bluuebunny/crossref_metadata_2025 huggingface dataset:
Cropland expansion changes deforestation dynamics in the southern Brazilian Amazon
Authors: Morton Douglas C. , DeFries Ruth S. , Shimabukuro Yosio E. , Anderson Liana O. , Arai Egidio , del Bon Espirito-Santo Fernando , Freitas Ramon , Morisette Jeff
Published: September 2006

Intensive mechanized agriculture in the Brazilian Amazon grew by >3.6 million hectares (ha) during 2001–2004. Whether this cropland expansion resulted from intensified use of land previously cleared for cattle ranching or new deforestation has not been quantified and has major implications for future deforestation dynamics, carbon fluxes, forest fragmentation, and other ecosystem services. We combine deforestation maps, field surveys, and satellite-based information on vegetation phenology to characterize the fate of large (>25-ha) clearings as cropland, cattle pasture, or regrowing forest in the years after initial clearing in Mato Grosso, the Brazilian state with the highest deforestation rate and soybean production since 2001. Statewide, direct conversion of forest to cropland totaled >540,000 ha during 2001–2004, peaking at 23% of 2003 annual deforestation. Cropland deforestation averaged twice the size of clearings for pasture (mean sizes, 333 and 143 ha, respectively), and conversion occurred rapidly; >90% of clearings for cropland were planted in the first year after deforestation. Area deforested for cropland and mean annual soybean price in the year of forest clearing were directly correlated (R2= 0.72), suggesting that deforestation rates could return to higher levels seen in 2003–2004 with a rebound of crop prices in international markets. Pasture remains the dominant land use after forest clearing in Mato Grosso, but the growing importance of larger and faster conversion of forest to cropland defines a new paradigm of forest loss in Amazonia and refutes the claim that agricultural intensification does not lead to new deforestation.
A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of
Chlamydia trachomatis
Authors: Muschiol Sandra , Bailey Leslie , Gylfe Åsa , Sundin Charlotta , Hultenby Kjell , Bergström Sven , Elofsson Mikael , Wolf-Watz Hans , Normark Staffan , Henriques-Normark Birgitta
Published: September 2006

The intracellular pathogen
Chlamydia trachomatis
possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of
Yersinia pseudotuberculosis
. Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of
C. trachomatis
at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3β to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.
Diversity of zebrafish peripheral oscillators revealed by luciferase reporting
Authors: Kaneko Maki , Hernandez-Borsetti Nancy , Cahill Gregory M.
Published: September 2006

In various multicellular organisms, circadian clocks are present not only in the central nervous system, but also in peripheral organs and tissues. In mammals peripheral oscillators are not directly responsive to light, but are entrained by the central oscillator in the suprachiasmatic nucleus. These individual oscillators are diverse in their free-running periods and phases. In contrast, cultured peripheral tissues and cell lines from zebrafish are not only rhythmic, but can also be directly entrained by light. Because of the convenience of studying rhythms in cultured cells, however, little has been known about properties of individual oscillators in intact zebrafish. Here, we show the remarkable diversity and consistency of oscillator properties in various peripheral organs and tissues from the
period3-luciferase
(
per3-luc
) transgenic zebrafish. Tissue-dependent differences were found in free-running period, phase, response to light, and temperature compensation. Furthermore, cycling amplitudes were reduced at lower temperatures in some, but not all, of the organs tested. Finally, we found that
per3-luc
rhythms can free run in both constant dark and constant light with remarkably similar amplitudes, phases, and periods, despite the fact that the mRNA of
per2
and
per1
has been shown not to oscillate in constant light.
Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis
Authors: Wang Miao , Zukas Alicia M. , Hui Yiqun , Ricciotti Emanuela , Puré Ellen , FitzGerald Garret A.
Published: September 2006

Prostaglandin (PG) E
2
is formed from PGH
2
by a series of PGE synthase (PGES) enzymes. Microsomal PGES-1
−/−
(mPGES-1
−/−
) mice were crossed into low-density lipoprotein receptor knockout (LDLR
−/−
) mice to generate mPGES-1
−/−
LDLR
−/−
s. Urinary 11α-hydroxy-9, 15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M) was depressed by mPGES-1 deletion. Vascular mPGES-1 was augmented during atherogenesis in LDLR
−/−
s. Deletion of mPGES-1 reduced plaque burden in fat-fed LDLR
−/−
s but did not alter blood pressure. mPGES-1
−/−
LDLR
−/−
plaques were enriched with fibrillar collagens relative to LDLR
−/−
, which also contained small and intermediate-sized collagens. Macrophage foam cells were depleted in mPGES-1
−/−
LDLR
−/−
lesions, whereas the total areas rich in vascular smooth muscle cell (VSMC) and matrix were unaltered. mPGES-1 deletion augmented expression of both prostacyclin (PGI
2
) and thromboxane (Tx) synthases in endothelial cells, and VSMCs expressing PGI synthase were enriched in mPGES-1
−/−
LDLR
−/−
lesions. Stimulation of mPGES-1
−/−
VSMC and macrophages with bacterial LPS increased PGI
2
and thromboxane A
2
to varied extents. Urinary PGE-M was depressed, whereas urinary 2,3-dinor 6-keto PGF
1α
, but not 2,3-dinor-TxB
2
, was increased in mPGES-1
−/−
LDLR
−/−
s. mPGES-1-derived PGE
2
accelerates atherogenesis in LDLR
−/−
mice. Disruption of this enzyme retards atherogenesis, without an attendant impact on blood pressure. This may reflect, in part, rediversion of accumulated PGH
2
to augment formation of PGI
2
. Inhibitors of mPGES-1 may be less likely than those selective for cyclooxygenase 2 to result in cardiovascular complications because of a divergent impact on the biosynthesis of PGI
2
.
Rapid high-yield expression of full-size IgG antibodies in plants coinfected with noncompeting viral vectors
Authors: Giritch Anatoli , Marillonnet Sylvestre , Engler Carola , van Eldik Gerben , Botterman Johan , Klimyuk Victor , Gleba Yuri
Published: September 2006

