bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethnic Differences in Renal Responses to Furosemide
Authors: Chun Tae-Yon , Bankir Lise , Eckert George J. , Bichet Daniel G. , Saha Chandan , Zaidi Syed-Adeel , Wagner Mary Anne , Pratt J. Howard
Published: July 2008

Blacks have a greater tendency to retain Na than whites. The present study sought evidence for ethnic differences in parameters reflective of Na uptake by the Na,K,2Cl cotransporter in the thick ascending limb, namely, the urine concentration and urinary excretion of certain cations before and after furosemide administration (40 mg IV). Subjects were healthy (ages 18 to 36 years). During the preceding overnight period, urine volume was lower, and osmolality was higher in blacks than in whites, an ethnic difference that disappeared when water intake was restricted to infused normal saline (60 mL/h). Plasma vasopressin levels were higher in black males than in other sex/ethnic groups. Baseline urinary excretion rates of K, Ca, and Mg were significantly lower in blacks than in whites. After furosemide (0 to 1 hour), K and Ca excretion rates increased, but the proportionate ethnic difference decreased from 44% to 22% and from 22% to 10%, respectively, consistent with blacks having more basal Na,K,2Cl cotransporter activity to inhibit. During a later postfurosemide period (1 to 5 hours), urinary concentrations of Ca and Mg recovered more slowly in blacks, consistent with greater reuptake in the thick ascending limb. In summary, there were distinct ethnic differences in renal handling of Ca and Mg basally and in response to furosemide that were consistent with a more active Na,K,2Cl cotransporter in the thick ascending limb in blacks. An increase in vasopressin levels appeared to explain greater urine concentrations in black males but not black females.
Salt Excess Causes Left Ventricular Diastolic Dysfunction in Rats With Metabolic Disorder
Authors: Matsui Hiromitsu , Ando Katsuyuki , Kawarazaki Hiroo , Nagae Ai , Fujita Megumi , Shimosawa Tatsuo , Nagase Miki , Fujita Toshiro
Published: July 2008

Metabolic syndrome is a highly predisposing condition for cardiovascular disease and could be a cause of excess salt–induced organ damage. Recently, several investigators have demonstrated that salt loading causes left ventricular diastolic dysfunction associated with increased oxidative stress and mineralocorticoid receptor activation. We, therefore, investigated whether excess salt induces cardiac diastolic dysfunction in metabolic syndrome via increased oxidative stress and upregulation of mineralocorticoid receptor signals. Thirteen-week-old spontaneously hypertensive rats and SHR/NDmcr-cps, the genetic model of metabolic syndrome, were fed a normal salt (0.5% NaCl) or high-salt (8% NaCl) diet for 4 weeks. In SHR/NDmcr-cps, salt loading induced severe hypertension, abnormal left ventricular relaxation, and perivascular fibrosis. Salt-loaded SHR/NDmcr-cps also exhibited overproduction of reactive oxygen species and upregulation of mineralocorticoid receptor–dependent gene expression, such as Na
+
/H
+
exchanger-1 and serum- and glucocorticoid-inducible kinase-1 in the cardiac tissue. However, in spontaneously hypertensive rats, salt loading did not cause these cardiac abnormalities despite a similar increase in blood pressure. An antioxidant, tempol, prevented salt-induced diastolic dysfunction, perivascular fibrosis, and upregulation of mineralocorticoid receptor signals in SHR/NDmcr-cps. Moreover, a selective mineralocorticoid receptor antagonist, eplerenone, prevented not only diastolic dysfunction but also overproduction of reactive oxygen species in salt-loaded SHR/NDmcr-cps. These results suggest that metabolic syndrome is a predisposed condition for salt-induced left ventricular diastolic dysfunction, possibly via increased oxidative stress and enhanced mineralocorticoid receptor signals.
Activation of the PGI
2
/IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock
Authors: Höcherl Klaus , Schmidt Christoph , Kurt Birgül , Bucher Michael
Published: July 2008

