bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA methylation is widespread and associated with differential gene expression in castes of the honeybee,
Apis mellifera
Authors: Elango Navin , Hunt Brendan G. , Goodisman Michael A. D. , Yi Soojin V.
Published: June 2009

The recent, unexpected discovery of a functional DNA methylation system in the genome of the social bee
Apis mellifera
underscores the potential importance of DNA methylation in invertebrates. The extent of genomic DNA methylation and its role in
A. mellifera
remain unknown, however. Here we show that genes in
A. mellifera
can be divided into 2 distinct classes, one with low-CpG dinucleotide content and the other with high-CpG dinucleotide content. This dichotomy is explained by the gradual depletion of CpG dinucleotides, a well-known consequence of DNA methylation. The loss of CpG dinucleotides associated with DNA methylation also may explain the unusual mutational patterns seen in
A. mellifera
that lead to AT-rich regions of the genome. A detailed investigation of this dichotomy implicates DNA methylation in
A. mellifera
development. High-CpG genes, which are predicted to be hypomethylated in germlines, are enriched with functions associated with developmental processes, whereas low-CpG genes, predicted to be hypermethylated in germlines, are enriched with functions associated with basic biological processes. Furthermore, genes more highly expressed in one caste than another are overrepresented among high-CpG genes. Our results highlight the potential significance of epigenetic modifications, such as DNA methylation, in developmental processes in social insects. In particular, the pervasiveness of DNA methylation in the genome of
A. mellifera
provides fertile ground for future studies of phenotypic plasticity and genomic imprinting.
Impaired long-term stability of CA1 place cell representation in mice lacking the transcription factor
zif268
/
egr1
Authors: Renaudineau Sophie , Poucet Bruno , Laroche Serge , Davis Sabrina , Save Etienne
Published: June 2009

Zif268
is a transcriptional regulator that plays a crucial role in maintenance of the late phases of hippocampal long-term potentiation (LTP) and consolidation of spatial memories. Because the hippocampal place cell system is essential for long-term spatial memory, we tested the hypothesis that
zif268
is required for long-term stability of hippocampal place cell representations by recording CA1 place cells in mice lacking
zif268
. We found that
zif268
gene deletion destabilized the representation of a familiar environment after exposure to a novel environment and impaired the long-term (24 h), but not short-term (1 h), stability of newly formed representations. These impairments could be rescued by repeated exposure to the novel environment, however. These results indicate that
zif268
contributes to the long-term stability of spatial representations in CA1 and support the notion that the long-term stability of place cell representations requires transcription-dependent mechanisms similar to those observed in LTP.
ESR evidence for 2 coexisting liquid phases in deeply supercooled bulk water
Authors: Banerjee D. , Bhat S. N. , Bhat S. V. , Leporini D.
Published: June 2009

Using electron spin resonance spectroscopy (ESR), we measure the rotational mobility of probe molecules highly diluted in deeply supercooled bulk water and negligibly constrained by the possible ice fraction. The mobility increases above the putative glass transition temperature of water,

T
g

= 136 K, and smoothly connects to the thermodynamically stable region by traversing the so called “no man's land” (the range 150–235 K), where it is believed that the homogeneous nucleation of ice suppresses the liquid water. Two coexisting fractions of the probe molecules are evidenced. The 2 fractions exhibit different mobility and fragility; the slower one is thermally activated (low fragility) and is larger at low temperatures below a fragile-to-strong dynamic cross-over at ≈225 K. The reorientation of the probe molecules decouples from the viscosity below ≈225 K. The translational diffusion of water exhibits a corresponding decoupling at the same temperature [Chen S-H, et al. (2006) The violation of the Stokes–Einstein relation in supercooled water.
Proc Natl Acad Sci USA
103:12974–12978]. The present findings are consistent with key issues concerning both the statics and the dynamics of supercooled water, namely the large structural fluctuations [Poole PH, Sciortino F, Essmann U, Stanley HE (1992) Phase behavior of metastable water.
Nature
360:324–328] and the fragile-to-strong dynamic cross-over at ≈228 K [Ito K, Moynihan CT, Angell CA (1999) Thermodynamic determination of fragility in liquids and a fragile-to-strong liquid transition in water.
Nature
398:492–494].
Extinction implications of a chenopod browse diet for a giant Pleistocene kangaroo
Authors: Prideaux Gavin J. , Ayliffe Linda K. , DeSantis Larisa R. G. , Schubert Blaine W. , Murray Peter F. , Gagan Michael K. , Cerling Thure E.
Published: June 2009