Plant viral vectors allow expression of heterologous proteins at high yields, but so far, they have been unable to express heterooligomeric proteins efficiently. We describe here a rapid and indefinitely scalable process for high-level expression of functional full-size mAbs of the IgG class in plants. The process relies on synchronous coinfection and coreplication of two viral vectors, each expressing a separate antibody chain. The two vectors are derived from two different plant viruses that were found to be noncompeting. Unlike vectors derived from the same virus, noncompeting vectors effectively coexpress the heavy and light chains in the same cell throughout the plant body, resulting in yields of up to 0.5 g of assembled mAbs per kg of fresh-leaf biomass. This technology allows production of gram quantities of mAbs for research purposes in just several days, and the same protocol can be used on an industrial scale in situations requiring rapid response, such as pandemic or terrorism events.
Soft X-ray optics characterization on SURF II
Authors: J R Roberts  , J Kerner  , E B Saloman
Published: September 2006

We describe the present capabilities and future plans for soft X-ray optics characterization at the NIST storage ring, SURF II. The existing facility is made up of a monochromator and a reflectometer capable of characterizing the reflectivity of soft X-ray devices, including multilayers, gratings and grazing incidence optics. This system can also be used to characterize the transmission of components such as filters. The present capabilities include a wavelength range from 80 Å to 600 Å. The reflectometer will handle components up to several cm in diameter and its detector can be scanned in two independent angular directions. This allows the mapping of scattered photons from the sample, as well as the measurement of reflectivity as a function of angle and wavelength. Results of measurements on users' samples will be shown.

We plan to modernize and expand the capabilities of this facility in the following ways:

(1) Construct a new monochromator capable of scanning wavelengths from 30 Å to greater than 600 Å.

(2) Construct a new reflectometer with independent, computer-controlled angular and translational motion for the sample and detector. This will permit automated wavelength scans and Θ/2Θ scans at fixed wavelengths, as well as mapping of the sample surface. The reflectometer will have a multidetector capability. It will also allow the measurement of optical constants of thin films.

(3) Construct an optical test bench for characterizing the imaging properties of focusing optics.

Other considerations for expanded capabilities, depending on the needs of the soft X-ray user community, include:

(1) In-situ deposition of thin films with a vacuum transfer capability.

(2) Provisions for other types of characterization, such as scanning tunneling microscopy (STM) and interferometric profilometry.
Journeys in the Country of the Blind: Entanglement Theory and the Effects of Blinding on Trials of Homeopathy and Homeopathic Provings
Authors: Milgrom Lionel R.
Published: September 2006

The idea of quantum entanglement is borrowed from physics and developed into an algebraic argument to explain how double‐blinding randomized controlled trials could lead to failure to provide unequivocal evidence for the efficacy of homeopathy, and inability to distinguish proving and placebo groups in homeopathic pathogenic trials. By analogy with the famous double‐slit experiment of quantum physics, and more modern notions of quantum information processing, these failings are understood as blinding causing information loss resulting from a kind of quantum superposition between the remedy and placebo.
Mate choice assays and mating propensity differences in natural yeast populations
Authors: Murphy Helen A , Kuehne Heidi A , Francis Chantal A , Sniegowski Paul D
Published: September 2006

In sexual microbes, mating occurs by fusion of individual cells. This complete fitness investment suggests that cell behaviour could potentially mediate prezygotic isolation between microbial species, a topic about which very little is known. To investigate this possibility, we conducted individual cell mate choice trials and mass-culture mating propensity assays with isolates from sympatric natural populations of the closely related yeasts
Saccharomyces cerevisiae
and
Saccharomyces paradoxus
. Although we found no evidence for active species recognition in mate choice, we observed a marked difference in mating propensity between these two species. We briefly discuss the possibility that this mating propensity difference may contribute to reproductive isolation between
S. cerevisiae
and
S. paradoxus
in nature.
Consistent annual schedules in a migratory shorebird
Authors: Battley Phil F
Published: September 2006