Prostacyclin levels are increased in septic patients and several animal models of septic shock, and selective inhibition of cyclooxygenase-2 improved cardiovascular dysfunction in rats treated with lipopolysaccharide (LPS). Here, we examine the specific role of prostacyclin and of the receptor for prostacyclin (IP) in the development of LPS-induced circulatory failure. Intravenous injection of LPS (10 mg/kg) into male Sprague-Dawley rats caused a strong increase in plasma prostacyclin levels, which was paralleled by a decrease in blood pressure and an increase in heart rate. Moreover, LPS injection increased the mRNA expression of the IP receptor in the heart, aorta, lung, liver, adrenal glands, and kidneys. Cotreatment with the IP antagonist CAY-10441 (1, 10, 30, and 100 mg/kg) dose-dependently moderated the LPS-induced changes in mean arterial blood pressure, heart rate, cardiac output, and systemic vascular resistance. The development of cardiovascular failure was ameliorated by CAY-10441 in spite of the typical LPS-induced increases in plasma levels of cytokines and NO. In vitro, cytokines dose- and time-dependently induced IP expression in rat vascular smooth muscle cells. Incubation of cells with the stable IP agonist iloprost in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-mehylxanthine resulted in higher cAMP levels in cytokine-treated cells compared with untreated cells. Taken together, our data demonstrate a prominent role of the prostacyclin/IP system in the development of LPS-induced cardiovascular failure.
Paricalcitol Reduces Albuminuria and Inflammation in Chronic Kidney Disease
Authors: Alborzi Pooneh , Patel Nina A. , Peterson Carla , Bills Jennifer E. , Bekele Dagim M. , Bunaye Zerihun , Light Robert P. , Agarwal Rajiv
Published: July 2008

Vitamin D receptor activation is associated with improved survival in patients with chronic kidney disease, but the mechanism of this benefit is unclear. To better understand the effects of vitamin D on endothelial function, blood pressure, albuminuria, and inflammation in patients with chronic kidney disease (2 patients stage 2, remaining stage 3), we conducted a pilot trial in 24 patients who were randomly allocated equally to 3 groups to receive 0, 1, or 2 μg of paricalcitol, a vitamin D analog, orally for 1 month. Placebo-corrected change in flow mediated dilatation with a 1-μg dose was 0.5% and 0.4% with a 2-μg dose (
P
>0.2). At 1 month, the treatment:baseline ratio of high sensitivity C-reactive protein was 1.5 (95% CI: 1.1 to 2.1;
P
=0.02) with placebo, 0.8 (95% CI: 0.3 to 1.9;
P
=0.62) with a 1-μg dose, and 0.5 (95% CI: 0.3 to 0.9;
P
=0. 03) with a 2-μg dose of paricalcitol. At 1 month, the treatment:baseline ratio of 24-hour albumin excretion rate was 1.35 (95% CI: 1.08 to 1.69;
P
=0.01) with placebo, 0.52 (95% CI: 0.40 to 0.69;
P
<0.001) with a 1-μg dose, and 0.54 (95% CI: 0.35 to 0.83;
P
=0. 01) with a 2-μg dose (
P
<0.001 for between group changes). No differences were observed in iothalamate clearance, 24-hour ambulatory blood pressure, or parathyroid hormone with treatment or on washout. Thus, paricalcitol-induced reduction in albuminuria and inflammation may be mediated independent of its effects on hemodynamics or parathyroid hormone suppression. Long-term randomized, controlled trials are required to confirm these benefits of vitamin D analogs.
Cold War Economics: Soviet Aid to Indonesia
Authors: Boden Ragna
Published: July 2008

Indonesia was one of the first developing countries to receive Soviet aid on a large scale. Declassified Soviet and East German archival sources, which illuminate the discussions and other interactions of government leaders and Communist party officials, diplomats, and experts from the two sides, greatly enrich our understanding of this important case of Nikita Khrushchev's ambitious policy in the Third World. This article presents for the first time detailed, reliable information about the amount, composition, and goals of Soviet aid to Indonesia during the Khrushchev era. A close analysis of this case contributes to our understanding of the mechanisms of the global Cold War, which deeply affected center and periphery alike.
Exploring Contextual Theology in Australia in Dialogue with Indigenous People
Authors: Budden Chris
Published: July 2008

This article considers the difference made to contextual theology (in belief and practice) in Australia, if it takes seriously the claim that the primary relationship shaping such a theology is with the First People of the continent. Hence, it considers how theology takes shape in the context of invasion, dispossession and ongoing oppression. Drawing on the insights gained during a gathering of Indigenous people, which began to explore the outlines of a Christian theology that would provide a foundation for more than simple survival, this article seeks to identify the primary issues shaping contextual theology in Australia. It is an invitation for others to join the conversation, and to take seriously the reality that theology in Australia is done on what has always been and still is Aboriginal land.
The War on Terror in Ruatoki
Authors: Rae Murray
Published: July 2008

This article offers some theological reflections on a recent episode in Aotearoa (New Zealand) in which a Maori community housing an alleged terrorist network was subjected to a police raid. Many innocent people, including children, were caught up in the raid thus bringing to mind other episodes in New Zealand's history in which Maori have been subjected to police and state aggression. These episodes provide a starting point for reflection upon public theology and the limits of state power, upon the nature of forgiveness, and upon the offering of public apologies for past offences.
Yes, No, Cancel: Clicking Our Way to a Public Theology of Cyberdemocracy
Authors: Stoddart Eric
Published: July 2008