Kangaroos are the world's most diverse group of herbivorous marsupials. Following late-Miocene intensification of aridity and seasonality, they radiated across Australia, becoming the continent's ecological equivalents of the artiodactyl ungulates elsewhere. Their diversity peaked during the Pleistocene, but by approximately 45,000 years ago, 90% of larger kangaroos were extinct, along with a range of other giant species. Resolving whether climate change or human arrival was the principal extinction cause remains highly contentious. Here we combine craniodental morphology, stable-isotopic, and dental microwear data to reveal that the largest-ever kangaroo,
Procoptodon goliah
, was a chenopod browse specialist, which may have had a preference for
Atriplex
(saltbushes), one of a few dicots using the C
4
photosynthetic pathway. Furthermore, oxygen isotope signatures of
P. goliah
tooth enamel show that it drank more in low-rainfall areas than its grazing contemporaries, similar to modern saltbush feeders. Saltbushes and chenopod shrublands in general are poorly flammable, so landscape burning by humans is unlikely to have caused a reduction in fodder driving the species to extinction. Aridity is discounted as a primary cause because
P. goliah
evolved in response to increased aridity and disappeared during an interval wetter than many it survived earlier. Hunting by humans, who were also bound to water, may have been a more decisive factor in the extinction of this giant marsupial.
Proof of Ira Gessel's lattice path conjecture
Authors: Kauers Manuel , Koutschan Christoph , Zeilberger Doron
Published: June 2009

We present a computer-aided, yet fully rigorous, proof of Ira Gessel's tantalizingly simply stated conjecture that the number of ways of walking 2
n
steps in the region
x
+
y
≥ 0,
y
≥ 0 of the square lattice with unit steps in the east, west, north, and south directions, that start and end at the origin, equals

16

n

(
5
/
6
)

n

(
1
/
2
)

n

(
5
/
3
)

n

(
2
)

n

.
Structural and molecular basis of the assembly of the TRPP2/PKD1 complex
Authors: Yu Yong , Ulbrich Maximilian H. , Li Ming-Hui , Buraei Zafir , Chen Xing-Zhen , Ong Albert C. M. , Tong Liang , Isacoff Ehud Y. , Yang Jian
Published: June 2009

Mutations in PKD1 and TRPP2 account for nearly all cases of autosomal dominant polycystic kidney disease (ADPKD). These 2 proteins form a receptor/ion channel complex on the cell surface. Using a combination of biochemistry, crystallography, and a single-molecule method to determine the subunit composition of proteins in the plasma membrane of live cells, we find that this complex contains 3 TRPP2 and 1 PKD1. A newly identified coiled-coil domain in the C terminus of TRPP2 is critical for the formation of this complex. This coiled-coil domain forms a homotrimer, in both solution and crystal structure, and binds to a single coiled-coil domain in the C terminus of PKD1. Mutations that disrupt the TRPP2 coiled-coil domain trimer abolish the assembly of both the full-length TRPP2 trimer and the TRPP2/PKD1 complex and diminish the surface expression of both proteins. These results have significant implications for the assembly, regulation, and function of the TRPP2/PKD1 complex and the pathogenic mechanism of some ADPKD-producing mutations.
Hypertension of Kcnmb1
−/−
is linked to deficient K secretion and aldosteronism
Authors: Grimm P. Richard , Irsik Debra L. , Settles Deann C. , Holtzclaw J. David , Sansom Steven. C.
Published: June 2009

Mice lacking the β1-subunit (gene,
Kcnmb1
; protein, BK-β1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-β1 is an ancillary subunit. However, the β1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1
−/−
has a renal origin. We found that Kcnmb1
−/−
are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1
−/−
with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1
−/−
under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1
−/−
is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.
Hematological indices at birth in relation to arterial and venous Doppler in small‐for‐gestational‐age fetuses
Authors: MARTINELLI SILVIO , FRANCISCO ROSSANA PULCINELLI VIEIRA , BITTAR ROBERTO EDUARDO , ZUGAIB MARCELO
Published: June 2009

Objective. To correlate Doppler results with hematological indices at birth in small‐for‐gestational‐age (SGA) fetuses. Design. Prospective study. Setting. Tertiary teaching hospital, Sao Paulo, Brazil. Population. One hundred singleton pregnancies with SGA fetuses of >27 weeks gestational age. Methods. All women had Doppler velocimetry of the umbilical arteries, middle cerebral artery, and ductus venosus within <72 hours prior to delivery. After birth, umbilical artery blood was collected for hematological analysis. Main outcome measures. The association between fetal Doppler velocimetry pulsatility index (PI) and some hematological indices. Results. Umbilical artery PI showed a positive correlation with nucleated red blood cell count in the umbilical cord (r = 0.46; p<0.01), and a negative correlation with platelet count (r= − 0.53; p<0.01) and white blood cell count (r= − 0.42; p<0.01). Middle cerebral artery PI was positively correlated with platelet count (r = 0.43; p<0.01) and white blood cell count (r = 0.38; p<0.01), and was negatively correlated with nucleated red blood cell count (r= − 0.39; p<0.01). The ductus venosus pulsatility index showed a positive correlation with nucleated red blood cell count (r = 0.36; p<0.01), and a negative correlation with platelet count (r= − 0.37; p<0.01) and white blood cell count (r= − 0.26; p<0.01). Conclusion. A significant positive or negative correlation between nucleated red blood cell, platelet and white blood cell counts, and Doppler indices suggests an association between placental insufficiency and the fetal hematological response.
Use of criterion‐based clinical audit to improve the quality of obstetric care: A systematic review
Authors: KONGNYUY EUGENE JUSTINE , UTHMAN OLALEKAN ABULRAHMAN
Published: June 2009

