bluuebunny/crossref_metadata_2025 huggingface dataset:
Ecto-nucleoside triphosphate diphosphohydrolase 3 in the ventral and lateral hypothalamic area of female rats: morphological characterization and functional implications
Authors: Kiss David S , Zsarnovszky Attila , Horvath Krisztina , Gyorffy Andrea , Bartha Tibor , Hazai Diana , Sotonyi Peter , Somogyi Virag , Frenyo Laszlo V , Diano Sabrina
Published: April 2009

Background

Based on its distribution in the brain, ecto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3) may play a role in the hypothalamic regulation of homeostatic systems, including feeding, sleep-wake behavior and reproduction. To further characterize the morphological attributes of NTPDase3-immunoreactive (IR) hypothalamic structures in the rat brain, here we investigated: 1.) The cellular and subcellular localization of NTPDase3; 2.) The effects of 17β-estradiol on the expression level of hypothalamic NTPDase3; and 3.) The effects of NTPDase inhibition in hypothalamic synaptosomal preparations.

Methods

Combined light- and electron microscopic analyses were carried out to characterize the cellular and subcellular localization of NTPDase3-immunoreactivity. The effects of estrogen on hypothalamic NTPDase3 expression was studied by western blot technique. Finally, the effects of NTPDase inhibition on mitochondrial respiration were investigated using a Clark-type oxygen electrode.

Results

Combined light- and electron microscopic analysis of immunostained hypothalamic slices revealed that NTPDase3-IR is linked to ribosomes and mitochondria, is predominantly present in excitatory axon terminals and in distinct segments of the perikaryal plasma membrane. Immunohistochemical labeling of NTPDase3 and glutamic acid decarboxylase (GAD) indicated that γ-amino-butyric-acid- (GABA) ergic hypothalamic neurons do not express NTPDase3, further suggesting that in the hypothalamus, NTPDase3 is predominantly present in excitatory neurons. We also investigated whether estrogen influences the expression level of NTPDase3 in the ventrobasal and lateral hypothalamus. A single subcutaneous injection of estrogen differentially increased NTPDase3 expression in the medial and lateral parts of the hypothalamus, indicating that this enzyme likely plays region-specific roles in estrogen-dependent hypothalamic regulatory mechanisms. Determination of mitochondrial respiration rates with and without the inhibition of NTPDases confirmed the presence of NTPDases, including NTPDase3 in neuronal mitochondria and showed that blockade of mitochondrial NTPDase functions decreases state 3 mitochondrial respiration rate and total mitochondrial respiratory capacity.

Conclusion

Altogether, these results suggest the possibility that NTPDases, among them NTPDase3, may play an estrogen-dependent modulatory role in the regulation of intracellular availability of ATP needed for excitatory neuronal functions including neurotransmission.
Close phylogenetic relationship between Angolan and Romanian HIV-1 subtype F1 isolates
Authors: Guimarães Monick L , Vicente Ana Carolina P , Otsuki Koko , da Silva Rosa Ferreira FC , Francisco Moises , da Silva Filomena Gomes , Serrano Ducelina , Morgado Mariza G , Bello Gonzalo
Published: April 2009

Background

Here, we investigated the phylogenetic relationships of the HIV-1 subtype F1 circulating in Angola with subtype F1 strains sampled worldwide and reconstructed the evolutionary history of this subtype in Central Africa.

Methods

Forty-six HIV-1-positive samples were collected in Angola in 2006 and subtyped at theenv-gp41 region. Partialenv-gp120 andpol-RTsequences and near full-length genomes from thoseenv-gp41 subtype F1 samples were further generated. Phylogenetic analyses of partial and full-length subtype F1 strains isolated worldwide were carried out. The onset date of the subtype F1 epidemic in Central Africa was estimated using a Bayesian Markov chain Monte Carlo approach.

Results

Nine Angolan samples were classified as subtype F1 based on the analysis of theenv-gp41 region. All nine Angolan sequences were also classified as subtype F1 in bothenv-gp120andpol-RTgenomic regions, and near full-length genome analysis of four of these samples confirmed their classification as "pure" subtype F1. Phylogenetic analyses of subtype F1 strains isolated worldwide revealed that isolates from the Democratic Republic of Congo (DRC) were the earliest branching lineages within the subtype F1 phylogeny. Most strains from Angola segregated in a monophyletic group together with Romanian sequences; whereas South American F1 sequences emerged as an independent cluster. The origin of the subtype F1 epidemic in Central African was estimated at 1958 (1934–1971).

Conclusion

"Pure" subtype F1 strains are common in Angola and seem to be the result of a single founder event. Subtype F1 sequences from Angola are closely related to those described in Romania, and only distantly related to the subtype F1 lineage circulating in South America. Original diversification of subtype F1 probably occurred within the DRC around the late 1950s.
Effect of conjugated linoleic acids from beef or industrial hydrogenation on growth and adipose tissue characteristics of rats
Authors: He Mao L , Mir Priya S , Okine Erasmus K , Napadajlo Helen
Published: April 2009

Background

The conjugated linoleic acid (CLA) content of beef can be increased by supplementing appropriate beef cattle diets with vegetable oil or oil seed. Yet the effect of consumption of such beef on adipose tissue characteristics is unclear, thus the study was conducted to compare adipose tissue responses of rats to diets containing beef from steers either not provided or provided the oil supplements to alter CLA composition of the fat in muscle.