Many migratory birds start prebreeding moult and premigratory fuelling some months before the breeding season and face severe time constraints, while travelling up to 15 000 km between non-breeding and breeding grounds. Shorebirds typically leave Southern Hemisphere non-breeding areas over a 3–4 week period, but whether they benefit from interannually consistent timing of departure is unknown. Here, I show that individual bar-tailed godwits (Limosa limosa baueri) from New Zealand are highly consistent in their migratory scheduling. Most birds left within the same week each year (between-year repeatability,r, of 0.83) and adult males, which moult into a bright breeding plumage, were also highly repeatable in the extent of their prebreeding moult (r=0.86). This is consistent with the hypothesis that birds have individually optimized migration schedules. Within adult males, but not females, smaller birds tended to migrate earlier than large birds. Whether this reflects differences in size-related migration speed, optimal breeding time at different sites or size-related natural or sexual selection pressures, remains unknown.
Metabolic costs of brain size evolution
Authors: Isler Karin , van Schaik Carel P
Published: September 2006

In the ongoing discussion about brain evolution in vertebrates, the main interest has shifted from theories focusing on energy balance to theories proposing social or ecological benefits of enhanced intellect. With the availability of a wealth of new data on basal metabolic rate (BMR) and brain size and with the aid of reliable techniques of comparative analysis, we are able to show that in fact energetics is an issue in the maintenance of a relatively large brain, and that brain size is positively correlated with the BMR in mammals, controlling for body size effects. We conclude that attempts to explain brain size variation in different taxa must consider the ability to sustain the energy costs alongside cognitive benefits.
Modelling protein–protein interaction networks via a stickiness index
Authors: Pržulj Nataša , Higham Desmond J
Published: September 2006

What type of connectivity structure are we seeing in protein–protein interaction networks? A number of random graph models have been mooted. After fitting model parameters to real data, the models can be judged by their success in reproducing key network properties. Here, we propose a very simple random graph model that inserts a connection according to the degree, or ‘stickiness’, of the two proteins involved. This model can be regarded as a testable distillation of more sophisticated versions that attempt to account for the presence of interaction surfaces or binding domains. By computing a range of network similarity measures, including relative graphlet frequency distance, we find that our model outperforms other random graph classes. In particular, we show that given the underlying degree information, fitting a stickiness model produces better results than simply choosing a degree-matching graph uniformly at random. Therefore, the results lend support to the basic modelling methodology.
Skyrmions and the α-particle model of nuclei
Authors: Battye Richard A , Manton Nicholas S , Sutcliffe Paul M
Published: September 2006

We compute new solutions of the Skyrme model with massive pions. Concentrating on baryon numbers which are multiples of four, we find low-energy Skyrmion solutions that are composed of charge four subunits, as in the α-particle model of nuclei. We summarize our current understanding of these solutions, and discuss their relationship to configurations in the α-particle model.
Impact of mating systems on patterns of sequence polymorphism in flowering plants
Authors: Glémin Sylvain , Bazin Eric , Charlesworth Deborah
Published: September 2006

A fundamental challenge in population genetics and molecular evolution is to understand the forces shaping the patterns of genetic diversity within and among species. Among them, mating systems are thought to have important influences on molecular diversity and genome evolution. Selfing is expected to reduce effective population size,Ne, and effective recombination rates, directly leading to reduced polymorphism and increased linkage disequilibrium compared with outcrossing. Increased isolation between populations also results directly from selfing or indirectly from evolutionary changes, such as small flowers and low pollen output, leading to greater differentiation of molecular markers than under outcrossing. The lower effective recombination rate increases the likelihood of hitch-hiking, further reducing within-deme diversity of selfers and thus increasing their genetic differentiation. There are also indirect effects on molecular evolutionary processes. LowNereduces the efficacy of selection; in selfers, selection should thus be less efficient in removing deleterious mutations. The rarity of heterozygous sites in selfers leads to infrequent action of biased conversion towards GC, which tends to increase sequences' GC content in the most highly recombining genome regions of outcrossers. To test these predictions in plants, we used a newly developed sequence polymorphism database to investigate the effects of mating system differences on sequence polymorphism and genome evolution in a wide set of plant species. We also took into account other life-history traits, including life form (whether annual or perennial herbs, and woody perennial) and the modes of pollination and seed dispersal, which are known to affect enzyme and DNA marker polymorphism. We show that among various life-history traits, mating systems have the greatest influence on patterns of polymorphism.
Life history and environmental variation interact to determine effective population to census size ratio
Authors: Turner Thomas F , Osborne Megan J , Moyer Gregory R , Benavides Melissa A , Alò Dominique
Published: September 2006

Successful recovery and sustainability of threatened and exploited species depends in part on retention and maintenance of genetic diversity. Theory indicates that genetic diversity is lost at a rate inversely proportional to the genetically effective population size (Ne), which is roughly equal to one-half the adult census size (N) in many organisms. However,Nehas been reported to be up to five orders of magnitude lower thanNin species with life histories that result in type III survivorship (high fecundity, but heavy mortality in early life stages, e.g. bony fishes), prompting speculation that low values ofNemay be a general feature of such organisms despite sometimes vast abundances. Here, we comparedNeand the ratioNe/Nacross three ecologically similar fish species from the arid southwestern United States, all with type III life histories but with differing expectations of egg and larval survivorship that correlate with the degree of human-imposed habitat fragmentation. Our study indicates that type III life history may be necessary, but this alone is insufficient to account for extraordinarily low values ofNe/N. Rather, life history interacts with environmentally imposed mortality to determine the rate and magnitude of change in genetic diversity in these desert fish species.
Cationic liposome–DNA complexes: from liquid crystal science to gene delivery applications
Authors: Safinya Cyrus R , Ewert Kai , Ahmad Ayesha , Evans Heather M , Raviv Uri , Needleman Daniel J , Lin Alison J , Slack Nelle L , George Cyril , Samuel Charles E
Published: September 2006