Although there is evidence that audit and feedback can improve health outcomes, little is known about the effect of audit on the quality of care from client's perspective. The aim of the current review was to explore the use of criterion‐based audit to improve quality of obstetric care from both the midwives/doctors’ and women/mothers’ perspectives. Electronic searches of Cochrane Library, MEDLINE, and EMBASE were conducted. Randomized controlled trials (RCTs) and before‐and‐after studies that assessed the effect of criterion‐based audit on health outcomes or women/mothers’ perception of obstetric care were set as selection criteria. Data were extracted, analyzed using Revman 4.2 software, and results expressed as weighted mean differences for continuous data, and odds ratios for dichotomous data. Nineteen studies (one RCT and 18 before‐and‐after studies) involving 32,972 participants met our inclusion criteria. None of these studies assessed the effect of audit on quality from the women/mothers’ perspective and none of the studies compared the effectiveness of different types of feedback. Ninety‐five percentage (18/19) of studies showed significant improvement in at least one standard measured. Criterion‐based audit has been used in obstetrics to improve quality from one dimension, namely the midwives/doctors’ perspective. Midwives/doctors should consider the use of audit to improve quality of care from the mothers’ view. There is need for well‐designed RCTs to assess the effectiveness of different types of feedback in criterion‐based audit.
Mythbusters: A Tool for Teaching Research Methods in Psychology
Authors: Burkley Edward , Burkley Melissa
Published: June 2009

Mythbusters uses multiple research methods to test interesting topics, offering research methods students an entertaining review of course material. To test the effectiveness of Mythbusters clips in a psychology research methods course, we systematically selected and showed 4 clips. Students answered questions about the clips, offered their opinions of them, and ultimately responded to Mythbusters-related exam items. Students indicated that the clips helped them understand course concepts, helped them apply their knowledge to real-world research studies, and provided them with an enjoyable educational experience. More important, students performed better on Mythbusters-related exam items than on control items, suggesting the clips were effective pedagogical tools for psychology research methods courses. We discuss specific Mythbusters clips that are relevant to psychological concepts.
Turning up the Heat on Online Teaching Evaluations: Does “Hotness” Matter?
Authors: Freng Scott , Webber David
Published: June 2009

Previous research has linked teachers' physical attractiveness and students' evaluations of teaching. We expanded on this literature by using data from RateMyProfessors.com (RMP), a database popular among college students. Additionally, we examined the unique variance that physical attractiveness explains in student evaluations of teaching while controlling for factors previously shown to predict teaching evaluations (e.g., rater interest, ease of professor or course). We selected student evaluations from 2,281 professors listed on RMP. After controlling for the number of student ratings, rater interest, and ease, we found that physical attractiveness (i.e., hotness) accounted for over 8% of the variance in student evaluations of teaching.
The Dreaded Essay Exam
Authors: Sommer Robert , Sommer Barbara A.
Published: June 2009

Surveys in 2 undergraduate psychology classes (N = 86) found that students felt less comfortable taking all-essay tests than taking multiple-choice or short-answer tests. The dominant examination format for students in university and in high school had been multiple-choice tests. We describe measures to encourage essay writing in large classes.
Comparative Psychology as an Effective Supplement to Undergraduate Core Psychology Courses
Authors: Thomas Nathaniel R.
Published: June 2009

This article describes the design and implementation of a 1-credit-hour seminar in comparative psychology as a supplement to an introductory biopsychology course. The purpose of the course was to introduce students to the ecological and evolutionary aspects of animal behavior by building on topics that are introduced in many biopsychology courses. This article provides suggestions for course assignments and course reading materials. The current approach of introducing undergraduate students to comparative psychology by attaching a seminar to an existing course offers a framework that could possibly be used with many other undergraduate psychology courses.
The Compleat Teacher-Scholar: An Interview with Stephen F. Davis
Authors: Buskist William
Published: June 2009

Stephen F. Davis is Emeritus Professor of Psychology at Emporia State University. He served as the 2002–2003 Knapp Distinguished Professor of Arts and Sciences at the University of San Diego. Currently, he is Distinguished Guest Professor at Morningside College and Visiting Distinguished Professor of Psychology at Texas Wesleyan University. Since 1966, he has published more than 300 articles and 28 textbooks, and has presented more than 900 professional papers; the vast majority of these publications and presentations include student coauthors. He has served as president of the Society for the Teaching of Psychology (STP; Division 2 of the American Psychological Association [APA]), Southern Society for Philosophy and Psychology, Southwestern Psychological Association, and Psi Chi. In addition, he received the first Psi Chi Florence L. Denmark Faculty Advisor Award. He is a fellow of APA Divisions 1 (General), 2 (STP), 3 (Experimental), and 6 (Behavioral Neuroscience and Comparative Psychology), and a recipient in 1988 of the American Psychological Foundation's (APF) Distinguished Teaching of Psychology Award.

