activated kinase 1 (PAK1). Here we report the possible role of ILK phosphorylation by PAK1 in ILK-mediated signaling and intracellular translocation. We found that PAK1 phosphorylates ILK at threonine-173 and serine-246
in vitro
and
in vivo
. Depletion of PAK1 decreased the levels of endogenous ILK phosphorylation
in vivo
. Mutation of PAK1 phosphorylation sites on ILK to alanine reduced cell motility and cell proliferation. Biochemical fractionation, confocal microscopy, and chromatin-interaction analyses of human cells revealed that ILK localizes predominantly in the cytoplasm but also resides in the nucleus. Transfection of MCF-7 cells with point mutants ILK-T173A, ILK-S246A, or ILK-T173A; S246A (ILK-DM) altered ILK localization. Selective depletion of PAK1 dramatically increased the nuclear and focal point accumulation of ILK, further demonstrating a role for PAK1 in ILK translocation. We also identified functional nuclear localization sequence and nuclear export sequence motifs in ILK, delineated an apparently integral role for ILK in maintaining normal nuclear integrity, and established that ILK interacts with the regulatory region of the
CNKSR3
gene chromatin to negatively modulate its expression. Together, these results suggest that ILK is a PAK1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin.
De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells
Authors: Tadokoro Yuko , Ema Hideo , Okano Masaki , Li En , Nakauchi Hiromitsu
Published: April 2007

DNA methylation is an epigenetic modification essential for development. The DNA methyltransferases Dnmt3a and Dnmt3b execute de novo DNA methylation in gastrulating embryos and differentiating germline cells. It has been assumed that these enzymes generally play a role in regulating cell differentiation. To test this hypothesis, we examined the role of Dnmt3a and Dnmt3b in adult stem cells. CD34−/low, c-Kit+, Sca-1+, lineage marker− (CD34− KSL) cells, a fraction of mouse bone marrow cells highly enriched in hematopoietic stem cells (HSCs), expressed both Dnmt3a and Dnmt3b. Using retroviral Cre gene transduction, we conditionally disrupted Dnmt3a, Dnmt3b, or both Dnmt3a and Dnmt3b (Dnmt3a/Dnmt3b) in CD34− KSL cells purified from mice in which the functional domains of these genes are flanked by two loxP sites. We found that Dnmt3a and Dnmt3b function as de novo DNA methyltransferases during differentiation of hematopoietic cells. Unexpectedly, in vitro colony assays and in vivo transplantation assays showed that both myeloid and lymphoid lineage differentiation potentials were maintained in Dnmt3a-, Dnmt3b-, and Dnmt3a/Dnmt3b-deficient HSCs. However, Dnmt3a/Dnmt3b-deficient HSCs, but not Dnmt3a- or Dnmt3b-deficient HSCs, were incapable of long-term reconstitution in transplantation assays. These findings establish a critical role for DNA methylation by Dnmt3a and Dnmt3b in HSC self-renewal.
Antiviral CD4+ memory T cells are IL-15 dependent
Authors: Purton Jared F. , Tan Joyce T. , Rubinstein Mark P. , Kim David M. , Sprent Jonathan , Surh Charles D.
Published: April 2007

Survival and intermittent proliferation of memory CD4+ and CD8+ T cells appear to be controlled by different homeostatic mechanisms. In particular, contact with interleukin (IL)-15 has a decisive influence on memory CD8+ cells, but not memory CD4+ cells. Past studies of memory CD4+ cells have relied heavily on the use of naturally occurring memory phenotype (MP) cells as a surrogate for antigen (Ag)-specific memory cells. However, we show here that MP CD4+ cells contain a prominent subset of rapidly proliferating major histocompatibility complex (MHC) II–dependent cells. In contrast, Ag-specific memory CD4 cells have a slow turnover rate and are MHC II independent. In irradiated hosts, these latter cells ignore IL-15 and expand in response to the elevated levels of IL-7 in the lymphopenic hosts. In contrast, in normal nonlymphopenic hosts where IL-7 levels are low, memory CD4 cells are heavily dependent on IL-15. Significantly, memory CD4+ responsiveness to endogenous IL-15 reflects marked competition from other cells, especially CD8+ and natural killer cells, and increases considerably after removal of these cells. Therefore, under normal physiological conditions, homeostasis of CD8+ and CD4+ memory cells is quite similar and involves IL-15 and IL-7.
Enhancement and suppression of signaling by the conserved tail of IgG memory–type B cell antigen receptors
Authors: Horikawa Keisuke , Martin Stephen W. , Pogue Sarah L. , Silver Karlee , Peng Kaiman , Takatsu Kiyoshi , Goodnow Christopher C.
Published: April 2007