Methods

Effects of feeding synthetic (industrial hydrogenation) CLA or CLA from beef on growth and adipose tissue responses of weanling, male, Wistar rats (n = 56; 14 per treatment diet) were investigated in a completely randomized design experiment. Diets were: control (CON) diet containing casein and soybean oil, synthetic CLA (SCLA) diet; where 1.69% synthetic CLA replaced soybean oil, two beef-diets; CONM and CLAM, containing freeze dried beef from steers either not fed or fed 14% sunflower seeds to increase CLA content of beef. Diets were isonitrogenous (20% protein) and isocaloric. Rat weights and ad libitum intakes were recorded every 2 wk. After 9 wk, rats were fasted for 24 h, blood sampled by heart puncture, sacrificed, tissue and organs were harvested and weights recorded. The adipose tissue responses with regard to cellularity and fatty acid compositions of retroperitoneal and inguinal adipose tissue were determined.

Results

Body weights and gains were comparable, but organ weights as percent of body weight were greater for rats fed SCLA than CONM. Fasting blood glucose concentration was lower (p < 0.01) in rats fed SCLA than those fed CONM or CLAM. Retroperitoneal and inguinal fat weights, as percent of body weight were greater (p < 0.01) in rats fed CONM or CLAM than those fed CON or SCLA diets. Adipocyte numbers were least in retroperitoneal tissue of rats fed SCLA, while inguinal tissue cell density and total number were lower (p = 0.02) in rats fed CLAM (7.26 × 107 cells/g and 8.03 × 108 cells) than those fed CONM (28.88 × 107 cells/g and 32.05 × 108 cells, respectively).

Conclusion

Study suggests that dietary CLA either as synthetic or high CLA-beef may alter adipose tissue characteristics by decreasing the number of adipocytes and by decreasing the size of the tissue.
Nitric oxide production by Biomphalaria glabrata haemocytes: effects of Schistosoma mansoni ESPs and regulation through the extracellular signal-regulated kinase pathway
Authors: Zahoor Zahida , Davies Angela J , Kirk Ruth S , Rollinson David , Walker Anthony J
Published: April 2009

Background

Schistosoma mansoni uses Biomphalaria glabrata as an intermediate host during its complex life cycle. In the snail, the parasite initially transforms from a miracidium into a mother sporocyst and during this process excretory-secretory products (ESPs) are released. Nitric oxide (NO) and its reactive intermediates play an important role in host defence responses against pathogens. This study therefore aimed to determine the effects of S. mansoni ESPs on NO production in defence cells (haemocytes) from schistosome-susceptible and schistosome-resistant B. glabrata strains. As S. mansoni ESPs have previously been shown to inhibit extracellular signal-regulated kinase (ERK) phosphorylation (activation) in haemocytes from susceptible, but not resistant, B. glabrata the regulation of NO output by ERK in these cells was also investigated.

Results

Haemocytes from resistant snails challenged with S. mansoni ESPs (20 μg/ml) over 5 h displayed an increase in NO production that was 3.3 times greater than that observed for unchallenged haemocytes; lower concentrations of ESPs (0.1–10 μg/ml) did not significantly increase NO output. In contrast, haemocytes from susceptible snails showed no significant change in NO output following challenge with ESPs at any concentration used (0.1–20 μg/ml). Western blotting revealed that U0126 (1 μM or 10 μM) blocked the phosphorylation (activation) status of ERK in haemocytes from both snail strains. Inhibition of ERK signalling by U0126 attenuated considerably intracellular NO production in haemocytes from both susceptible and resistant B. glabrata strains, identifying ERK as a key regulator of NO output in these cells.

Conclusion

S. mansoni ESPs differentially influence intracellular NO levels in susceptible and resistant B. glabrata haemocytes, possibly through modulation of the ERK signalling pathway. Such effects might facilitate survival of S. mansoni in its intermediate host.
Effect of sugar on male Anopheles gambiae mating performance, as modified by temperature, space, and body size
Authors: Gary Richard E , Cannon James W , Foster Woodbridge A
Published: April 2009

Background

Anopheles gambiae plant-sugar feeding was thought to be rare and physiologically optional. Unlike adult females, males have no alternative source of energy and soon die with only water, yet they might be competent to inseminate all females within their brief lifespan. This study was designed to detect sugar's effect, if any, on male performance.

Methods

Males with and without 20% sucrose were evaluated at two body sizes and two temperatures, 23° and 27°C. Survival was recorded twice daily, and sexual behaviour was recorded each night after adult emergence. Insemination at a 2:1 male:female ratio was examined in three cage sizes, including walk-in mesocosms.

Results

Without sugar, males of both sizes lived longer at 23° than 27°C, and large males lived longer at each temperature. Survival of large males at low temperature averaged 3.7 days, small males at high temperature, 1.9 days. With sugar, males in all four treatments suffered minimal mortality. With sugar, in small cages, large males at 27°C matured most rapidly. A few erected fibrillae and inseminated females on night 1. On night 2, maximal proportions erected fibrillae and swarmed, and over one-third of females became inseminated. Small sugar-fed males at 23°C matured most slowly but had achieved nearly maximal levels of swarming by night 3. By night 5, small males had inseminated more than half the females, and large males had inseminated nearly all of them. Without sugar, large males progressed similarly during the first two nights. On night 3, however, the proportion erecting fibrillae and swarming declined precipitously at 27°C, and to a lesser degree at 23°C. Cumulative insemination never reached high levels. Small males never achieved high levels of fibrillar erection or swarming and inseminated few females, even at 23°C. In larger cages and under more semi-natural conditions, regardless of body size, without sugar male insemination capacity was virtually nonexistent.