William Buskist is Distinguished Professor in the Teaching of Psychology at Auburn University and a faculty fellow at Auburn's Biggio Center for the Enhancement of Teaching and Learning. From 2005 to 2007, he served as section editor for The Generalist's Corner section of Teaching of Psychology. He is also a member of the National Institute on the Teaching of Psychology (NITOP) planning committee. Together with Steve Davis, he has edited 2 volumes on the teaching of psychology: The Teaching of Psychology: Essays in Honor of Wilbert J. McKeachie and Charles L. Brewer (Davis & Buskist, 2002) and Handbook of the Teaching of Psychology (Buskist & Davis, 2005); and together with Barry Perlman and Lee McCann, he has edited Voices of Experience: Memorable Talks From the National Institute on the Teaching of Psychology (Perlman, McCann, & Buskist, 2005). He has also coedited several electronic books for STP. He is a fellow of APA Divisions 1 (General Psychology) and 2 (STP) and served as president of STP in 2007.
Students Teaching Students: An Experiential Learning Opportunity for Large Introductory Psychology Classes in Collaboration with Local Elementary Schools
Authors: Muir Gary M. , van der Linden Gretchen J.
Published: June 2009

Students in large, lecture-based introductory psychology classes often do not have the benefit of experiential learning (EL) opportunities due to logistical constraints. To overcome this obstacle, we developed an EL project in which introductory psychology students in small groups present some aspect of the course material to local elementary school classes. The project challenges undergraduate students to demonstrate a deep level of understanding of the presentation material. Such depth of understanding enables them to flexibly communicate material in an age-appropriate manner to kindergarten through 5th-grade students. Feedback results from undergraduate students, elementary school students, and teachers demonstrated that this project supported learning outcomes in undergraduates in a positive and enjoyable way for both student groups.
Fractures of self-expanding metallic stents in periampullary malignant biliary obstruction
Authors: Rasmussen I. C. , Dahlstrand U. , Sandblom G. , Eriksson L. G. , Nyman R.
Published: June 2009

Background: Self-expanding metallic stents are widely used for relieving biliary duct obstruction in patients with unresectable periampullary malignancies. However, only a few studies have assessed the occurrence of fractures in these stents.

Purpose: To determine the prevalence and significance of stent fracture after placement of self-expanding metallic stents for periampullary malignant biliary obstruction.

Material and Methods: Over a 5-year period, 48 patients underwent placement of self-expanding metallic stents for periampullary malignant biliary obstructions. Stents were introduced 2–6 weeks after a percutaneous transhepatic biliary decompression. The medical records and relevant images were reviewed for stent patency, stent fracture, type of stent, and stent-related complications.

Results: Stent fracture was detected in four of the 48 patients (8%): in one patient at 1 month and in three patients between 10 and 21 months after stenting. All four fractures involved one type of nitinol stent used in 38 patients. In one of the patients, fracture was complicated by life-threatening gastrointestinal bleeding. The mean survival time for all patients was 251 days (standard deviation [SD]±275 days) and the mean overall patency time for all stents was 187 days (SD±205 days).

Conclusion: Stent fracture occurs after placement of self-expanding nitinol stents for periampullary malignant biliary obstruction. The low reported incidence of this complication may be due to a lack of awareness of and difficulty in detecting stent fracture. Fracture should be considered as a possible contributing factor in recurrent biliary obstruction after self-expanding metallic stent insertion.
Does theoretical background influence therapists' attitudes to therapist self‐disclosure? A qualitative study
Authors: Carew Lynda
Published: June 2009

Aims: This study investigated therapists' attitudes towards therapist self‐disclosure over different theoretical orientations and to establish how classical theoretical background and training effected and informed practice. Classical theoretical background was intended to refer to traditional Psychodynamic understanding. Method: Participants were experienced therapists drawn from four groups by a recruitment screening measure. Three groups were from the students’ cohort within a university Masters programme in Psychological Therapies. Participants were practicing from CBT, Systemic and Psychodynamic orientations. A further group was drawn from Person‐Centred therapist/trainers at a further education College. Data was gathered using focus groups and analysed using thematic analysis. Findings: Three major and one lesser theme emerged. These revealed that there was a spectrum of willingness to disclose throughout all groups, classical training influenced all participants; total restriction of TSD was impracticable and attitudes were affected by concerns for the therapeutic relationship. Implications for practice: TSD needs to be more thoroughly explored within therapy training and supervision. A structured framework could help inform practice. Conclusions: The study supported the idea that Classical Training influenced TSD.
On pliability and progress: challenging current conceptions of eighteenth-century French educational thought
Authors: Gilead Tal
Published: June 2009

Examining the educational writings of three of the eighteenth-century's most innovative thinkers, the Abbé de Saint-Pierre, Morelly and Helvétius, this article challenges the currently accepted view that it was a belief in human pliability which gave rise to the contemporary
groundbreaking faith in the power of education to improve society. The article delineates an intellectual process that culminated in the stance that man's innate behavioural tendencies are unalterable. It argues that, at least prior to Rousseau, the eighteenth-century faith in the power of
education to improve society rested on a conviction that it is possible to beneficially direct man's fixed behavioural tendencies.
Uneasy translations: taking theories of supervision into teaching
Authors: Grant Barbara M.
Published: June 2009