Immunological memory is characterized by heightened immunoglobulin (Ig) G antibody production caused in part by enhanced plasma cell formation conferred by conserved transmembrane and cytoplasmic segments in isotype-switched IgG B cell receptors. We tested the hypothesis that the IgG tail enhances intracellular B cell antigen receptor (BCR) signaling responses to antigen by analyzing B cells from Ig transgenic mice with IgM receptors or chimeric IgMG receptors containing the IgG tail segment. The IgG tail segment enhanced intracellular calcium responses but not tyrosine or extracellular signal–related kinase (ERK) phosphorylation. Biochemical analysis and crosses to CD22-deficient mice established that IgG tail enhancement of calcium and antibody responses, as well as marginal zone B cell formation, was not due to diminished CD22 phosphorylation or inhibitory function. Microarray profiling showed no evidence for enhanced signaling by the IgG tail for calcium/calcineurin, ERK, or nuclear factor κB response genes and little evidence for any enhanced gene induction. Instead, almost half of the antigen-induced gene response in IgM B cells was diminished 50–90% by the IgG tail segment. These findings suggest a novel “less-is-more” hypothesis to explain how switching to IgG enhances B cell memory responses, whereby decreased BCR signaling to genes that oppose marginal zone and plasma cell differentiation enhances the formation of these key cell types.
Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection
Authors: Shin Haina , Blackburn Shawn D. , Blattman Joseph N. , Wherry E. John
Published: April 2007

Efficient maintenance of memory CD8 T cells is central to long-term protective immunity. IL-7– and IL-15–driven homeostatic proliferation is essential for long-term memory CD8 T cell persistence after acute infections. During chronic infections, however, virus-specific CD8 T cells respond poorly to these cytokines. Yet, virus-specific CD8 T cells often persist for long periods of time during chronic infections. We have addressed this apparent paradox by examining the mechanism for maintaining virus-specific CD8 T cells during chronic infection. We find that homeostatic cytokines (e.g., IL-7/15), inflammatory signals, and priming of recent thymic emigrants are not sufficient to maintain virus-specific CD8 T cells over time during chronic infection. Rather, our results demonstrate that viral peptide is required for virus-specific CD8 T cell persistence during chronic infection. Moreover, this viral antigen-dependent maintenance results in a dramatically different type of T cell division than is normally observed during memory T cell homeostasis. Rather than undergoing slow, steady homeostatic turnover during chronic viral infection, CD8 T cells undergo extensive peptide-dependent division, yet cell numbers remain relatively stable. These results indicate that antigen-specific CD8 T cell responses during persisting infection are maintained by a mechanism distinct from that after acute infection.
IgG1 B cell receptor signaling is inhibited by CD22 and promotes the development of B cells whose survival is less dependent on Igα/β
Authors: Waisman Ari , Kraus Manfred , Seagal Jane , Ghosh Snigdha , Melamed Doron , Song Jian , Sasaki Yoshiteru , Classen Sabine , Lutz Claudia , Brombacher Frank , Nitschke Lars , Rajewsky Klaus
Published: April 2007