This article defines cyberdemocracy within the framework of a digital and social space. It places this emerging practice in the context of the displacement of political power and action, and a range of visions for digital technologies in general. A number of dimensions of the 'digital divide' are explored. Representative theological perspectives on technology are used to develop a theological digital technology that identifies it as a dimension of giftedness instantiated in human co-creativity with God. In this article the bifurcation of 'spiritual' and 'technology' is rejected in favour of a model that encourages the celebratory and ethical aspects of digital technology. It finds contemporary predilections for multiple 'data-images' in our online presence promiscuous and inhibiting to relationality when viewed from a Christian perichoretic perspective. Finally, the article draws conclusions that encourage political responses to the ideology of interactivity and that contend for both state and civil society to be in partnership in addressing the multiple factors of the 'digital divide'.
The Construction of Public Theology: An Ethnographic Study of the Relationship between the Theological Academy and Local Clergy in South Africa
Authors: Day Katie
Published: July 2008

This article presents findings of research conducted in the summer of 2006, and it focuses on how public theology is understood in the academy in relation to the realities encountered by clergy and lay leaders in a challenging ministry context. Through ethnographic research based in South Africa, I examined the relationship between congregations confronting the AIDS epidemic and widespread poverty, and the construction of public theology in the theological academy at Stellenbosch University, South Africa. The research asked: what is the nature of the correspondence between 'formal' public theology and the local, 'lived' theologies of those doing ministry in South Africa; how does local experience influence the ways that the academy prepares leaders for public ministry. The findings from this study, as discussed in this article, have implications for theological education, in terms of enhancing the public orientation of institutions and understanding the link between context and curriculum.
British Humanitarian Assistance: Wartime Planning and Postwar Realities
Authors: Steinert Johannes-Dieter
Published: July 2008

The organisation of post-war relief is the first step in post-war reconstruction. The needs of the countries ravaged by the war will be immense and can be met only by international cooperative action on a very large scale. After the last war, there was considerable delay in organising relief; the scale on which it could be granted was very inadequate; and the financial conditions on which relief was available hampered the subsequent restoration of world economic relations. It is very desirable that plans should be prepared beforehand to provide relief after this war on an adequate scale and on a basis which will promote international recovery. . . . Voluntary organisations should be coordinated and linked up with these Relief Missions.1
`We Shall Rebuild Anew a Powerful Nation': UNRRA, Internationalism and National Reconstruction in Poland
Authors: Reinisch Jessica
Published: July 2008

This article evaluates UNRRA as one of the first international agencies established during the war to manage the transition from war to peace and to provide liberated countries with essential relief. It argues that this organization was a forum for debates on questions not only of internationalism, but also of the future of the nation-state, national reconstruction, national sovereignty, patriotism and citizens' relationships to their states. Moreover, the article explores this chapter of international history at the national level, by asking how the problem of Polish reconstruction after 1945 was framed, discussed and understood by UNRRA's diplomats and relief workers in Poland and in the DP camps. Problems of Polish sovereignty and reconstruction were interpreted differently in different sections of UNRRA, as a pragmatic interpretation of civic usefulness and patriotic responsibilities coexisted with an ethnological understanding of Polish cultural traditions, shared land and ancestry. But even as these different interpretations came into conflict, both models continued to be grounded in a world view which saw nation-states as unavoidable constituents of the international order, and international organizations as having to bind nations together without abolishing them.
`The Mountain Laboured and Brought Forth a Mouse': UNRRA's Operations in the Cyclades Islands, c.1945—46
Authors: Tsilaga Flora
Published: July 2008

Like many a recently liberated country with the experience of starvation and hardship vivid in its people's physical state, Greece emerged in the immediate aftermath of the second world war in great need of assistance, facing a wrecked economy and drained resources. Relief provision became the responsibility of the United Nations Relief and Rehabilitation Administration (UNRRA), an international relief organization established in late 1943 with the purpose of furnishing essential supplies and services to war-devastated states. For over two years (April 1945-June 1947), Greece received goods worth approximately $350 million, as much as its pre-war commercial imports, and almost 12 per cent of total UNRRA assistance. This article traces the provision of UNRRA aid in the micro-context of the Cyclades, a famine-stricken group of some 25 Aegean islands. Drawing on UNRRA's mostly undisclosed archive, it examines the implementation of welfare policies and the conversion of general plans to particular actions to disclose the interplay between relief strategies and the development of the local economy.
On the Reasons We Want Teachers of Good Disposition and Moral Character
Authors: Osguthorpe Richard D.
Published: July 2008