Graduate supervision is a puzzling pedagogy requiring a thoughtful response from its practitioners. In this article, I reflect upon teaching theories of supervision produced through my own research with the aim of galvanizing the imaginations and practices of supervisors. I address
a curious reluctance to introduce those theories that require significant translation to be relevant or acceptable to my audience, a reluctance that turns on uneasy issues of translation along with a sense of severance between my teacher and researcher selves. I close by considering what this
reflection has to say about the demanding condition of the contemporary academic who must not only teach and research 'excellently' but also somehow link the two.
Corrupting the curriculum? The case of geography
Authors: Lambert David , Morgan John
Published: June 2009

This paper considers influences on the contemporary school curriculum in England. It does so mainly through a critical analysis of one significant critique of the curriculum made by the think tank Civitas in their collection of essays asserting the 'corruption' of the curriculum, published
in 2007. The paper places the Civitas position in a wider perspective. It then focuses on one subject critique in particular – geography – drawing from a wider selection of writings which attempt to show the distortion of school geography under pressure from 'good causes' such
as global citizenship and sustainable development. The main conclusions of the paper are that whilst the Civitas position takes a rather restricted view of subjects which denies how the discipline has developed in recent years, there is nevertheless an important point for teachers, as curriculum-makers,
to note. However, the role of the subject disciplines in the school curriculum continues to evolve. The disciplines, not least geography, are far less static than the Civitas position appears to suggest.
The credit crunch and education: an historical perspective from the Kondratiev Cycle
Authors: Carpentier Vincent
Published: June 2009

The current recession invites us to revisit the past and to reflect on the historical relationship between education and economic prosperity as well as economic downturn. My aim here is to discuss the potential contribution of history to a better understanding of the current economic
crisis and its impact on education within the British and French contexts.
Semantic relatedness among objects promotes the activation of multiple phonological codes during object naming
Authors: Oppermann Frank , Jescheniak Jörg D. , Schriefers Herbert , Görges Frauke
Published: June 2009

In a picture–word interference experiment the authors demonstrate that a semantic–categorical relation between a to-be-named target picture and a context picture promotes the phonological activation of the to-be-ignored context picture. No such phonological activation is observed if the objects are semantically unrelated. This finding gives further insight into the mechanisms that modulate the activation flow in the conceptual-lexical system during speech planning. In contrast to recent picture–picture interference studies, the results provide direct evidence that the phonological activation of a context object is dependent on its semantic processing.
Sexual selection explains sex-specific growth plasticity and positive allometry for sexual size dimorphism in a reef fish
Authors: Walker Stefan P. W. , McCormick Mark I.
Published: June 2009

In 1950, Rensch noted that in clades where males are the larger sex, sexual size dimorphism (SSD) tends to be more pronounced in larger species. This fundamental allometric relationship is now known as ‘Rensch's rule’. While most researchers attribute Rensch's rule to sexual selection for male size, experimental evidence is lacking. Here, we suggest that ultimate hypotheses for Rensch's rule should also apply to groups of individuals and that individual trait plasticity can be used to test those hypotheses experimentally. Specifically, we show that in the sex-changing fish
Parapercis cylindrica
, larger males have larger harems with larger females, and that SSD increases with harem size. Thus, sexual selection for male body size is the ultimate cause of sexual size allometry. In addition, we experimentally illustrate a positive relationship between polygyny potential and individual growth rate during sex change from female to male. Thus, sexual selection is the ultimate cause of variation in growth rate, and variation in growth rate is the proximate cause of sexual size allometry. Taken together, our results provide compelling evidence in support of the sexual selection hypothesis for Rensch's rule and highlight the potential importance of individual growth modification in the shaping of morphological patterns in Nature.
Do release-site biases reflect response to the Earth's magnetic field during position determination by homing pigeons?
Authors: Mora Cordula V. , Walker Michael M.
Published: June 2009

How homing pigeons (Columba livia) return to their loft from distant, unfamiliar sites has long been a mystery. At many release sites, untreated birds consistently vanish from view in a direction different from the home direction, a phenomenon called the release-site bias. These deviations in flight direction have been implicated in the position determination (or map) step of navigation because they may reflect local distortions in information about location that the birds obtain from the geophysical environment at the release site. Here, we performed apost hocanalysis of the relationship between vanishing bearings and local variations in magnetic intensity using previously published datasets for pigeons homing to lofts in Germany. Vanishing bearings of both experienced and naïve birds were strongly associated with magnetic intensity variations at release sites, with 90 per cent of bearings lying within ±29° of the magnetic intensity slope or contour direction. Our results (i) demonstrate that pigeons respond in an orderly manner to the local structure of the magnetic field at release sites, (ii) provide a mechanism for the occurrence of release-site biases and (iii) suggest that pigeons may derive spatial information from the magnetic field at the release site that could be used to estimate their current position relative to their loft.
Intracellular 2-keto-3-deoxy-6-phosphogluconate is the signal for carbon catabolite repression of phenylacetic acid metabolism in Pseudomonas putida KT2440
Authors: Kim Juhyun , Yeom Jinki , Jeon Che Ok , Park Woojun
Published: June 2009