We describe a mouse strain in which B cell development relies either on the expression of membrane-bound immunoglobulin (Ig) γ1 or μ heavy chains. Progenitor cells expressing γ1 chains from the beginning generate a peripheral B cell compartment of normal size with all subsets, but a partial block is seen at the pro– to pre–B cell transition. Accordingly, γ1-driven B cell development is disfavored in competition with developing B cells expressing a wild-type (WT) IgH locus. However, the mutant B cells display a long half-life and accumulate in the mature B cell compartment, and even though partial truncation of the Igα cytoplasmic tail compromises their development, it does not affect their maintenance, as it does in WT cells. IgG1-expressing B cells showed an enhanced Ca2+ response upon B cell receptor cross-linking, which was not due to a lack of inhibition by CD22. The enhanced Ca2+ response was also observed in mature B cells that had been switched from IgM to IgG1 expression in vivo. Collectively, these results suggest that the γ1 chain can exert a unique signaling function that can partially replace that of the Igα/β heterodimer in B cell maintenance and may contribute to memory B cell physiology.
The mode and tempo of genome size evolution in eukaryotes
Authors: Oliver Matthew J. , Petrov Dmitri , Ackerly David , Falkowski Paul , Schofield Oscar M.
Published: April 2007

Eukaryotic genome size varies over five orders of magnitude; however, the distribution is strongly skewed toward small values. Genome size is highly correlated to a number of phenotypic traits, suggesting that the relative lack of large genomes in eukaryotes is due to selective removal. Using phylogenetic contrasts, we show that the rate of genome size evolution is proportional to genome size, with the fastest rates occurring in the largest genomes. This trend is evident across the 20 major eukaryotic clades analyzed, indicating that over long time scales, proportional change is the dominant and universal mode of genome-size evolution in eukaryotes. Our results reveal that the evolution of eukaryotic genome size can be described by a simple proportional model of evolution. This model explains the skewed distribution of eukaryotic genome sizes without invoking strong selection against large genomes.
Flavonoids inhibit the platelet TxA2signalling pathway and antagonize TxA2receptors (TP) in platelets and smooth muscle cells
Authors: Guerrero José A. , Navarro‐Nuñez Leyre , Lozano María L. , Martínez Constantino , Vicente Vicente , Gibbins Jonathan M. , Rivera José
Published: April 2007

What is already known about this subject

• Flavonoids are largely recognized as potential inhibitors of platelet function, through nonspecific mechanisms such as antioxidant activity and/or inhibition of several enzymes and signalling proteins.

• In addition, we, and few others, have shown that certain antiaggregant flavonoids may behave as specific TXA2 receptor (TP) ligands in platelets.

• Whether flavonoids interact with TP isoforms in other cell types is not known, and direct evidence that flavonoid–TP interaction inhibits signalling downstream TP has not been shown.

What this study adds

• This study first demonstrates that certain flavonoids behave as ligands for both TP isoforms, not only in platelets, but also in human myometrium and in TP‐transfected HEK 293T cells.

• Differences in the effect of certain flavonoids in platelet signalling, induced by either U46619 or thrombin, suggest that abrogation of downstream TP signalling is related to their specific blockage of the TP, rather than to a nonspecific effect on tyrosine kinases or other signalling proteins.

Aims

Flavonoids may affect platelet function by several mechanisms, including antagonism of TxA2receptors (TP). These TP are present in many tissues and modulate different signalling cascades. We explored whether flavonoids affect platelet TP signalling, and if they bind to TP expressed in other cell types.

Methods

Platelets were treated with flavonoids, or other selected inhibitors, and then stimulated with U46619. Similar assays were performed in aspirinized platelets activated with thrombin. Effects on calcium release were analysed by fluorometry and changes in whole protein tyrosine phosphorylation and activation of ERK 1/2 by Western blot analysis. The binding of flavonoids to TP in platelets, human myometrium and TPα‐ and TPβ‐transfected HEK 293T cells was explored using binding assays and the TP antagonist3H‐SQ29548.

Results

Apigenin, genistein, luteolin and quercetin impaired U46619‐induced calcium mobilization in a concentration‐dependent manner (IC5010–30 µm). These flavonoids caused a significant impairment of U46619‐induced platelet tyrosine phosphorylation and of ERK 1/2 activation. By contrast, in aspirin‐treated platelets all these flavonoids, except quercetin, displayed minor effects on thrombin‐induced calcium mobilization, ERK 1/2 and total tyrosine phosphorylation. Finally, apigenin, genistein and luteolin inhibited by >50%3H‐SQ29548 binding to different cell types.