The point of this article is to make a case for teachers of moral disposition without regard for the moral development of students. The article concludes that there are multiple reasons for wanting teachers of good disposition and moral character; that teachers' dispositions are best conceived as modifiers to the methods that they employ; and that the crux of the dispositions debate is ultimately grounded in avoiding poor moral character. Implications of the article point teacher educators toward a conception of teacher education that focuses on preparing teachers of good disposition and moral character simply for the sake of teaching that accords with what is good, right, and virtuous. The analysis suggests that the scope of a teacher's dispositions should be broadened to include all matters of classroom life and teacher effectiveness.
Effects of Package Holiday Information Presentation on Destination Choice
Authors: Rewtrakunphaiboon Walaiporn , Oppewal Harmen
Published: July 2008

Holiday travel packaging is an important tool for destination marketing. However, little is known on how presentation of travel package information influences tourists' decisions. This article reports on an experiment that tested whether package information and package heading can influence destination choice. It is hypothesized that destinations with a less favorable image will benefit from being presented in a format with more attribute information and with a price heading. The hypotheses were tested with 200 university students and 200 United Kingdom residents. They were asked to evaluate experimentally designed beach package holidays to Mediterranean destinations. Results show that effects of package presentation format do not differ between less favorable and more favorable image destinations. Variations in package presentation format show similar effects regardless of the destination presented. The student sample shows a higher intention to visit when price is used as the package heading. Implications and avenues for future research are discussed.
Developing narrative research in supportive and palliative care: the focus on illness narratives
Authors: Bingley AF , Thomas C , Brown J , Reeve J , Payne S
Published: July 2008

The phenomenon of the ‘illness narrative’ is well-documented, in the last 25 years, of increasing interest to researchers in health and social sciences. Personal stories about the experience of facing the end of life also have an established history of particular relevance for palliative care clinicians. In this article, we review and describe a range of narrative analysis approaches that may be of use in palliative care. In particular, we distinguish between qualitative analysis applied to narratives and narrative analysis as a method. We discuss the potential benefits and challenges in the use of narrative research methods as a means to deepen our understanding of patient, carer and health professionals’ experience, and to support improvements in end of life care policy and practice.
The nature and use of bereavement support services in a hospice setting
Authors: Roberts A , McGilloway S
Published: July 2008

This study formed part of a larger project designed to evaluate a hospice-based bereavement support service in Ireland. It involved a detailed assessment of the views of service attenders and non-attenders. A postal survey was administered to all bereaved clients who were invited to one or more bereavement support services ( n = 517). Respondents ( n = 243; 47%) completed: 1) a Bereavement Services Questionnaire; 2) a measure of grief reaction (TRIG) and 3) a measure of religiosity (SCSORF). A total of 243 people (47%) returned completed questionnaires, most of whom were satisfied with the service, (although not all had attended all elements of the bereavement service). However, a number of improvements were emphasised. Several statistically significant differences ( P < 0.05) also emerged between service attenders and non-attenders with respect to grief reaction and other key factors (e.g., the age and relationship to the deceased). The findings emphasise the needs and views of both attenders and non-attenders and provide important lessons for the implementation and development of hospice-based bereavement support services.
Interconnectedness in Nursing
Authors: Love Katie L.
Published: July 2008

Aim: Interconnectedness will be clarified and defined by providing a description and context and take an important step toward increasing use in nursing literature and research. Background: The literature is limited by focusing on relationships between people, but connection can be physical as with physics or spiritual by reflecting a higher power or purpose. Thorough examination will increase understanding of interconnectedness in nursing. Methods: Chinn and Kramer's method for creating conceptual meaning includes definitions, visual images, popular/classical literature, music, poetry, and professional research across many disciplines. Findings: Interconnectedness reflects that people and the universe are connected in a powerful way. Its essential meaning reflects that regardless of the worldly barriers of politics, religion, or culture, people can share in a universal reciprocity of love and responsibility. Conclusion: Nursing maintains the values of compassion, responsibility, holism, and to greater meaning in experiences, and interconnectedness will likely have increased significance in nursing.
Persistent T1 hypointensity as an MRI marker for treatment efficacy in multiple sclerosis
Authors: van den Elskamp IJ , Lembcke J , Dattola V , Beckmann K , Pohl C , Hong W , Sandbrink R , Wagner K , Knol DL , Uitdehaag B , Barkhof F
Published: July 2008

Background

MRI is often used as primary outcome measure in phase II clinical trials in multiple sclerosis (MS). Since persistent T1 hypointense lesions are a surrogate parameter for axonal damage and demyelination, they may serve as a marker for monitoring the efficacy of neuroprotective drugs. At present, a power analysis using black hole (BH) evolution as primary outcome measure has not been performed.