At present, there is an unprecedented level of interest in the properties and structures of complexes consisting of DNA mixed with oppositely charged cationic liposomes (CLs). The interest arises because the complexes mimic natural viruses as chemical carriers of DNA into cells in worldwide human gene therapy clinical trials. However, since our understanding of the mechanisms of action of CL–DNA complexes interacting with cells remains poor, significant additional insights and discoveries will be required before the development of efficient chemical carriers suitable for long-term therapeutic applications. Recent studies describe synchrotron X-ray diffraction, which has revealed the liquid crystalline nature of CL–DNA complexes, and three-dimensional laser-scanning confocal microscopy, which reveals CL–DNA pathways and interactions with cells. The importance of the liquid crystalline structures in biological function is revealed in the application of these modern techniques in combination with functional transfection efficiency measurements, which shows that the mechanism of gene release from complexes in the cell cytoplasm is dependent on their precise liquid crystalline nature and the physical and chemical parameters (for example, the membrane charge density) of the complexes. In
§5
, we describe some recent new results aimed at developing bionanotube vectors for gene delivery.
Self-assembly processes in the prebiotic environment
Authors: Deamer David , Singaram Sara , Rajamani Sudha , Kompanichenko Vladimir , Guggenheim Stephen
Published: September 2006

An important question guiding research on the origin of life concerns the environmental conditions where molecular systems with the properties of life first appeared on the early Earth. An appropriate site would require liquid water, a source of organic compounds, a source of energy to drive polymerization reactions and a process by which the compounds were sufficiently concentrated to undergo physical and chemical interactions. One such site is a geothermal setting, in which organic compounds interact with mineral surfaces to promote self-assembly and polymerization reactions. Here, we report an initial study of two geothermal sites where mixtures of representative organic solutes (amino acids, nucleobases, a fatty acid and glycerol) and phosphate were mixed with high-temperature water in clay-lined pools. Most of the added organics and phosphate were removed from solution with half-times measured in minutes to a few hours. Analysis of the clay, primarily smectite and kaolin, showed that the organics were adsorbed to the mineral surfaces at the acidic pH of the pools, but could subsequently be released in basic solutions. These results help to constrain the range of possible environments for the origin of life. A site conducive to self-assembly of organic solutes would be an aqueous environment relatively low in ionic solutes, at an intermediate temperature range and neutral pH ranges, in which cyclic concentration of the solutes can occur by transient dry intervals.
SAS-mediated acetylation of histone H4 Lys 16 is required for H2A.Z incorporation at subtelomeric regions in Saccharomyces cerevisiae
Authors: Shia Wei-Jong , Li Bing , Workman Jerry L.
Published: September 2006

The yeast SAS (Something About Silencing) complex and the histone variant H2A.Z have both previously been linked to an antisilencing function at the subtelomeric regions. SAS is an H4 Lys 16-specific histone acetyltransferase complex. Here we demonstrate that the H4 Lys 16 acetylation by SAS is required for efficient H2A.Z incorporation near telomeres. The presence of H4 Lys 16 acetylation and H2A.Z synergistically prevent the ectopic propagation of heterochromatin. Overall, our data suggest a novel antisilencing mechanism near telomeres.
Pdm and Castor specify late-born motor neuron identity in the NB7-1 lineage
Authors: Grosskortenhaus Ruth , Robinson Kristin J. , Doe Chris Q.
Published: September 2006

Embryonic development requires generating cell types at the right place (spatial patterning) and the right time (temporal patterning). Drosophila neuroblasts undergo stem cell-like divisions to generate an ordered sequence of neuronal progeny, making them an attractive system to study temporal patterning. Embryonic neuroblasts sequentially express Hunchback, Krüppel, Pdm1/Pdm2 (Pdm), and Castor (Cas) transcription factors. Hunchback and Krüppel specify early-born temporal identity, but the role of Pdm and Cas in specifying temporal identity has never been addressed. Here we show that Pdm and Cas regulate late-born motor neuron identity within the NB7-1 lineage: Pdm specifies fourth-born U4 motor neuron identity, while Pdm/Cas together specify fifth-born U5 motor neuron identity. We conclude that Pdm and Cas specify late-born neuronal identity; that Pdm and Cas act combinatorially to specify a temporal identity distinct from either protein alone, and that Cas repression of pdm expression regulates the generation of neuronal diversity.
A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer
Authors: Eeckhoute Jérôme , Carroll Jason S. , Geistlinger Timothy R. , Torres-Arzayus Maria I. , Brown Myles
Published: September 2006

Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor α (ERα) through the activation of the cyclin D1 (CCND1) oncogene. However, our knowledge of ERα transcriptional mechanisms remains limited. Hence, it is still elusive why ERα ectopically expressed in ER-negative breast cancer cells (BCC) is functional on ectopic reporter constructs but lacks activity on many endogenous target genes, including CCND1. Here, we show that estradiol (E2) stimulation of CCND1 expression in BCC depends on a novel cell-type-specific enhancer downstream from the CCND1 coding region, which is the primary ERα recruitment site in estrogen-responsive cells. The pioneer factor FoxA1 is specifically required for the active chromatin state of this enhancer and as such is crucial for both CCND1 expression and subsequent cell cycle progression. Interestingly, even in BCC, CCND1 levels and proliferation are tightly controlled by E2 through the establishment of a negative feedforward loop involving the induction of NFIC, a putative tumor suppressor capable of directly repressing CCND1 transcription. Taken together, our results reveal an estrogen-regulated combinatorial network including cell-specific cis- and trans-regulators of CCND1 expression where ERα collaborates with other transcription factors associated with the ER-positive breast cancer phenotype, including FoxA1 and NFIC.
The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1β
Authors: Shchors Ksenya , Shchors Elena , Rostker Fanya , Lawlor Elizabeth R. , Brown-Swigart Lamorna , Evan Gerard I.
Published: September 2006

Although induction of blood vessel growth is acknowledged as a pivotal requirement for the evolution of macroscopic tumors, the events that trigger onset of tumor angiogenesis remain largely obscure. The pervasive Myc oncoprotein is itself a potent inducer of angiogenesis in a wide range of tissues. We have used a reversibly switchable mouse transgenic model of Myc-dependent β-cell carcinogenesis to delineate the kinetics and causal sequence of angiogenic processes following acute Myc activation. We show that onset of endothelial cell proliferation is induced shortly after Myc-induced cell cycle entry of β cells. Endothelial cell proliferation is not indirectly induced by local tissue hypoxia but instead via a diffusible angiogenic signal produced by Myc-expressing β cells. This signal triggers the release of pre-existing, sequestered VEGF from the islet extracellular matrix, that then homes to the endothelial compartment where it induces endothelial cell proliferation. Myc activation in β cells rapidly induces expression and release of the proinflammatory cytokine interleukin 1β (IL-1β). We show that IL-1β is the principal effector downstream of Myc responsible for triggering rapid onset of islet angiogenesis. Together, our data delineate a complete pathway in vivo by which the highly pleiotropic Myc oncoproteins elicits coexpansion of the vascular compartment during tumorigenic progression.
The C-terminal tail of the Hedgehog receptor Patched regulates both localization and turnover
Authors: Lu Xingwu , Liu Songmei , Kornberg Thomas B.
Published: September 2006

Patched (Ptc) is a membrane protein whose function in Hedgehog (Hh) signal transduction has been conserved among metazoans and whose malfunction has been implicated in human cancers. Genetic analysis has shown that Ptc negatively regulates Hh signal transduction, but its activity and structure are not known. We investigated the functional and structural properties of Drosophila Ptc and its C-terminal domain (CTD), 183 residues that are predicted to reside in the cytoplasm. Our results show that Ptc, as well as truncated Ptc deleted of its CTD, forms a stable trimer. This observation is consistent with the proposal that Ptc is structurally similar to trimeric transporters. The CTD itself trimerizes and is required for both Ptc internalization and turnover. Two mutant forms of the CTD, one that disrupts trimerization and the other that mutates the target sequence of the Nedd4 ubiquitin ligase, stabilize Ptc but do not prevent internalization and sequestration of Hh. Ptc deleted of its CTD is stable and localizes to the plasma membrane. These data show that degradation of Ptc is regulated at a step subsequent to endocytosis, although endocytosis is a likely prerequisite. We also show that the CTD of mouse Ptc regulates turnover.
CKI and CKII mediate the FREQUENCY-dependent phosphorylation of the WHITE COLLAR complex to close the Neurospora circadian negative feedback loop
Authors: He Qun , Cha Joonseok , He Qiyang , Lee Heng-Chi , Yang Yuhong , Liu Yi
Published: September 2006

The eukaryotic circadian oscillators consist of circadian negative feedback loops. In Neurospora, it was proposed that the FREQUENCY (FRQ) protein promotes the phosphorylation of the WHITE COLLAR (WC) complex, thus inhibiting its activity. The kinase(s) involved in this process is not known. In this study, we show that the disruption of the interaction between FRQ and CK-1a (a casein kinase I homolog) results in the hypophosphorylation of FRQ, WC-1, and WC-2. In the ck-1aL strain, a knock-in mutant that carries a mutation equivalent to that of the Drosophila dbtL mutation, FRQ, WC-1, and WC-2 are hypophosphorylated. The mutant also exhibits ~32 h circadian rhythms due to the increase of FRQ stability and the significant delay of FRQ progressive phosphorylation. In addition, the levels of WC-1 and WC-2 are low in the ck-1aL strain, indicating that CK-1a is also important for the circadian positive feedback loops. In spite of its low accumulation in the ck-1aL strain, the hypophosphorylated WCC efficiently binds to the C-box within the frq promoter, presumably because it cannot be inactivated through FRQ-mediated phosphorylation. Furthermore, WC-1 and WC-2 are also hypophosphorylated in the ckaRIP strain, which carries the disruption of the catalytic subunit of casein kinase II. In the ckaRIP strain, WCC binding to the C-box is constantly high and cannot be inhibited by FRQ despite high FRQ levels, resulting in high levels of frq RNA. Together, these results suggest that CKI and CKII, in addition to being the FRQ kinases, mediate the FRQ-dependent phosphorylation of WCs, which inhibit their activity and close the circadian negative feedback loop.
Accuracy and Bias in Perceptions of Spouses' Life‐Sustaining Medical Treatment Preferences1
Authors: Lemay Edward P. , Pruchno Rachel A. , Feild Lucy
Published: September 2006