The growth pattern ofPseudomonas putidaKT2440 in the presence of glucose and phenylacetic acid (PAA), where the sugar is used in preference to the aromatic compound, suggests that there is carbon catabolite repression (CCR) of PAA metabolism by glucose or gluconate. Furthermore, CCR is regulated at the transcriptional level. However, this CCR phenomenon does not occur in PAA-amended minimal medium containing fructose, pyruvate or succinate. We previously identified 2-keto-3-deoxy-6-phosphogluconate (KDPG) as an inducer of glucose metabolism, and this has led to this investigation into the role of KDPG as a signal compound for CCR. Two mutant strains, theeddmutant (non-KDPG producer) and theedamutant (KDPG overproducer), grew in the presence of PAA but not in the presence of glucose. Theeddmutant utilized PAA even in the presence of glucose, indicating that CCR had been abolished. This observation has additional support from the finding that there is high phenylacetyl-CoA ligase activity in theeddmutant, even in the presence of glucose+PAA, but not in wild-type cells under the same conditions. Unlike theeddmutant, theedamutant did not grow in the presence of glucose+PAA. Interestingly, there was no uptake and/or metabolism of PAA in theedamutant cells under the same conditions. Targeted disruption of PaaX, a repressor of the PAA operon, had no effect on CCR of PAA metabolism in the presence of glucose, suggesting that there is another transcriptional repression system associated with the KDPG signal. This is the first study to demonstrate that KDPG is the true CCR signal of PAA metabolism inP. putidaKT2440.
Identification of cellular and viral factors related to anti‐hepatitis C virus activity of cyclophilin inhibitor
Authors: Goto Kaku , Watashi Koichi , Inoue Daisuke , Hijikata Makoto , Shimotohno Kunitada
Published: June 2009

We have so far reported that an immunosuppressant cyclosporin A (CsA), a well‐known cyclophilin (CyP) inhibitor (CPI), strongly suppressed hepatitis C virus (HCV) replication in cell culture, and that CyPB was a cellular cofactor for viral replication. To further investigate antiviral mechanisms of CPI, we here developed cells carrying CsA‐resistant HCV replicons, by culturing the HCV subgenomic replicon cells for 4 weeks in the presence of CsA with G418. Transfection of total RNA from the isolated CsA‐resistant cells to naïve Huh7 cells conferred CsA resistance, suggesting that the replicon RNA itself was responsible for the resistant phenotype. Of the identified amino acid mutations, D320E in NS5A conferred the CsA resistance. The replicon carrying the D320E mutation was sensitive to interferon‐α, but was resistant to CsA and other CPIs including NIM811 and sanglifehrin A. Knockdown of individual CyP subtypes revealed CyP40, in addition to CyPA and CyPB, contributed to viral replication, and CsA‐resistant replicons acquired independence from CyPA for efficient replication. These data provide important evidence on the mechanisms underlying the regulation of HCV replication by CyP and for designing novel and specific anti‐HCV strategies with CPIs. (Cancer Sci 2009; 100: 1943–1950)
Tumor histology in lymph vessels and lymph nodes for the accurate prediction of outcome among breast cancer patients treated with neoadjuvant chemotherapy
Authors: Tamura Nobuko , Hasebe Takahiro , Okada Nao , Houjoh Takashi , Akashi‐Tanaka Sadako , Shimizu Chikako , Shibata Tatsuhiro , Sasajima Yuko , Iwasaki Motoki , Kinoshita Takayuki
Published: June 2009

The present study investigated fibrotic foci (FFs), the grading system for lymph vessel tumor emboli (LVTEs), and the histological characteristics of nodal metastatic tumors that were significantly associated with the outcomes of 115 patients with invasive ductal carcinoma (IDC) who had received neoadjuvant chemotherapy. We compared the outcome predictive power of FFs, the grading system for LVTEs, and the histological characteristics of metastatic tumors in lymph nodes with the well‐known clinicopathological characteristics of tumor recurrence and tumor‐related death in multivariate analyses. The presence of FFs, as assessed by a biopsy performed before neoadjuvant chemotherapy, significantly increased the hazard rates (HRs) for tumor‐related death in all the cases and in cases with nodal metastasis. The grading system for LVTEs, which was assessed using surgical specimens obtained after neoadjuvant chemotherapy, was significantly associated with increasing hazard rates (HRs) for tumor recurrence and tumor‐related death in all the cases and in cases with nodal metastasis. Moderate to severe stroma in nodal metastatic tumors and five or more mitotic figures in nodal metastatic tumors were significantly associated with elevated HRs for tumor recurrence and tumor‐related death among all the cases. These results indicated that FFs, the grading system for LVTEs, and the histological characteristics of tumor cells in lymph nodes play important roles in predicting the tumor progression of IDCs of the breast in patients treated with neoadjuvant chemotherapy. (Cancer Sci 2009; 100: 1823–1833)
Nicotiana plumbaginifolia plants silenced for the ATP‐binding cassette transporter gene NpPDR1 show increased susceptibility to a group of fungal and oomycete pathogens
Authors: BULTREYS ALAIN , TROMBIK TOMASZ , DROZAK ANNA , BOUTRY MARC
Published: June 2009