Objective

To assess the feasibility of using BH evolution on serial brain MR images as primary outcome measure in proof of concept studies in MS.

Methods

MRI-data obtained from 169 active RRMS patients were analysed for BH evolution by determining the cumulative number of contrast enhancing lesions (CEL) evolving into a persistent black hole (PBH) after 3 months. With a parametric simulation procedure, based on a statistical distribution fitting the data, sample sizes were calculated.

Results

21.2% of the total number of CELs observed during the study period evolved into a PBH. Ring enhancing lesions evolved most frequently into a PBH (59.4%), followed by lesions larger than 10 mm (57.4%) and periventricular CELs (30.6%). The simulation procedure, based on the statistical negative binomial (NB) model resulted in a sample sizes between 200 subjects and 30 subjects per arm, for treatment effects ranging from 50% to 90% reduction of the number of CELs evolving into a PBH, respectively.

Conclusion

To perform a MRI monitored phase II clinical trial with a feasible sample size, using the evolution of CELs into PBHs as primary outcome parameter, a potent drug is required to obtain sufficient power.
Atrophy in white matter fiber tracts in multiple sclerosis is not dependent on tract length or local white matter lesions
Authors: Kezele IB , Arnold DL , Collins DL
Published: July 2008

The pathogenesis of tissue injury outside the white matter (WM) plaques of multiple sclerosis (MS) has not yet been clearly defined. To better understand the pathogenesis of this injury and the associated atrophy, we investigated volume loss over time in 20 WM fiber tracts. We defined two main aims: (1) to examine whether certain fiber tracts were more prone to atrophy, and to test the possible relation of tract atrophy to tract length and selected MS-specific variables; and (2) to investigate the possible relation of atrophy to lesion load (whole brain and in the specific tract). Local volume change was assessed between two distant time points for each MS patient studied. Fiber tracts were segmented automatically using a tractography-based atlas. Results demonstrate volume loss in all fiber tracts. The uncinate fasciculus and anterior-thalamic radiation had the greatest yearly percentage atrophy. Disease type, duration, median expanded disability status scale, total lesion load, and gender exhibited significant effects on atrophy in at least one tract. Together, these data are more consistent with a pathogenesis for the degeneration related to diffuse inflammation rather than the secondary effects of focal lesions.
Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes
Authors: Kisand Kai , Link Maire , Wolff Anette S. B. , Meager Anthony , Tserel Liina , Org Tõnis , Murumägi Astrid , Uibo Raivo , Willcox Nick , Trebušak Podkrajšek Katarina , Battelino Tadej , Lobell Anna , Kämpe Olle , Lima Kari , Meloni Antonella , Ergun-Longmire Berrin , Maclaren Noel K. , Perheentupa Jaakko , Krohn Kai J. E. , Scott Hamish S. , Husebye Eystein S. , Peterson Pärt
Published: July 2008

Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-α cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-ω but not IFN-α showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity.
Validation of a flow cytometric scoring system as a prognostic indicator for posttransplantation outcome in patients with myelodysplastic syndrome
Authors: Scott Bart L. , Wells Denise A. , Loken Michael R. , Myerson David , Leisenring Wendy M. , Deeg H. Joachim
Published: July 2008

A total of 152 patients with myelodysplastic syndrome (MDS) receiving a first stem cell transplant had marrow cells prospectively analyzed to calculate the flow cytometric scoring system (FCSS) score. The FCSS scores were retrospectively compared with patient outcomes in both univariate and multivariate models. The cumulative incidence of posttransplantation relapse at 3 years was 15%, 10%, and 36% for patients with mild, moderate, and severe FCSS scores, respectively, with the hazard for relapse of 2.8 (P = .02) for severe scores in comparison to patients with mild or normal FCSS scores. In multivariate analyses, the FCSS score was associated with relapse even after accounting for International Prognostic Scoring System (IPSS) score or for marrow myeloblast percentage. Among patients with intermediate-1 risk by IPSS, severe FCSS scores were associated with an increased hazard of relapse (3.8; P = .02) compared with patients with normal/mild/moderate FCSS scores. Among patients with less than 5% marrow myeloblasts, myeloblast dyspoiesis was associated with an increased hazard of relapse (3.7; P = .02). This analysis confirmed that FCSS scores are predictive of posttransplantation outcomes in patients with MDS even after adjusting for risk factors such as marrow myeloblast percentage and IPSS score.
2DB: a Proteomics database for storage, analysis, presentation, and retrieval of information from mass spectrometric experiments
Authors: Allmer Jens , Kuhlgert Sebastian , Hippler Michael
Published: July 2008