This research investigated accuracy, projection bias, and base‐rate utilization in spouses' perceptions of end‐stage renal disease patients' preferences for life‐sustaining medical treatment in hypothetical conditions of declining health. Multilevel models revealed that spouses' perceptions were largely biased, determined by their own preferences for the patients' treatment (projection bias) and by typical treatment preferences (base‐rate utilization). Both biases, however, served as indirect routes to a modest degree of accuracy. Moreover, spouses who overestimated patients' preferences for life‐sustaining treatment and who perceived patients' preferences as consistent with their own reported higher levels of marital adjustment than did those who were less biased. Results suggest that spouses' biases in judgments of patients' treatment preferences may promote accuracy and marital adjustment functionally.
Responses to the Stigmatized: Disjunctions in Affect, Cognitions, and Behavior
Authors: Bromgard Gregg , Stephan Walter G.
Published: September 2006

This study examined affective, cognitive, and behavioral responses to members of a stigmatized group – homosexual men. Male participants were placed in a situation in which they anticipated interacting with a gray or a non‐stigmatized conversation partner. The topic of the impending conversation was either potentially threatening or non‐threatening. Participants in the gay conversation partner condition sat either farther away from the conversation partner (in the threat condition) or closer to the conversation partner (in the no‐threat condition) than they did from non‐stigmatized conversation partners. There were no differences in attitudes toward the conversation partner as a function of experimental condition. The results were interpreted in terms of predictions based on ambivalence‐amplification theory, aversive racism theory, and the integrated threat theory.
Views of Employee Participation, Higher Order Needs, Altruism, Pride in Craftsmanship, and Collectivism: Implications for Organizational Practice and Public Policy
Authors: Ghorpade Jai , Lackritz Jim , Singh Gangaram
Published: September 2006

Using a sample of 749 individuals, we examine the correlation of views of employee participation and higher order needs, altruism, pride in craftsmanship, and collectivism. Structural equation modeling (accounting for measurement errors) shows that views of employee participation are correlated positively with higher order needs, altruism, pride in craftsmanship, and collectivism. Our model also shows equivalency across 3 different age groups. Implications of our results for organizational practice and public policy are discussed.
Perceptions and Punishments of Workplace Aggression: The Role of Aggression Content, Context, and Perceiver Variables1
Authors: Brown Theresa J. , Sumner Kenneth E.
Published: September 2006

Aggressiveness and sanctioning ratings made by 360 undergraduates to scenarios of workplace aggression suggest that aggressor gender, occupational status of aggressor relative to the target of aggression, and type of aggression content (i.e., hostility, obstructionism, or overt) affected these ratings. The results support hypothesized main effects for aggression content and aggressor gender, and also a significant interaction between occupational status and aggressor gender. However, the results failed to confirm hypotheses that perceiver variables (e.g., trait aggression) would add significantly to the prediction of either aggressiveness ratings or sanctioning ratings. Implications for policy formation to manage aggressive individuals in organizations are discussed.
The Influence of Personality on Workplace Bullying and Discrimination
Authors: Parkins Irina Sumajin , Fishbein Harold D. , Ritchey P. Neal
Published: September 2006

This study explored the similarity of underlying personality traits of workplace bullying and discrimination. University students self‐reported the frequency of bullying others in the workplace and discriminating against African Americans, homosexuals, and the obese. They completed questionnaires measuring prejudice and personality traits. The major findings were that social dominance orientation, low social desirability scores, and being male affected bullying and discrimination. Perspective taking affected bullying; and right‐wing authoritarianism, anxiety, and being White affected discrimination. Prejudice influenced relations between personality and discrimination, but not bullying. It was concluded that despite strong behavioral similarities, bullying and discrimination have somewhat different underlying determinants. Certain traits make them distinct, increasing the likelihood of one choosing either a prejudice‐based target or a non‐prejudice‐based target.
Long‐term results of thalidomide in refractory and relapsed multiple myeloma with emphasis on response duration
Authors: Cibeira M. Teresa , Rosiñol Laura , Ramiro Laia , Esteve Jordi , Torrebadell Montserrat , Bladé Joan
Published: September 2006

Objective: Thalidomide administered as a single agent produces a response rate of about 40% in patients with refractory or relapsed multiple myeloma (MM). The aim of our study was to determine the quality and duration of such responses.

Patients and methods: Forty‐two consecutive patients with refractory (20) or relapsed (22) MM were given thalidomide as a single agent at our institution. Most of them (70%) had previously received two or more lines of therapy, and 38% had undergone autologous stem cell transplantation.