Conclusion

Under some conditions, a limited number of sugar-deprived males can survive long enough to inseminate females. However, in nature males that cannot obtain sugar at frequent intervals will not be competitive with those that can, suggesting that male performance is closely tied to plant communities.
BTLA targeting modulates lymphocyte phenotype, function, and numbers and attenuates disease in nonobese diabetic mice
Authors: Truong Wayne , Hancock Wayne W , Plester Jennifer C , Merani Shaheed , Rayner David C , Thangavelu Govindarajan , Murphy Kenneth M , Anderson Colin C , Shapiro A. M. James
Published: April 2009

Targeting coinhibitory T cell receptors using monoclonal antibodies attenuates autoimmune diabetes by altering lymphocyte number and function.

The novel coinhibitory receptor BTLA may have a regulatory role in maintaining peripheral tolerance; however, its role in autoimmune diabetes is unknown. In this study, we show that anti-BTLA mAb 6F7 selectively depleted pathogenic B and CD4+ TH cells; enhanced the proportion of cells with the forkhead box p3+ PD-1+CD4+ regulatory T phenotype; and increased the production of potentially protective (IL-10) and detrimental (IL-2, IFN-γ) cytokines in NOD mice. As interactions between BTLA and PD-1 coinhibitory pathways have been described in the cardiac allograft model, we also investigated if these pathways may have significant interaction in autoimmune diabetes. Anti-BTLA inhibited anti-PD-1-potentiated total IL-12 (p40+p70) production, suggesting the possibility that anti-BTLA may have a greater effect in the setting of anti-PD-1-triggered diabetes. To test this, NOD mice at 4 and 10 weeks of age were treated with anti-BTLA mAb, anti-PD-1 mAb, both mAb, or isotype control and were monitored for diabetes development. Although anti-BTLA mAb delayed diabetes onset significantly in 10- but not 4-week-old NOD mice, anti-BTLA mAb attenuated anti-PD-1-induced diabetes in both age groups. Hence, strategies targeting BTLA+ lymphocytes or therapies enhancing the BTLA-negative cosignal may prove valuable in treating autoimmune diabetes.
Angle-domain common-image gathers in generalized coordinates
Authors: Shragge Jeff
Published: April 2009

The theory of angle-domain common-image gathers (ADCIGs) is extended to migrations performed in generalized 2D coordinate systems. I have developed an expression linking the definition of reflection opening angle to differential traveltime operators and spatially varying weights derived from the non-Cartesian geometry. Generalized-coordinate ADCIGs can be calculated directly using Radon-based offset-to-angle approaches for coordinate systems satisfying the Cauchy-Riemann differentiability criteria. The canonical examples of tilted-Cartesian, polar, and elliptical coordinates can be used to illustrate the ADCIG theory. I have compared analytically and numerically generated image volumes for a set of elliptically shaped reflectors. Experiments with a synthetic data set showed that elliptical-coordinate ADCIGs better resolve the reflection opening angles of steeply dipping structure, relative to conventional Cartesian image volumes, because of improved large-angle propagation and enhanced sensitivity to steep structural dips afforded by coordinate system transformations.
3D polarimetric GPR coherency attributes and full-waveform inversion of transmission data for characterizing fractured rock
Authors: Sassen Douglas S. , Everett Mark E.
Published: April 2009

Ground-penetrating radar (GPR) can detect and describe fractures to help us characterize fractured rock formations. A fracture alters the incident waveform, or wave shape, of a GPR signal through constructive and destructive interference, depending on the aperture, fill, and orientation of the fracture. Because the electromagnetic (EM) waves of GPR are vectorial, features exhibiting strong directionality can change the state of polarization of the incident field. GPR methods that focus on changes in waveform or polarization can improve detection and discrimination of fractures within rock bodies. An algorithm based on coherency, a seismic attribute that delineates discontinuities in wavelet shape, is developed for polarimetric GPR. It uses the largest eigenvalue of the time-domain scattering matrix when calculating coherence. This algorithm is sensitive to wave shape and is unbiased by the polarization of GPR antennas. Polarimetric coherency works better than scalar coherency in removing the effects of polarization on field data collected from a fractured limestone plot used for hydrologic experimentation. Another method, for time-domain full-waveform inversion of transmission data, quantitatively determines fracture aperture and EM properties of fill, based on a thin-layer model. Inversion results from field data show consistency with the location of fractures from reflection data. These two methods offer better fracture-detection capability and quantitative information on fracture aperture, dielectric permittivity, and electrical conductivity of the fill than traditional GPR imaging and scalar-coherency attributes.
Fault imaging in hydrothermal dolomite reservoirs: A case study
Authors: Ogiesoba O. C. , Hart B. S.
Published: April 2009