The behaviour of Nicotiana plumbaginifolia plants silenced for the ATP‐binding cassette transporter gene NpPDR1 was investigated in response to fungal and oomycete infections. The importance of NpPDR1 in plant defence was demonstrated for two organs in which NpPDR1 is constitutively expressed: the roots and the petal epidermis. The roots of the plantlets of two lines silenced for NpPDR1 expression were clearly more sensitive than those of controls to the fungal pathogens Botrytis cinerea, Fusarium oxysporum sp., F. oxysporum f. sp. nicotianae, F. oxysporum f. sp. melonis and Rhizoctonia solani, as well as to the oomycete pathogen Phytophthora nicotianae race 0. The Ph gene‐linked resistance of N. plumbaginifolia to P. nicotianae race 0 was totally ineffective in NpPDR1‐silenced lines. In addition, the petals of the NpPDR1‐silenced lines were spotted 15%–20% more rapidly by B. cinerea than were the controls. The rapid induction (after 2–4 days) of NpPDR1 expression in N. plumbaginifolia and N. tabacum mature leaves in response to pathogen presence was demonstrated for the first time with fungi and one oomycete: R. solani, F. oxysporum and P. nicotianae. With B. cinerea, such rapid expression was not observed in healthy mature leaves. NpPDR1 expression was not observed during latent infections of B. cinerea in N. plumbaginifolia and N. tabacum, but was induced when conditions facilitated B. cinerea development in leaves, such as leaf ageing or an initial root infection. This work demonstrates the increased sensitivity of NpPDR1‐silenced N. plumbaginifolia plants to all of the fungal and oomycete pathogens investigated.
Health care seeking for abdominal bloating and visible distention
Authors: JIANG X. , LOCKE G. R. , ZINSMEISTER A. R. , SCHLECK C. D. , TALLEY N. J.
Published: June 2009

Background  While knowledge has accumulated regarding health care seeking in several functional gastrointestinal disorders (FGIDs), little is known about health care seeking in those with bloating and distention.

Aim  To identify predictors of health care seeking for bloating and distention.

Methods  The validated Talley Bowel Disease Questionnaire was mailed to a cohort selected at random from the population of Olmsted County, Minnesota; 2259 subjects (53% females; mean age 62 years) answered questions about bloating and distention. The complete medical record of each respondent was reviewed. Logistic regression was used to compare consulting for bloating and distention with consulting for other GI symptoms, and nonconsulters.

Results  A total of 131 (6%) subjects in the community consulted a physician for bloating or distention. Older age [odds ratio (OR), 1.8; 95% confidence interval (CI): 1.5, 2.1], higher somatic symptom scores (OR, 2.0; CI: 1.4, 2.8), lower education level (OR, 2.7; CI: 1.2, 5.6), early satiety (OR, 2.0; CI: 1.1, 3.8) and abdominal pain (OR, 2.4; CI: 1.6, 3.7) were associated with people seeking health care for bloating or distention vs. non‐consulters. Similarly, older age (OR, 1.4; CI: 1.2, 1.7), chronic constipation (OR, 2.0; CI: 1.2, 3.2) and visible distention (OR, 3.0; CI: 1.8, 4.9) had greater odds of presenting for bloating or distention compared with presenting for other GI symptoms; somatic symptoms were not a predictor (OR, 1.1; CI: 0.8, 1.5).

Conclusions  Factors that lead people to present for bloating and distention are similar to those for other GI symptoms visits; however, specific biological rather than somatic features may predict visits for bloating and distention.
Population pharmacokinetics and optimal design of paediatric studies for famciclovir
Authors: Ogungbenro Kayode , Matthews Ivan , Looby Michael , Kaiser Guenther , Graham Gordon , Aarons Leon
Published: June 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Famciclovir is licensed in adults for the treatment of herpes zoster and herpes simplex viral infections.

• The pharmacokinetics of famciclovir has been extensively studied in adults, but no population pharmacokinetic model has been published to date.

• There is limited information about the pharmacokinetics of famciclovir in children.

WHAT THIS STUDY ADDS

• A population pharmacokinetic model of penciclovir (famciclovir is a prodrug of penciclovir) was developed in adults and children.

• New paediatric pharmacokinetic studies have been designed using a 10 mg kg−1dose in children that gives similar exposure to 500 mg in adults.

• A sampling windows design for sparse sampling based on an adequate number of subjects in three paediatric age groups has also been developed.

AIMS

To develop a population pharmacokinetic model for penciclovir (famciclovir is a prodrug of penciclovir) in adults and children and suggest an appropriate dose for children. Furthermore, to develop a limited sampling design based on sampling windows for three different paediatric age groups (1–2, 2–5 and 5–12 years) using an adequate number of subjects for future pharmacokinetic studies.

METHODS

Penciclovir plasma data from six different adult and paediatric studies were supplied by Novartis. Population pharmacokinetic modelling was undertaken in NONMEM version VI. Simulations in MATLAB were used to select an oral paediatric dose that gives similar exposure to 500 mg in adults. Optimal sampling times and sampling windows were obtained in MATLAB and simulations in NONMEM were used to select adequate sample sizes for three paediatric age groups.