Results: Eighteen patients (43%) responded to thalidomide [11 minimal responses (MR) and seven partial responses (PR)] according to the European Marrow Transplant Registry (EBMT) criteria. The median time to response was 3 months and the median duration of therapy in responding patients was 9 months. Treatment was discontinued because of toxicity in 10 responding patients. The toxicity mainly led to peripheral neuropathy and fatigue. At the time of this analysis, all responding patients had progressed except one who remains in continued stable PR. The median time to progression was 15.6 months (range 1.3 to 70+), with a trend towards a longer duration for patients who achieved PR vs. MR (21.2 vs. 11.2 months, P = 0.11). The median duration of response was 12.4 months (range: 0.3–67+) (17.2 months for PR vs. 9.7 months for MR, P = 0.11).

Conclusion: These results show that the effect of thalidomide in refractory/relapsed MM can be sustained, particularly in patients who achieve a greater degree of response, and support the finding that this drug can be used for maintenance therapy.
Molecular genetic analysis of a variant Bernard–Soulier syndrome due to compound heterozygosity for two novel glycoprotein Ibβ mutations
Authors: Kunishima Shinji , Sako Masahiro , Yamazaki Tomio , Hamaguchi Motohiro , Saito Hidehiko
Published: September 2006

Bernard–Soulier syndrome (BSS) is a rare bleeding disorder characterized by giant platelets, thrombocytopenia, and prolonged bleeding time. It is caused by abnormalities in the glycoprotein (GP) Ib/IX/V complex, the receptor for von Willebrand factor (vWF). Most cases of BSS described so far involve quantitative rather than qualitative defects in the complex. In this study, we investigated the effects of two naturally occurring mutations in the GPIbβ gene, C122S and 443delG, on the expression of the GPIb/IX complex identified in a variant type of BSS in which the platelets had severely reduced GPIbα (∼10%) and less markedly reduced GPIbβ and GPIX (∼20%) expression. Immunoblot analysis showed the absence of non‐reduced GPIb (GPIbα/GPIbβ) in the patient's platelets. Transient transfection experiments in 293T cells revealed the expression of GPIbβ Ser122 polypeptide and absence of GPIbβ 443delG polypeptide. Although no disulfide‐linked association was observed between GPIbβ Ser122 and GPIbα, GPIbβ Ser122 was non‐covalently associated with both GPIbα and GPIX subunits on the cell surface when cotransfected with wild‐type GPIbα and GPIX. Chinese hamster ovary cells stably expressing GPIbα/Ibβ Ser122/IX had the ability to bind soluble vWF and to aggregate in the presence of ristocetin. These results suggest that despite disruption of the disulfide linkage between GPIbα and GPIbβ, GPIb/IX is formed, but its stability may be impaired, resulting in low levels of the complex on the platelet membranes.
Venlafaxine‐induced ecchymoses and impaired platelet aggregation
Authors: Sarma Anita , Horne McDonald K.
Published: September 2006

Objective: To describe a case of venlafaxine‐induced ecchymoses.

Methods: A patient with a history of ecchymoses coincident with venlafaxine therapy was rechallenged with the drug. Her platelet function was assessed with aggregation and ATP release studies before the rechallenge and after she developed ecchymoses. In addition, the effect of venlafaxine on platelet aggregation and ATP release was studied in vitro by adding the drug to platelet‐rich plasma from normal donors.

Results: After 4 wk of treatment with venlafaxine our patient developed extensive ecchymoses. At that time her platelet aggregation and release responses to epinephrine, ADP, collagen, and arachidonic acid were markedly suppressed. Adding venlafaxine to normal platelet‐rich plasma also dramatically reduced the aggregation and release responses to the same agonists as well as to serotonin, but the concentrations of venlafaxine required were 1000‐fold greater than those normally achieved clinically.

Conclusions: Our patient demonstrated an idiosyncratic hypersensitivity to the platelet inhibitory effects of venlafaxine. Because venlafaxine is an inhibitor of serotonin uptake by platelets and neurons, this mechanism may contribute to the impact of this drug on platelet function. However, our in vitro studies suggest that this hypothesis is inadequate to explain the observations completely.
Exisulind induces apoptosis in advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia/MDS
Authors: Czibere Akos , Prall Wolf C. , Zerbini Luiz F. , Jäger Markus , Kobbe Guido , Knipp Sabine , Libermann Towia A. , Haas Rainer , Aivado Manuel
Published: September 2006

The influence of Exisulind on the viability and apoptosis of CD34+ stem cells from patients with advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)/MDS was investigated. In eight out of 10 patient samples Exisulind reduced the fraction of viable cells by inducing apoptosis. We found evidence that Exisulind‐mediated apoptosis depends on c‐Jun NH2‐terminal kinase (JNK) activation. Addition of a specific JNK‐inhibitor to Exisulind‐treated advanced MDS and AML/MDS cells partly abrogated apoptosis. We propose that Exisulind is tested in clinical phase I/II trials for the treatment of advanced MDS and AML/MDS.
Participatory evaluation (I) – sharing lessons from fieldwork in Asia
Authors: Crishna B.
Published: September 2006

Background  There is a need to study methodologies for evaluating social development projects. Traditional methods of evaluation are often not able to capture or measure the ‘spirit of change’ in people, which is the very essence of human development. Using participatory methodologies is a positive way to ensure that evaluations encourage an understanding of the value of critical analysis among service providers and other stakeholders. Participatory evaluation provides a systematic process of learning through experiences.