Conclusions

These data further suggest that flavonoids may inhibit platelet function by binding to TP and by subsequent abrogation of downstream signalling. Binding of these compounds to TP occurs in human myometrium and in TP‐transfected HEK 293T cells and suggests that antagonism of TP might mediate the effects of flavonoids in different tissues.
Effect of timing of dosing in relation to food intake on the pharmacokinetics of esomeprazole
Authors: Sostek Mark B. , Chen Yusong , Andersson Tommy
Published: April 2007

What is already known about this subject

Systemic esomeprazole exposure is decreased when administered simultaneously with food.

What this study adds

Taking esomeprazole within 15 min of eating a high‐fat, high‐calorie meal results in reduced systemic drug exposure.

Aim

To investigate the pharmacokinetics of esomeprazole before a high‐fat meal vs. fasting.

Methods

This open‐label, randomized, crossover study consisted of two 5‐day dosing periods of esomeprazole 40 mg per day. On days 1 and 5, subjects received esomeprazole 15 min before a high‐fat meal (fed) or 4 h before a non‐high‐fat meal (fasting).

Results

On days 1 and 5, ratio of fed to fasting area under the plasma concentration–time curve [0.56, 90% confidence interval (CI) 0.50, 0.64, and 0.78, 90% CI 0.74, 0.82, respectively] and peak plasma concentration (0.34, 90% CI 0.28, 0.41, and 0.47, 90% CI 0.41, 0.52, respectively) were outside of the limits of bioequivalence.

Conclusions

Esomeprazole bioavailability was reduced when taken within 15 min before eating a high‐fat meal vs. that while fasting.
Effect of renal impairment on the pharmacokinetics of exenatide
Authors: Linnebjerg Helle , Kothare Prajakti A. , Park Soomin , Mace Kenneth , Reddy Shobha , Mitchell Malcolm , Lins Robert
Published: April 2007

What is already known about this subject

• Nonclinical studies have shown that exenatide is primarily cleared by the renal system.

• It was not known to what degree the clinical pharmacokinetics and tolerability would be affected by increasing renal impairment (RI).

What this study adds

• Patients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide.

• However, exenatide is not recommended in patients with severe RI or end‐stage renal disease.

Aims

To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI).

Methods

Exenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft–Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end‐stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single‐dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL.

Results

Mean half‐life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.).

Conclusions

Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD.
A systematic review of lay views about infant size and growth
Authors: Reading Richard
Published: April 2007

.
 
Lucas, P.,
Arai, L.,
Baird, J.,
Kleijnen, J.,
Law, C. &
Roberts, H.
(
2007
)

,
92
,
120
–
127
.
 
DOI: 10.1136/adc.2005.087288.

Objectives  To understand lay views on infant size and growth and their implications for a British population.

Methods  A systematic review of parental and other lay views about the meanings and importance of infant size and growth using Medline, PsycInfo, CINAHL, Sociological Abstracts, IBSS, ASSIA, British Nursing Index ChildData, Caredata, SIGLE, Dissertation Abstracts (US), Index to Theses. A total of 19 studies, most of which reported the views of mothers, from the USA, Canada, the UK and Finland, were reviewed.

Results  Notions of healthy size and growth were dominated by the concept of normality. Participants created norms by assessing and comparing size and growth against several reference points. When size or growth differed from these norms, explanations were sought for factors that would account for this difference. When no plausible explanation could be found, growth or size became a worry for parents.

Conclusions  Parents consider the importance of contextual factors when judging what is appropriate or healthy growth. For public health advice to be effective, lay, as well as scientific, findings and values need to be considered.
Maternal effects and evolution at ecological time‐scales
Authors: RÄSÄNEN K. , KRUUK L. E. B.
Published: April 2007

Genetic and environmental maternal effects can play an important role in the evolutionary dynamics of a population: they may have a substantial impact on the rate and direction of genetic change in response to selection, and they may generate immediate phenotypic change via phenotypic plasticity. Because of this potential to generate rapid phenotypic change in a population, maternal effects may be particularly important for evolution at ecological time‐scales.