Background

The amount of information stemming from proteomics experiments involving (multi dimensional) separation techniques, mass spectrometric analysis, and computational analysis is ever-increasing. Data from such an experimental workflow needs to be captured, related and analyzed. Biological experiments within this scope produce heterogenic data ranging from pictures of one or two-dimensional protein maps and spectra recorded by tandem mass spectrometry to text-based identifications made by algorithms which analyze these spectra. Additionally, peptide and corresponding protein information needs to be displayed.

Results

In order to handle the large amount of data from computational processing of mass spectrometric experiments, automatic import scripts are available and the necessity for manual input to the database has been minimized. Information is in a generic format which abstracts from specific software tools typically used in such an experimental workflow. The software is therefore capable of storing and cross analysing results from many algorithms. A novel feature and a focus of this database is to facilitate protein identification by using peptides identified from mass spectrometry and link this information directly to respective protein maps. Additionally, our application employs spectral counting for quantitative presentation of the data. All information can be linked to hot spots on images to place the results into an experimental context. A summary of identified proteins, containing all relevant information per hot spot, is automatically generated, usually upon either a change in the underlying protein models or due to newly imported identifications. The supporting information for this report can be accessed in multiple ways using the user interface provided by the application.

Conclusion

We present a proteomics database which aims to greatly reduce evaluation time of results from mass spectrometric experiments and enhance result quality by allowing consistent data handling. Import functionality, automatic protein detection, and summary creation act together to facilitate data analysis. In addition, supporting information for these findings is readily accessible via the graphical user interface provided. The database schema and the implementation, which can easily be installed on virtually any server, can be downloaded in the form of a compressed file from our project webpage.
High divergence in primate-specific duplicated regions: Human and chimpanzee Chorionic Gonadotropin Betagenes
Authors: Hallast Pille , Saarela Janna , Palotie Aarno , Laan Maris
Published: July 2008

Background

Low nucleotide divergence between human and chimpanzee does not sufficiently explain the species-specific morphological, physiological and behavioral traits. As gene duplication is a major prerequisite for the emergence of new genes and novel biological processes, comparative studies of human and chimpanzee duplicated genes may assist in understanding the mechanisms behind primate evolution. We addressed the divergence between human and chimpanzee duplicated genomic regions by using Luteinizing Hormone Beta (LHB)/Chorionic Gonadotropin Beta (CGB) gene cluster as a model. The placentalCGBgenes that are essential for implantation have evolved from an ancestral pituitaryLHBgene by duplications in the primate lineage.

Results

We shotgun sequenced and compared the human (45,165 bp) and chimpanzee (39,876 bp)LHB/CGBregions and hereby present evidence for structural variation resulting in discordant number ofCGBgenes (6 in human, 5 in chimpanzee). The scenario of species-specific parallel duplications was supported (i) as the most parsimonious solution requiring the least rearrangement events to explain the interspecies structural differences; (ii) by the phylogenetic trees constructed with fragments of intergenic regions; (iii) by the sequence similarity calculations. Across the orthologous regions ofLHB/CGBcluster, substitutions and indels contributed approximately equally to the interspecies divergence and the distribution of nucleotide identity was correlated with the regional repeat content. Intraspecies gene conversion may have shaped theLHB/CGBgene cluster. The substitution divergence (1.8–2.59%) exceeded two-three fold the estimates for single-copy loci and the fraction of transversional mutations was increased compared to the unique sequences (43% versus ~30%). Despite the high sequence identity amongLHB/CGBgenes, there are signs of functional differentiation among the gene copies. Estimates for dn/dsrate ratio suggested a purifying selection onLHBandCGB8, and a positive evolution ofCGB1.

Conclusion

If generalized, our data suggests that in addition to species-specific deletions and duplications, parallel duplication events may have contributed to genetic differences separating humans from their closest relatives. Compared to unique genomic segments, duplicated regions are characterized by high divergence promoted by intraspecies gene conversion and species-specific chromosomal rearrangements, including the alterations in gene copy number.
Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation
Authors: Chen Xia , Liang Shuang , Zheng WenLing , Liao ZhiJun , Shang Tao , Ma WenLi
Published: July 2008

Background

Epstein-Barr virus (EBV) presumably plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC), but the molecular mechanism of EBV-dependent neoplastic transformation is not well understood. The combination of bioinformatics with evidences from biological experiments paved a new way to gain more insights into the molecular mechanism of cancer.