Most hydrocarbon fields found within the Ordovician Trenton and Black River Groups of the eastern United States and eastern Canada are associated with basement-related faults. These faults are best imaged by 3D seismic technology. Because of environmental conditions, seismic data often are contaminated by noise that masks fault terminations and reduces signal-to-noise ratio. As a result, seismic horizons are discontinuous, calculated coherence values are affected adversely, and horizon interpretation and fault identification are difficult, if not impossible. Poststack processing is required to attenuate this noise before an optimal interpreta-tion can be done. We conducted a three-step poststack processing flow to attenuate noise and highlight fault terminations. Noise-reducing algorithms consist of frequency-space [Formula: see text] deconvolution, zero-phase filtering, and [Formula: see text] filtering. The structural grain of major faults identified with these techniques agrees with the regional strike of major faults previously defined in the area. These faults were confirmed by drilling results. Our calculated semblance of cosine of phase provides better fault definition than does regular coherency and serves as an alternative attribute for mapping faults. The processing sequence could apply in areas with similar geologic settings and noise problems.
Capacitive conductivity logging and electrical stratigraphy in a high-resistivity aquifer, Boise Hydrogeophysical Research Site
Authors: Mwenifumbo C. Jonathan , Barrash Warren , Knoll Michael D.
Published: April 2009

We tested a prototype capacitive-conductivity borehole tool in a shallow, unconfined aquifer with coarse, unconsolidated sediments and very-low-conductivity water at the Boise Hydrogeophysical Research Site (BHRS). Examining such a high-resistivity system provides a good test for the capacitive-conductivity tool because the conventional induction-conductivity tool (known to have limited effectiveness in high-resistivity systems) did not generate expressive well logs at the BHRS. The capacitive-conductivity tool demonstrated highly repeatable, low-noise behavior but poor correlation with the induction tool in the lower-conductivity portions of the stratigraphy where the induction tool was relatively unresponsive. Singular spectrum analysis of capacitive-conductivity logs reveals similar vertical-length scales of structures to porosity logs at the BHRS. Also, major stratigraphic units identified with porosity logs are evident in the capacitive-conductivity logs. However, a previously unrecognized subdivision in the upper portion of one of the major stratigraphic units can be identified consistently as a relatively low-conductivity body (i.e., an electrostratigraphic unit) between the overlying stratigraphic unit and the relatively high-conductivity lower portion — despite similar porosity and lithology in adjacent units. The high repeatability and resolution and the wide dynamic range of the capacitive-conductivity tool are demonstrated here to extend to high-resistivity, unconsolidated sedimentary aquifer environments.
Acerca de la relación entre el Radicalismo argentino y la “clase media” (una vez más)
Authors: Adamovsky Ezequiel
Published: April 2009

Es una creencia profundamente arraigada en el sentido común que la Unión Cívica Radical (UCR) –el más antiguo de los partidos políticos argentinos– canalizó los intereses de una “clase media” que, según se afirma, experimentó un crecimiento notable a partir de fines del siglo XIX de la mano de un proceso de “modernización”. Más aún, el caso de los radicales argentinos ha sido utilizado como ejemplo de procesos y tensiones de la modernización que afectaron a todo el subcontinente. En los últimos tiempos, el papel de la clase media en América Latina viene siendo reexaminado. La propia utilización de los conceptos de “clase media” y de “modernización” ha sido objeto de análisis críticos. En estudios recientes, la clase media viene dejando de ser una entidad cuya existencia social se presupone, para convertirse en un tipo de identidad específica cuya emergencia es necesario explicar. El objetivo de este artículo es contribuir al debate analizando los modos en los que la UCR pudo haber participado en la constitución de una “clase media” en Argentina, y los contextos políticos específicos en los que esto tuvo lugar. Sostendremos que, más que canalizar los intereses de una clase media previamente existente, la UCR contribuyó a la formación de tal identidad social mediante apelaciones discursivas motivadas más por necesidades y oportunidades político-ideológicas que por una vocación de vehiculizar intereses sectoriales particulares.
Economic Elites, Regional Cleavages, and the First Attempts at Introducing the Income Tax in Argentina
Authors: Román José Antonio Sánchez
Published: April 2009

This article analyzes Minister Víctor Molina’s 1924 income tax proposal, one of the first attempts to introduce this tax in Argentina, and explores the reasons for its failure. Argentine governments did not show a permanent commitment to fiscal reform during the 1920’s, mainly because the economic situation was not dire and the Treasury was able to finance its deficits through foreign debts due to the good performance of Argentine external sector. Nonetheless, Molina’s proposal was passed by the Chamber of Deputies and therefore it could have been the first income tax law in the country. Public opinion, intellectuals, and economists seemed to be persuaded that income tax was the solution to Argentine fiscal problems. Moreover, some key social sectors like rural or industrial entrepreneurs, without enthusiastically supporting the income tax, were disposed to tolerate it. In this article, I argue that we need a political interpretation of the failure of tax reform during 1920s. Molina’s draft was blocked in the Senate by the majority of the representatives of the interior provinces. In fact, income tax was considered to be a threat to the less affluent provinces of Argentina because it implied a step toward tax centralization and unification. Yet the economic weakness of the interior did not imply political weakness, and the interior provinces were the main obstacle to fiscal reform in Argentina until the 1930s.
The Idea of Universal Salvation in Piers Plowman B and C
Authors: Pearsall Derek
Published: April 2009

This essay takes up Nicholas Watson's important and influential article, “Visions of Inclusion: Universal Salvation and Vernacular Theology in Pre-Reformation England,” and argues that, for William Langland at least, the promise of universal salvation is at best ambiguous. The essay examines in detail Christ's speech after he has harrowed hell, the principal locus for the expression of Langland's views on the matter, but attempts to place this speech in the context of and as the climactic statement of Langland's salvation theology as it develops through the poem. Important variations between the B and C texts in their treatment of the subject are given special attention. The emphasis is always on the continuously evolving drama of Piers Plowman as a poem searching for the truth of belief rather than as a poem that expounds a system of already-existing belief.
Literacy After Iconoclasm in the English Reformation
Authors: Spolsky Ellen
Published: April 2009