Despite an increased interest in the prevalence, composition and adaptive benefits of maternal effects, little is still known of their impact on ecological and evolutionary processes in natural populations. We consider here the insights that a quantitative genetic framework provides into the pathways by which maternal effects can influence trait evolution in wild populations. Widespread evidence for a genetic basis of a range of maternal effects traits reinforces the notion that they cannot be treated as purely environmental sources of variation. We also provide an overview of the impact of environmental conditions on the expression and impact of maternal effects, and describe empirical evidence for their impact on evolution at ecological time‐scales.

We emphasize the need for empirical work to quantify the associations between maternal and offspring phenotype and genotype, and the suite of selection pressures generated by maternal effects, as well as the relationship between maternal effects and environmental variation. Future work should aim to identify the conditions under which maternal effects are likely to play a role in evolution, as well as explicitly test the contribution of maternal effects to evolutionary responses.
Is there a trade‐off between aggressiveness and overwinter survival in Phytophthora infestans?
Authors: MONTARRY J. , CORBIERE R. , ANDRIVON D.
Published: April 2007

Selection during interepidemic stages is crucial for the evolution of pathogen populations. Trade‐offs involving aggressiveness (quantitative pathogenicity) have rarely been explored in pathogens with a life cycle requiring the disease‐causing organism to change organs within the same host.

We investigated the existence of a trade‐off between aggressiveness and survival in Phytophthora infestans, the pathogen causing potato late blight. In France, P. infestans behaves as an obligate biotroph, surviving in infected tubers. Aggressive isolates, which are favoured during the epidemic, may exhaust their nutrient supply too quickly to bridge seasons, resulting in a possible trade‐off between the two life stages.

We inoculated tubers with isolates possessing different aggressiveness levels, let them overwinter as outdoor piles at three different sites, and scored the proportion of live tubers the following spring.

At two sites, infection caused early tuber sprouting, which can be seen either as a manipulation of the host by the pathogen, or as an attempt by the host to escape.

Overwinter survival was higher for control than for inoculated tubers, but did not differ between tubers inoculated with different isolates. This suggests that aggressiveness should gradually increase in P. infestans populations, unless a trade‐off occurs at another stage of the life cycle.
The perpetual forest: using undesirable species to bridge restoration
Authors: KIRKMAN L. KATHERINE , MITCHELL ROBERT J. , KAESER MELANIE J. , PECOT STEPHEN D. , COFFEY KIMBERLY L.
Published: April 2007

Conversion of established forests of undesirable species composition or structure to a multi‐age, native forest community is a common restoration goal. However, for some ecosystems, the complexity of multiple disturbances and biotic factors requires unique approaches to advance community development. We use the longleaf pine (Pinus palustrisMiller) ecosystem as a model of such a restoration paradigm with an approach that utilizes the undesirable species as a functional or structural bridge to foster ecological processes.

In the conversion of adult slash pine (Pinus elliottiiEngelm.) plantations to the biologically diverse longleaf pine forests that once dominated the south‐eastern US Coastal Plain, we examine techniques for restoring and maintaining critical structural and functional components. Through partial and variable retention of the undesirable slash pine canopy, establishment of longleaf pine seedlings is facilitated, while maintaining fuels essential for prescribed fire, a necessary management practice for longleaf pine. Furthermore, we project that with subsequent fires, fine fuels and species richness will be encouraged in the ground cover, and with future slash canopy harvest, established longleaf pine seedlings will be released.

In this study, we present a statistical approach that examines the compositional movement of vegetation in restoration sites over time relative to the reference conditions that are also changing through time.