Results

We profiled gene expression using a meta-analysis approach. Two sets of meta-genes were obtained. Meta-A genes were identified by finding those commonly activated/deactivated upon EBV infection/reactivation. These genes could be key players for pathways de-regulated by EBV during latent infection and lytic proliferation. Meta-B genes were obtained from differential genes commonly expressed in NPC and PEL (primary effusion lymphoma). We then integrated meta-A, meta-B and associated factors into an interaction network using acquired information. Our analysis suggests that NPC transformation depends on timely regulation of DEK, CDK inhibitor(s), p53, RB and several transcriptional cascades, interconnected by E2F, AP-1, NF-κB, STAT3 among others during latent and lytic cycles.

Conclusion

In conclusion, our meta-analysis strategy re-analyzed EBV-related tumor data sets and identified sets of meta-genes possibly involved in maintaining latent or switching to lytic cycles of EBV in NPC. The results of this analysis may shed new lights to further our understanding of the EBV-led neoplastic transformation.
NF-kappaB activation is associated with homocysteine-induced injury in Neuro2a cells
Authors: Ferlazzo Nadia , Condello Salvatore , Currò Monica , Parisi Giulia , Ientile Riccardo , Caccamo Daniela
Published: July 2008

Background

Perinatal exposure to hyperhomocysteinemia might disturb neurogenesis during brain development and growth. Also, high levels of homocysteine trigger neurodegeneration in several experimental models. However, the putative mechanisms of homocysteine-induced toxicity in the developing nervous system have poorly been elucidated. This study was aimed to investigate homocysteine effects in undifferentiated neuroblastoma cells, Neuro2a.

Results

A 4 h exposure to homocysteine in a concentration range of 10–100 μM did not affect cell viability and ROS production in Neuro2a cell cultures. Instead, ROS levels were increased by two-three folds in cells treated with 250 μM and 500 μM homocysteine, respectively, in comparison with control cells. Also, the highest homocysteine dose significantly reduced the viable cell number by 40%. Notably, the treatment with homocysteine (250 μM–500 μM) in the presence of antioxidants, such as N-acetylcysteine and IRFI 016, a synthetic α-tocopherol analogue, recovered cell viability and significantly reduced homocysteine-evoked increases in ROS production. Moreover, antioxidants, particularly IRFI 016, were able to counteract NF-κB activation induced by 250 μM homocysteine.

Cell treatment with 250 μM homocysteine also triggered the onset of apoptosis, as demonstrated by the increased expression of early apoptotic markers such as Bax, caspase-3 and p53. In contrast, Bcl2 expression was not affected by homocysteine exposure. Interestingly, the specific inhibition of NF-κB nuclear translocation by the synthetic peptide SN50 was able to almost completely suppress the homocysteine-evoked rises in pro-apoptotic protein expression as well as in caspase-3 activity. Further, also IRFI 016 and N-acetylcysteine were able to significantly reduce caspase-3 activation induced by homocysteine treatment.

Conclusion

These observations suggest an involvement of redox state alterations and activated NF-κB in apoptosis onset triggered by homocysteine in neuroblastoma cells Neuro2a. However, further investigations are needed to characterize molecular events involved in the NF-κB activation induced by homocysteine.
Transient middle cerebral artery occlusion induces microglial priming in the lumbar spinal cord: a novel model of neuroinflammation
Authors: Moisse Katie , Welch Ian , Hill Tracy , Volkening Kathryn , Strong Michael J
Published: July 2008

Background

Middle cerebral artery occlusion (MCAo) in mice results in a brain infarct, the volume of which depends on the length of occlusion. Following permanent occlusion, neuropathological changes – including a robust glial inflammatory response – also occur downstream of the infarct in the spinal cord.

Methods

We have performed short, transient MCAo in mice to induce penumbral damage spanning the motor cortex. A 30 minute MCAo using a poly-L-lysine-coated intraluminal suture introduced through a common carotid artery incision was performed in 17 female C57BL/6 mice. Five sham-operated mice received common carotid artery ligation without insertion of the suture. Neurobehavioural assessments were performed during occlusion, immediately following reperfusion, and at 24 and 72 hours post-reperfusion. Routine histological and immunohistochemical studies were performed at 24 and 72 hours.

Results

In 11 of the surviving 16 mice subjected to MCAo, we observed a focal, subcortical necrotic lesion and a reproducible, diffuse cortical lesion with accompanying upper motor neuron involvement. This was associated with contralateral ventral spinal cord microglial priming without significant reactive astrocytosis or lower motor neuron degeneration.