Believing that the destruction of church imagery was necessary to the amendment of Christian life, the religious reformers in sixteenth-century England aimed to change minds as well as church furnishings. Image worship was to be replaced by reading, and learning from pictures and statues was to be replaced by learning to read the English Bible. Literacy, however, isn't easy, even now. Taking up the issues of iconoclasm and literacy from the perspective of recent research in cognitive neuroscience, this essay explores the reformers' misunderstandings about how people could or couldn't reform their spiritual lives, and suggests a new view of why changing minds wasn't as easy as the reformers had hoped, and why stripping the churches of their rood screens, burning or hiding statues of saints, overpainting narrative wall murals, and replacing stained glass with plain windows turned out to be easier than producing Bible readers.
Manliness and the Visual Semiotics of Bodily Fluids in Early Modern Culture
Authors: Simons Patricia
Published: April 2009

The ubiquity and charm of pissing putti in early modern imagery has inured us to their valence, for an important proof of masculinity in the European tradition is to be able to emit fluids from the penis, usually with some force, and significantly while standing erect. In early modern culture, the fluids were multiple and metaphoric, inviting a range of erotic wordplays and visual puns about urine, semen, water, and wine. The sexual economy was as much characterized by liquidity as it was obsessed with penile penetration. The somatics and semiotics of early modern masculinity consisted of more than sexual intromission or inhibiting anxiety, and visual metaphors presented manliness in ways that were often humorous, usually public, and always assertive.
“Optimism of the Will”: Isabella Whitney and Utopia
Authors: Bartolovich Crystal
Published: April 2009

Isabella Whitney's “Wyll” has been misrecognized generically because temporal utopias–of which her poem is the first instance–are not supposed to exist in the sixteenth century. Because women had a different relationship to the social and economic disruptions of emergent capitalism that gave birth to the genre in More's Utopia, however, female utopian thought is differently manifested as well. In the “Wyll,” the contradictions attending the moment of transition are embodied in the dissonant form of a poem that, in its first half, describes a city of abundance, and in its second, the dark side of the “same” London for the poor. Proposing that London should be abundant for all its inhabitants through a redistribution of the city's wealth and pleasures, the “Wyll” situates the utopian city in a yet unrealized future that readers, as executors, are enjoined to realize.
FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy
Authors: Wuebbles Ryan D. , Hanel Meredith L. , Jones Peter L.
Published: April 2009

The genetic lesion that is diagnostic for facioscapulohumeral muscular dystrophy (FSHD) results in an epigenetic misregulation of gene expression, which ultimately leads to the disease pathology. FRG1 (FSHD region gene 1) is a leading candidate for a gene whose misexpression might lead to FSHD. Because FSHD pathology is most prominent in the musculature, most research and therapy efforts focus on muscle cells. Previously, using Xenopus development as a model, we showed that altering frg1 expression levels systemically leads to aberrant muscle development, illustrating the potential for aberrant FRG1 levels to disrupt the musculature. However, 50–75% of FSHD patients also exhibit retinal vasculopathy and FSHD muscles have increased levels of vascular- and endothelial-related FRG1 transcripts, illustrating an underlying vascular component to the disease. To date, no FSHD candidate gene has been proposed to affect the vasculature. Here, we focus on a role for FRG1 expression in the vasculature. We found that endogenous frg1 is expressed in both the developing and adult vasculature in Xenopus. Furthermore, expression of FRG1 was found to be essential for the development of the vasculature, as a knockdown of FRG1 resulted in decreased angiogenesis and reduced expression of the angiogenic regulator DAB2. Conversely, tadpoles subjected to frg1 overexpression displayed the pro-angiogenic phenotypes of increased blood vessel branching and dilation of blood vessels, and developed edemas, suggesting that their circulation was disrupted. Thus, the systemic upregulation of the FRG1 protein shows the potential for acquiring a disrupted vascular phenotype, providing the first link between a FSHD candidate gene and the vascular component of FSHD pathology. Overall, in conjunction with our previous analysis, we show that FRG1 overexpression is capable of disrupting both the musculature and vasculature, recapitulating the two most prominent features of FSHD.
Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated inFgfrl1null mice
Authors: Catela Catarina , Bilbao-Cortes Daniel , Slonimsky Esfir , Kratsios Paschalis , Rosenthal Nadia , te Welscher Pascal
Published: April 2009

Wolf-Hirschhorn syndrome (WHS) is caused by deletions in the short arm of chromosome 4 (4p) and occurs in about one per 20,000 births. Patients with WHS display a set of highly variable characteristics including craniofacial dysgenesis, mental retardation, speech problems, congenital heart defects, short stature and a variety of skeletal anomalies. Analysis of patients with 4p deletions has identified two WHS critical regions (WHSCRs); however, deletions targeting mouse WHSCRs do not recapitulate the classical WHS defects, and the genes contributing to WHS have not been conclusively established. Recently, the human FGFRL1 gene, encoding a putative fibroblast growth factor (FGF) decoy receptor, has been implicated in the craniofacial phenotype of a WHS patient. Here, we report that targeted deletion of the mouse Fgfrl1 gene recapitulates a broad array of WHS phenotypes, including abnormal craniofacial development, axial and appendicular skeletal anomalies, and congenital heart defects. Fgfrl1 null mutants also display a transient foetal anaemia and a fully penetrant diaphragm defect, causing prenatal and perinatal lethality. Together, these data support a wider role for Fgfrl1 in development, implicate FGFRL1 insufficiency in WHS, and provide a novel animal model to dissect the complex aetiology of this human disease.
Multicopy suppressor analysis of thermosensitiveYIP1alleles implicatesGOT1in transport from the ER
Authors: Lorente-Rodríguez Andrés , Heidtman Matthew , Barlowe Charles
Published: April 2009