Synthesis and applications. Restoration efforts that remove undesirable species initially may actually hinder rather than facilitate restoration. Restoration of fire‐maintained ecosystems in which the production of adequate fuels is an important consideration may require the retention of a portion of the existing canopy to provide fuels during the restoration process, even if the canopy is comprised of less preferred species. Individual species often provide similar structural features and influences on function within an ecosystem; thus, systems other than longleaf pine may also benefit from retention of the undesirable species through the restoration process. We conclude that a gradual approach to restoration may be advantageous when legacies of past management have altered complex ecological dynamics and promoted development along a successional pathway strongly differing from that of the reference conditions.
The Uppsala studies on developmental origins of health and disease
Authors: Koupil I.
Published: April 2007

Large‐scale epidemiological studies on developmental origins of health running in Uppsala benefit from the accessibility of well‐archived and high quality Swedish records, high participation rates in the surveys, and a long tradition of interdisciplinary research and international collaboration. The UBCoS Multigen study is unique in being able to study intergenerational determinants of health and health inequalities as ‘forward in time’ processes, starting at the beginning of the last century, whilst the Uppsala Family and ULSAM studies contribute evidence on gene–environment interactions and specific mechanisms of developmental origins of circulatory diseases.
Experimental IUGR and later diabetes
Authors: Martin‐Gronert M. S. , Ozanne S. E.
Published: April 2007

It is widely accepted that an association exists between the intrauterine environment in which a fetus grows and develops and the subsequent development of type 2 diabetes. Any disturbance in maternal ability to provide nutrients and oxygen to the fetus can lead to fetal intrauterine growth restriction (IUGR). Here we will review IUGR in rodent models, in which maternal metabolism has been experimentally manipulated to investigate the molecular basis of the relationship between IUGR and development of type 2 diabetes in later life, and the identification of the molecular derangements in specific metabolically ‐ sensitive organs/tissues.
Developmental plasticity and human disease: research directions
Authors: Gluckman P. D. , Hanson M. A.
Published: April 2007

The conceptual basis of the ‘developmental origins’ paradigm has converged on the role of developmental plasticity responding to signals from the early environment, with heightened risk of disease if the induced phenotype does not match the later environment. Nevertheless, numerous questions remain, including the current burden of disease that can be attributed to early environmental factors; the pathways, mechanisms and windows of plasticity; the identification of early markers of environmentally induced change; and the feasibility, costs and benefits of intervention. A focused agenda of research is needed to convince policy makers of the importance of developmental factors in human disease.
The origins of the developmental origins theory
Authors: Barker D. J. P.
Published: April 2007

Current orthodoxy states that coronary heart disease results from the unhealthy lifestyles of westernized adults together with a contribution from genetic inheritance. This does not provide a secure basis for prevention of the disease. Geographical studies gave the first clue that the disease originates during intra‐uterine development. Variations in mortality from the disease across England and Wales were shown to correlate closely with past differences in death rates among newborn babies. In the past most deaths among newborns were attributed to low birthweight. This led to the hypothesis that undernutrition in utero permanently changes the body's structure, function and metabolism in ways that lead to coronary heart disease in later life. The association between low birthweight and coronary heart disease has been confirmed in longitudinal studies of men and women around the world. The developmental model of the origins of the disease offers a new way forward.
Exogenous Androgen Treatment Delays the Stress Response Following Hamster Facial Nerve Injury
Authors: Tetzlaff J. , Tanzer L. , Jones K. J.
Published: April 2007

Following injury or stress of any type, cells undergo a stress response, involving the cessation of general protein synthesis and the up‐regulation of heat shock proteins (HSP), which have been implicated in promoting cell survival and repair. In a variety of neuronal injury models, including the hamster facial motoneurone (FMN) model, steroid hormones augment regeneration and are neuroprotective. We have previously shown that facial nerve axotomy induces expression of HSP70 (HSP70) and/or up‐regulates constitutively expressed HSP70 (HSC70) mRNA in axotomised hamster FMN and that testosterone propionate (TP) treatment reduces this response. These previous studies were unable to differentiate between HSC70 mRNA and HSP70 mRNA. Therefore, an objective of the present study was to determine which HSP (HSC70 or HSP70) was being up‐regulated by axotomy and reduced by TP. Axotomy increased HSC70 protein in axotomised and non‐axotomised FMN, relative to untreated baseline hamsters. Interestingly, TP transiently delayed the stress‐induced up‐regulation of HSC70 protein in axotomised FMN compared to axotomised FMN from non‐TP treated controls. A potential explanation for this delay may involve the TP‐induced liberation of HSP from the androgen receptor, which would provide the injured cell with an immediately available pool of protective HSP. An hypothesis is presented suggesting that this TP‐induced delay of stress‐induced HSC70 up‐regulation might allow for the diversion of cellular energy away from HSP synthesis and towards the synthesis of proteins required for regeneration and survival.
Evolution of reproductive seasonality in bears
Authors: SPADY THOMAS J. , LINDBURG DONALD G. , DURRANT BARBARA S.
Published: April 2007