Methods  Practical experiences of conducting a number of evaluation studies in social development projects have led the author to develop four basic principles of participatory evaluation strategies. This has been further conceptualized through an extensive literature search. The article develops and shares these principles through descriptions of field experiences in Asia.

Results  The article illustrates that the role of any evaluation remains a learning process, one which promotes a climate of reflection and self‐assessment. It shows how using participatory methods can create this environment of learning. However, one needs to keep in mind that participatory evaluation takes time, and that the role and calibre of the facilitator are crucial.

Conclusion  Participatory evaluation methods have been recommended for social development projects to ensure that stakeholders remain in control of their own lives and decisions.
Career choices for paediatrics: national surveys of graduates of 1974–2002 from UK medical schools
Authors: Turner G. , Lambert T. W. , Goldacre M. J. , Turner Steve
Published: September 2006

Background  Knowledge of UK doctors’ career intentions and pathways is essential for understanding future workforce requirements. The aim of this study was to report career choices for and career progression in paediatrics in the UK.

Methods  Postal questionnaire surveys of qualifiers from all UK medical schools in nine qualification years since 1974.

Results  In total, 74% (24 621/33 412) and 73% (20 720/28 459) of doctors responded at 1 and 3 years after graduation. Choices for paediatrics 1 year after qualifying fell from 7.8% of 1974 graduates to 5.0% of 1983 graduates, increased to 7.2% of 1993 graduates, and since the level has remained fairly constant. Approximately twice the percentage of women graduates than men graduates indicated a long‐term career choice for paediatrics. A total of 44% of those who chose paediatrics 1 year after graduation were working in it 10 years after qualifying. Experience of the subject as a student, and enthusiasm/commitment: what I really want to do, affected long‐term career choices more for paediatrics than for other medical careers.

Conclusions  The proportion of junior doctors wishing to become paediatricians has not changed much during the last 30 years. The planned increase in the number of medical school graduates is necessary to increase the number of UK‐trained consultant paediatricians. Medical students who experience enthusiastic and stimulating training in paediatrics may be more likely to become paediatricians.
CDX‐2 expression in pseudomyxoma peritonei: a clinicopathological study of 42 cases
Authors: Nonaka D , Kusamura S , Baratti D , Casali P , Younan R , Deraco M
Published: September 2006

Aims:  CDX‐2 is a highly sensitive and specific marker of intestinal epithelial cells and their neoplastic counterparts. CDX‐2 status in pseudomyxoma peritonei (PMP) has been barely reported. The aim of this study was to investigate the clinicopathological features of 42 cases of PMP with a special emphasis on CDX‐2.

Methods and results:  All patients were treated by cytoreduction. Immunohistochemistry was performed for CDX‐2, MUC‐2, MUC‐5AC, cytokeratin (CK) 7 and CK20. Statistical correlation was evaluated for age, sex, completeness of cytoreduction and histological subtype with overall and progression‐free survival (OS and PFS). PMP consisted of 32 cases of disseminated peritoneal adenomucinosis and 10 cases of peritoneal mucinous carcinomatosis. The appendix evaluated in 25 cases showed two mucinous adenocarcinomas and 21 low‐grade appendiceal mucinous neoplasms. CDX‐2 was diffusely positive in 40 cases, with the remaining two cases being focally positive. All cases demonstrated diffuse reactions to CK20 and MUC‐2, and variable reactions to MUC‐5AC, while CK7 was variably positive in 38 cases. Five‐year OS was 97%. Histological type was significantly correlated with PFS (P = 0.02).

Conclusions:  CDX‐2 is diffusely and strongly positive in PMP. This is a useful marker to confirm an appendiceal origin of PMP, particularly when used in conjunction with CK7, CK20, MUC‐2 and MUC‐5AC.
Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment II
Authors: Taylor C R , Levenson R M
Published: September 2006

Immunohistochemistry is entering its fourth decade of use on formalin‐fixed paraffin‐embedded tissues. Over this period the method has evolved to become a major part of the practice of diagnostic surgical pathology worldwide. From the beginning immunohistochemistry has been adapted to provide a range of markers of cell lineage and tissue type, with particular application to the diagnosis and classification of tumours. In this modality immunohistochemical methods were employed simply as ‘special stains’, the results of which were evaluated qualitatively by the pathologist, as for any other stain. More recently, attention has shifted to the demonstration of prognostic markers in tumour cells, driven by the advent of molecular biology and the discovery of numerous regulatory molecules, coupled with manufacture of the corresponding specific antibodies. Immunohistochemistry has rapidly adapted to this new use, but in so doing the demand for quantification has become paramount; it is no longer enough that the ‘stain’ is there; rather it is a question of ‘How much is there?’. This review explores the limitations of immunohistochemistry when employed in a semiquantitative mode, and explores the possibility of fulfilling the full potential of immunohistochemistry, as a true quantitative immunoassay applied in a tissue section environment.