Yip1p belongs to a conserved family of membrane-spanning proteins that are involved in intracellular trafficking. Studies have shown that Yip1p forms a heteromeric integral membrane complex, is required for biogenesis of ER-derived COPII vesicles, and can interact with Rab GTPases. However, the role of the Yip1 complex in vesicle budding is not well understood. To gain further insight, we isolated multicopy suppressors of the thermosensitive yip1-2 allele. This screen identified GOT1, FYV8 and TSC3 as novel high-copy suppressors. The strongest suppressor, GOT1, also displayed moderate suppressor activity toward temperature-sensitive mutations in the SEC23 and SEC31 genes, which encode subunits of the COPII coat. Further characterization of Got1p revealed that this protein was efficiently packaged into COPII vesicles and cycled rapidly between the ER and Golgi compartments. Based on the findings we propose that Got1p has an unexpected role in vesicle formation from the ER by influencing membrane properties.
Dominant roles of the polybasic proline motif and copper in the PrP23-89-mediated stress protection response
Authors: Haigh Cathryn L. , Drew Simon C. , Boland Martin P. , Masters Colin L. , Barnham Kevin J. , Lawson Victoria A. , Collins Steven J.
Published: April 2009

Beta-cleavage of the neurodegenerative disease-associated prion protein (PrP) protects cells from death induced by oxidative insults. The beta-cleavage event produces two fragments, designated N2 and C2. We investigated the role of the N2 fragment (residues 23-89) in cellular stress response, determining mechanisms involved and regions important for this reaction. The N2 fragment differentially modulated the reactive oxygen species (ROS) response induced by serum deprivation, with amelioration when copper bound. Amino acid residues 23-50 alone mediated a ROS reduction response. PrP23-50 ROS reduction was not due to copper binding or direct antioxidant activity, but was instead mediated through proteoglycan binding partners localised in or interacting with cholesterol-rich membrane domains. Furthermore, mutational analyses of both PrP23-50 and N2 showed that their protective capacity requires the sterically constraining double proline motif within the N-terminal polybasic region. Our findings show that N2 is a biologically active fragment that is able to modulate stress-induced intracellular ROS through interaction of its structurally defined N-terminal polybasic region with cell-surface proteoglycans.
Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A
Authors: Fernandez-Martinez Javier , Vela Eva M. , Tora-Ponsioen Mireille , Ocaña Oscar H. , Nieto M. Angela , Galceran Juan
Published: April 2009

Notch signalling is used throughout the animal kingdom to spatially and temporally regulate cell fate, proliferation and differentiation. Its importance is reflected in the dramatic effects produced on both development and health by small variations in the strength of the Notch signal. The Down-syndrome-associated kinase DYRK1A is coexpressed with Notch in various tissues during embryonic development. Here we show that DYRK1A moves to the nuclear transcription compartment where it interacts with the intracellular domain of Notch promoting its phosphorylation in the ankyrin domain and reducing its capacity to sustain transcription. DYRK1A attenuates Notch signalling in neural cells both in culture and in vivo, constituting a novel mechanism capable of modulating different developmental processes that can also contribute to the alterations observed during brain development in animal models of Down syndrome.
Lamin B1 maintains the functional plasticity of nucleoli
Authors: Martin Catherine , Chen Songbi , Maya-Mendoza Apolinar , Lovric Josip , Sims Paul F. G. , Jackson Dean A.
Published: April 2009

The dynamic ability of genomes to interact with discrete nuclear compartments appears to be essential for chromatin function. However, the extent to which structural nuclear proteins contribute to this level of organization is largely unresolved. To test the links between structure and function, we evaluated how nuclear lamins contribute to the organization of a major functional compartment, the nucleolus. HeLa cells with compromised expression of the genes encoding lamins were analyzed using high-resolution imaging and pull-down assays. When lamin B1 expression was depleted, inhibition of RNA synthesis correlated with complex structural changes within the nucleolar active centers until, eventually, the nucleoli were dispersed completely. With normal lamin expression, the nucleoli were highly plastic, with dramatic and freely reversible structural changes correlating with the demand for ribosome biogenesis. Preservation of the nucleolar compartment throughout these structural transitions is shown to be linked to lamin B1 expression, with the lamin B1 protein interacting with the major nucleolar protein nucleophosmin/B23.
A germline-specific isoform of eIF4E (IFE-1) is required for efficient translation of stored mRNAs and maturation of both oocytes and sperm
Authors: Henderson Melissa A. , Cronland Elizabeth , Dunkelbarger Steve , Contreras Vince , Strome Susan , Keiper Brett D.
Published: April 2009