Of the eight species of Ursidae, six are currently at risk of extinction and the remainder face significant risks to their future survival. One of the greatest threats to bears is human‐imposed environmental alteration (e.g. global warming, chemical pollutants, deforestation). An examination of the reproductive biology and phylogeny of the Ursidae reveals reproductive seasonality as a probable adaptation to adverse environmental conditions.

Seven of the eight extant species exhibit distinct mating and birth seasons, with the most ancient species evolving facultative seasonality as an adaptation to the increasingly seasonal climate of the Pliocene. The remainder of the extant species evolved during the Pleistocene glaciations, under conditions of severe seasonal food restriction. Under these conditions, an obligate mode of seasonality emerged and persists to the present.

Knowledge of the natural history of seasonal reproduction in the ursids and how it evolved in response to global climatic change provides a context for understanding the ramifications of current environmental change on the reproduction of these important species.
Modelling the distribution of badgers Meles meles: comparing predictions from field‐based and remotely derived habitat data
Authors: NEWTON‐CROSS GERALDINE , WHITE PIRAN C. L. , HARRIS STEPHEN
Published: April 2007

Environmental heterogeneity is important in determining the distribution and abundance of organisms at various spatial scales. The ability to understand and predict distribution patterns is important for solving many management problems in conservation biology and wildlife epidemiology.

The badger Meles meles is a highly adaptable, medium‐sized carnivore, distributed throughout temperate Eurasia, which shows a wide diversity of social and spatial organization. Within Britain, badgers are not only legally protected, but they also serve as a wildlife host for bovine tuberculosis Mycobacterium bovis. An evaluation of the role of badgers in the dynamics of this infection depends on understanding the responses of badgers to the environment at different spatial scales.

The use of digital data to provide information on habitats for distribution models is becoming common. Digital data are increasingly accessible and are generally cheaper than field surveys. There has been little research, however, to compare the accuracy of models based on field‐derived and remotely derived data.

In this paper, we make quantified comparisons between large‐scale presence/absence models for badgers in Britain, based on field‐surveyed habitat data and remotely derived digital data, comprising elevation, geology and soil.

We developed four models: 1980s badger survey data using field‐based and digital data, and 1990s badger survey data using field‐based and digital data. We divided each of the four datasets into two subsets and used one subset for training (developing) the model and the other for testing it.

All four training models had classification accuracies in excess of 69%. The models generated from digital data were slightly more accurate than those generated from field‐derived habitat data.

The high classificatory ability of the digital‐based models suggests that the use of digital data may overcome many of the problems associated with field data in wildlife‐habitat modelling, such as cost and restricted geographical coverage, without any significant impact on model performance for some species. The more widespread use of digital data in wildlife‐habitat models should enhance their accuracy, repeatability and applicability and make them better‐suited as tools to aid policy‐ and decision‐making processes.
Significant differences in GM allotype frequencies between two sympatric tribes with markedly differential susceptibility to malaria
Authors: PANDEY J. P. , NASR A. , ROCCA K. M. , TROY‐BLOMBERG M. , ELGHAZALI G.
Published: April 2007

Fulani and Masaleit, sympatric tribes in eastern Sudan, are characterized by marked differences in susceptibility to Plasmodium falciparum malaria. To determine whether the two tribes differ in the frequency of immunoglobulin GM/KM allotypes, which are associated with immunity to several pathogens, serum samples from 50 Fulani and 50 age‐ and sex‐matched Masaleit subjects were allotyped for several GM/KM determinants. The distribution of GM phenotypes as a whole, as well as a particular combination of KM and GM phenotypes, differed significantly between the two tribes (P = 0·03). These data suggest that GM allotypes may contribute to the genetic aetiology of malaria.