RESULTS

A two‐compartment, first‐order absorption model with an absorption lag time, allometric weight models onV1,V2andQ, and an allometric weight model, age and creatinine clearance as covariates on CL adequately describe the pharmacokinetics of penciclovir in adults and children. Estimated CL (l h−1 70 kg−1) andVss(l.70 kg−1) were 31.2 and 83.1, respectively. An oral dose of 10 mg kg−1body weight in children was predicted to give similar exposure as 500 mg in adults. A single sampling windows design (0.25–0.4, 0.5–1, 1.25–1.75, 2.75–3.5 and 7.25–8 h) for five samples per subject and 10 subjects in each of the paediatric age groups is recommended for future studies.

CONCLUSIONS

A population pharmacokinetic model of penciclovir in adults and children has been developed. A prospective study design, including dose adjustment, cohort size and blood sampling design has been recommended.
Proposals for model‐based paediatric medicinal development within the current European Union regulatory framework
Authors: Manolis Efthymios , Pons Gérard
Published: June 2009

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• The use of modelling and simulation (M&S) in paediatric drug development has been the subject of numerous scientific publications in the last decade.

• Many scientific teams have elaborated on the methodology and provided successful examples of the added value of M&S in this area.

• Furthermore, regulatory bodies and the US Food and Drug Administration in particular have provided guidance on good modelling and simulation practice and on the role of M&S in drug development.

WHAT THIS STUDY ADDS

• This paper attempts to position M&S in the European regulatory environment based on European Medicines Agency (EMEA) guidelines.

• It presents the personal views of the authors on the issues discussed in the EMEA workshop on modelling in paediatric medicines (14–15 April 2008) [1].

• It proposes an algorithm for the practical implementation of M&S in paediatric drug development and a forum for further discussions.

The new paediatric European Union (EU) regulation and the consequent demand for paediatric studies on one hand and the ethical need for minimizing the burden of studies in children on the other hand necessitate optimal techniques in the assessment of safety/efficacy and use of drugs in children. Modelling and simulation (M&S) is one way to circumvent some difficulties in developing medicinal products in children. M&S allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/ pharmacodynamics (PK/PD), extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. Together, industry, academia and regulators recognize the usefulness of modelling and simulation in this setting. However, even if M&S is an emerging science, its integration in the EU regulatory decision making is for the time being deficient and M&S expertise is concentrated in big pharmaceutical companies and academic institutions. The European Medicines Agency, acknowledging all the above conditions, organized and hosted a Workshop on Modelling in Paediatric Medicines. The article presents the personal views of the authors on the issues presented and discussed in the workshop. We attempt to identify the regulatory framework for the use of M&S in paediatric medicinal development and to make proposals for model‐based paediatric medicinal development. The objective is to open the discussion between industry, academia, paediatricians and regulators on the optimal use of M&S in paediatric medicinal development.
Abnormal centrosome‐centriole cycle in chronic myeloid leukaemia?
Authors: Patel Hetal , Gordon Myrtle Y.
Published: June 2009

Abnormal numbers, structures and functions of centrosomes in chronic myeloid leukaemia (CML) may influence cell proliferation and genomic instability, which are features of the disease. Centrosomes are regulators of mitotic spindle orientation and can act as scaffolds for centrosome‐associated regulators of the cell cycle. This study showed, for the first time, that p210BCR‐ABL1 and p145ABL1 are both centrosome‐associated proteins, as demonstrated by co‐immunoprecipitation with the pericentriolar protein, pericentrin. Furthermore, when CML cells were treated with imatinib there was a 55% and 20% reduction of p210BCR‐ABL1 and p145ABL1 binding to pericentrin, respectively. Cell lines expressing p210BCR‐ABL1 and primary CD34+ cells from CML patients exhibited more numerical and structural centrosomal abnormalities than p210BCR‐ABL1 negative cells. Primary cells from CML blast crisis (BC) patients exhibited a distinctive amorphous staining pattern of pericentrin compared to normal and CML chronic phase (CP) patients, suggesting a possible defect in pericentrin localisation at the centrosomes. Proteins, such as aurora kinases, pericentrin, survivin and separase, regulate centrosome structure and function, cell cycle and mitotic spindle formation. Levels of the protease, separase are abnormally high in CML CP and BC cells in comparison to normal CD34+ cells. The data imply that expression of p210BCR‐ABL1 is associated with abnormalities in the centrosome‐centriole cycle and increased separase expression.
Doppler‐defined pulmonary hypertension and the risk of death in children with sickle cell disease followed for a mean of three years
Authors: Lee Margaret T. , Small Tania , Khan Muhammad A. , Rosenzweig Erika B. , Barst Robyn J. , Brittenham Gary M.
Published: June 2009

Pulmonary hypertension (PH) is associated with increased mortality in adults with sickle cell disease (SCD), but its prognostic significance in children is unknown. Eighty‐eight children with SCD were followed after echocardiographic screening for PH. After a mean follow‐up of 3 years, all 18 subjects with PH were alive. In our children, as in adults with SCD, PH was associated with increased haemolysis. In contrast, our subjects with PH did not have overt systemic disease observed in adults. PH may be a manifestation of progressive organ damage from chronic haemolysis and systemic vasculopathy that ultimately leads to early death in adulthood.