Fertility and embryonic viability are measures of efficient germ cell growth and development. During oogenesis and spermatogenesis, new proteins are required for both mitotic expansion and differentiation. Qualitative and quantitative changes in protein synthesis occur by translational control of mRNAs, mediated in part by eIF4E, which binds the mRNAs 5′ cap. IFE-1 is one of five eIF4E isoforms identified in C. elegans. IFE-1 is expressed primarily in the germ line and associates with P granules, large mRNPs that store mRNAs. We isolated a strain that lacks IFE-1 [ife-1(bn127)] and demonstrated that the translation of several maternal mRNAs (pos-1, pal-1, mex-1 and oma-1) was inefficient relative to that in wild-type worms. At 25°C, ife-1(bn127) spermatocytes failed in cytokinesis, prematurely expressed the pro-apoptotic protein CED-4/Apaf-1, and accumulated as multinucleate cells unable to mature to spermatids. A modest defect in oocyte development was also observed. Oocytes progressed normally through mitosis and meiosis, but subsequent production of competent oocytes became limiting, even in the presence of wild-type sperm. Combined gametogenesis defects decreased worm fertility by 80% at 20°C; ife-1 worms were completely sterile at 25°C. Thus, IFE-1 plays independent roles in late oogenesis and spermatogenesis through selective translation of germline-specific mRNAs.
Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90α autocrine signaling to promote keratinocyte migration
Authors: Woodley David T. , Fan Jianhua , Cheng Chieh-Fang , Li Yong , Chen Mei , Bu Guojun , Li Wei
Published: April 2009

Hypoxia is a microenvironmental stress in many pathological conditions, including wound healing and tumor invasion. Under hypoxia, the cells are forced to adapt alternative and self-supporting mechanisms. Understanding these mechanisms may lead to new insights into human disorders. We report here a novel autocrine signaling mechanism by which hypoxia promotes human keratinocyte (HK) migration. First, hypoxia triggers HKs to secrete heat shock protein 90-alpha (HSP90α) via a HIF1-dependent pathway. The secreted HSP90α in turn promotes migration, but not proliferation, of the cells. Disruption of the secretion or extracellular function of HSP90α blocked hypoxia-stimulated HK migration. The ubiquitously expressed surface receptor, LRP1 (LDL-receptor-related protein 1), mediates the HSP90α signaling. Inhibition of LRP1 binding to extracellular HSP90α by neutralizing antibodies or genetic silencing of the LRP1 receptor by RNAi completely nullified hypoxia-driven HK migration. Finally, re-introducing a RNAi-resistant LRP1 cDNA into LRP1-downregulated HKs rescued the motogenic response of the cells to hypoxia. We propose that the hypoxia-HSP90α-LRP1 autocrine loop provides previously unrecognized therapeutic targets for human disorders such as chronic wounds and cancer invasion.
Drug abuse profile – patient delay, diagnosis delay and drug resistance pattern – among addict patients with tuberculosis
Authors: Shamaei M , Marjani M , Baghaei P , Chitsaz E , Rezaei Tabar E , Abrishami Z , Tabarsi P , Mansouri D , Masjedi M R
Published: April 2009

Socioeconomic problems limit the access of drug users to health-care services. This descriptive cross-sectional study was carried out by making use of the medical records of new case tuberculosis (TB) patients hospitalized at Masih Daneshvari Hospital, the national referral centre in Iran, from 2003 to 2006. Demographic and personal characteristics of the patients and type of disease were collected and categorized. Of the 944 patients with confirmed TB, 143 (15.1%) were drug users, among whom 140 (97.9%) were men with just three women drug users. The mean age of the drug users group was 43.04 ± 13.81 years. The type of drug used was opium in 100 cases (69.9%), heroin in 29 (20.3%), opium and heroin together in four (2.8%) and all three, opium, heroin and crack, in two (1.4%). For 238 high-risk patients, an HIV test was performed and HIV infection was confirmed in 33 cases. Patient delay was longer in drug users ( P = 0.000) against other patients, whereas diagnosis delay was shorter ( P = 0.007). Drug susceptibility tests were performed for 515 patients with positive cultures. One hundred and thirty-three (14.1%) were found to have ‘any resistance’ to anti-TB drugs, and 10 (1.1%) individuals had multidrug-resistant TB. Twenty-six (19.5%) of the individuals who showed resistance to first-line agents were drug users. There was no significant relation between drug resistance and drug use ( P = 0.4). In conclusion, it seems that active case finding for TB and HIV in addict cases must be contained in harm reduction packages. Moreover, the manifestations of the disease should be considered seriously regardless of attributing them to drug use.
Adverse events to antituberculosis therapy: influence of HIV and antiretroviral drugs
Authors: Marks D J B , Dheda K , Dawson R , Ainslie G , Miller R F
Published: April 2009

This study investigated whether serious adverse events (SAEs) during antituberculosis therapy occur more frequently in HIV co-infected patients in a South African population. A retrospective analysis examined incidences of hepatotoxicity, peripheral neuropathy, severe arthralgia, persistent vomiting and severe rash in 400 patients treated for tuberculosis in a community clinic. A total of 141 patients were co-infected with HIV, among whom only 16.3% were receiving antiretrovirals. Details of SAEs were ascertainable in 331/400 patients, and occurred in 26.7% of HIV-infected and 13.3% of HIV-uninfected individuals ( P = 0.003). The excess was attributable to increased peripheral neuropathy (8.3% and 1.9%, respectively, P = 0.009) and persistent vomiting (13.3% and 3.3%, P = 0.001). SAE occurrence was not related to antiretroviral use, although median CD4 counts were lower in those experiencing side-effects (130 and 259 cells/µL, P = 0.008). The treatment completion did not differ significantly between the two groups (76.6% and 84.2%, P = 0.08).
Frequency of isolated hepatitis B core antibody in HIV-hepatitis C virus co-infected individuals
Authors: Ramezani A , Mohraz M , Aghakhani A , Banifazl M , Eslamifar A , Khadem-Sadegh A , Velayati A A
Published: April 2009

Association between isolated hepatitis B core antibody (anti-HBc) and hepatitis C virus (HCV) infection has been noted in HIV-infected individuals. This study describes the frequency of isolated anti-HBc and its possible value for the detection of HBV-DNA in HIV-infected patients with or without HCV co-infection. Ninety-two HIV-infected patients were enrolled in the study. Hepatitis B surface antigen (HBs Ag), anti-HBs, anti-HBc, anti-HCV, HIV viral load and CD4 count were tested in all subjects. Then we compared 63 subjects with HIV-HCV co-infection with 29 subjects with HIV infection alone regarding isolated anti-HBc (HBs Ag negative, anti-HBs negative and anti-HBc positive). The presence of HBV-DNA was determined by real-time polymerase chain reaction in serum samples of patients with isolated anti-HBc. Of 63 anti-HCV-positive patients, 18 subjects (28.6%, 95% [confidence interval] CI: 22.6–34.6%), and of 29 anti-HCV-negative patients, five subjects (17.2%, 95% CI: 11.5–22.9%) had isolated anti-HBc. HBV-DNA was detectable in three of 18 anti-HCV-positive patients (16.7%, 95% CI: 9.7–23.7%) and none of the anti-HCV-negative patients with isolated anti-HBc. Our study showed that individuals co-infected with HIV and HCV were more likely to have isolated anti-HBc than subjects with HIV alone. This investigation also demonstrates that the presence of isolated anti-HBc in HIV-HCV-infected individuals may reflect occult HBV infection in these patients.
A novel use of AIDS surveillance data to assess the impact of initial treatment regimen on survival
Authors: Chen S Y , Moss W J , Pipkin S S , McFarland W
Published: April 2009

The expense in time and money limit the use of randomized clinical trials (RCT) and cohort studies for evaluating long-term AIDS treatment outcomes. We conducted a case-control study to characterize predictors of AIDS mortality after the availability of highly active antiretroviral therapy (HAART) in San Francisco, in which cases were matched with controls on stage of disease, year of AIDS diagnosis and year of HAART initiation. Overall, 266 cases and 1173 controls were included, representing >90% of eligible patients. The class of initial HAART regimen was not associated with mortality. Predictors of mortality were older age ([adjusted odds ratio] AOR 1.23, 95% [confidence interval] CI: 1.13–1.35), public versus private health insurance (AOR 2.80, 95% CI: 1.77–4.42), no versus private insurance (AOR 1.45, 95% CI: 1.02–2.07) and unboosted saquinavir (AOR 2.50, 95% CI: 1.34–4.65). Survival benefit was found in following the 2004 US Department of Health and Human Services preferred treatment guidelines; borderline survival benefits were found in following the guidelines from other years. Similar predictors were found for all-cause and AIDS-specific mortality. Our findings mirrored those of RCT and multi-centre cohort studies, and may be applicable to other settings. Our findings support similar survival benefit to persons initiating HAART with non-nucleoside reverse transcriptase inhibitor- or protease inhibitor-based regimens.
Relationship between heterosexual anal sex, injection drug use and HIV infection among black men and women
Authors: Risser J M H , Padgett P , Wolverton M , Risser W L
Published: April 2009

US blacks carry a disproportionate risk of heterosexually transmitted HIV. This study aimed to evaluate the association between self-reported heterosexual anal intercourse and HIV. Using respondent-driven sampling (RDS), we recruited and interviewed 909 blacks from areas of high poverty and HIV prevalence in Houston, Texas, and who reported heterosexual sex in the last year. All individuals were tested for HIV. Weighted prevalence values were calculated to account for non-random recruitment associated with RDS. The weighted population prevalence of HIV infection was 2.4% and 2.5% among men and women, respectively. Education, employment status, income and crack cocaine use were not associated with HIV infection. Lifetime injection drug use (odds ratio [OR] 3.31, 95% confidence interval [CI] 1.31–8.33%) and heterosexual anal intercourse (OR 2.41, 95% CI 1.02–5.73%) were associated with HIV infection. Individuals who reported both injection drug use and heterosexual anal intercourse had 6.21 increased odds of HIV (95% CI 2.47–15.61%). Our results suggest that heterosexual anal sex may be a vector for HIV transmission, especially in the context of injection drug use. Prevention strategies directed at curbing the HIV epidemic among black heterosexuals require that we correctly identify the risks so that appropriate interventions can be developed.
UK National Audit of Sexual History-taking: Case-notes audit
Authors: Carne C , McClean H , Bhaduri S , Gokhale R , Sethi G , Daniels D
Published: April 2009

A national audit of sexual history-taking was conducted in genitourinary medicine clinics in the UK in 2008. Data were aggregated by region and clinic, allowing practice to be compared between regions, as well as to national averages and against national Guidelines. In this paper the case-notes of 4121 patients were audited. A high proportion of the case-notes were deemed to be completely legible. In other respects there is considerable inter-regional variation in the adherence to national Guidelines. Interventions are especially required to improve documentation of practice in discussing condom use, HIV risk assessment, offer of a chaperone and assessment for hepatitis B vaccination and hepatitis C testing, and issues concerning sexual contacts.