Conclusion

The advantages to this method are that it yields a reproducible cortical lesion, the extent of which is predictable using behavioural testing during the period of ischemia, with upper motor neuron involvement and downstream priming, but not full activation, of microglia in the lumbar spinal cord. In addition, survival is excellent following the 30 minutes of occlusion, rendering this a novel and useful model for examining the effects of microglial priming in the spinal motor neuron pool.
VSV-G pseudotyping rescues HIV-1 CA mutations that impair core assembly or stability
Authors: Brun Sonia , Solignat Maxime , Gay Bernard , Bernard Eric , Chaloin Laurent , Fenard David , Devaux Christian , Chazal Nathalie , Briant Laurence
Published: July 2008

Background

The machinery of early HIV-1 replication still remains to be elucidated. Recently the viral core was reported to persist in the infected cell cytoplasm as an assembled particle, giving rise to the reverse transcription complex responsible for the synthesis of proviral DNA and its transport to the nucleus. Numerous studies have demonstrated that reverse transcription of the HIV-1 genome into proviral DNA is tightly dependent upon proper assembly of the capsid (CA) protein into mature cores that display appropriate stability. The functional impact of structural properties of the core in early replicative steps has yet to be determined.

Results

Here, we show that infectivity of HIV-1 mutants bearing S149A and S178A mutations in CA can be efficiently restored when pseudotyped with vesicular stomatitis virus envelope glycoprotein, that addresses the mutant cores through the endocytic pathway rather than by fusion at the plasma membrane. The mechanisms by which these mutations disrupt virus infectivity were investigated. S149A and S178A mutants were unable to complete reverse transcription and/or produce 2-LTR DNA. Morphological analysis of viral particles and in vitro uncoating assays of isolated cores demonstrated that infectivity defects resulted from disruption of the viral core assembly and stability for S149A and S178A mutants, respectively. Consistent with these results, both mutants failed to saturate TRIM-antiviral restriction activity.

Conclusion

Defects generated at the level of core assembly and stability by S149A and S178A mutations are sensitive to the way of delivery of viral nucleoprotein complexes into the target cell. Addressing CA mutants through the endocytic pathway may compensate for defects generated at the reverse transcription/nuclear import level subsequent to impairment of core assembly or stability.
Concerted gene recruitment in early plant evolution
Authors: Huang Jinling , Gogarten J Peter
Published: July 2008

Background

Horizontal gene transfer occurs frequently in prokaryotes and unicellular eukaryotes. Anciently acquired genes, if retained among descendants, might significantly affect the long-term evolution of the recipient lineage. However, no systematic studies on the scope of anciently acquired genes and their impact on macroevolution are currently available in eukaryotes.

Results

Analyses of the genome of the red alga Cyanidioschyzon identified 37 genes that were acquired from non-organellar sources prior to the split of red algae and green plants. Ten of these genes are rarely found in cyanobacteria or have additional plastid-derived homologs in plants. These genes most likely provided new functions, often essential for plant growth and development, to the ancestral plant. Many remaining genes may represent replacements of endogenous homologs with a similar function. Furthermore, over 78% of the anciently acquired genes are related to the biogenesis and functionality of plastids, the defining character of plants.

Conclusion

Our data suggest that, although ancient horizontal gene transfer events did occur in eukaryotic evolution, the number of acquired genes does not predict the role of horizontal gene transfer in the adaptation of the recipient organism. Our data also show that multiple independently acquired genes are able to generate and optimize key evolutionary novelties in major eukaryotic groups. In light of these findings, we propose and discuss a general mechanism of horizontal gene transfer in the macroevolution of eukaryotes.
Impulse Control of Brownian Motion: The Constrained Average Cost Case
Authors: Ormeci Melda , Dai J. G. , Vate John Vande
Published: July 2008

When a manufacturer places repeated orders with a supplier to meet changing production requirements, he faces the challenge of finding the right balance between holding costs and the operational costs involved in adjusting the shipment sizes. We consider an inventory whose content fluctuates as a Brownian motion in the absence of control. At any moment, a controller can adjust the inventory level by any positive or negative quantity, but incurs both a fixed cost and a cost proportional to the magnitude of the adjustment. The inventory level must be nonnegative at all times and continuously incurs a linear holding cost. The objective is to minimize long-run average cost. We show that control band policies are optimal for the average cost Brownian control problem and explicitly calculate the parameters of the optimal control band policy. This form of policy is described by three parameters {q,Q,S}, 0 < q ≤ Q < S. When the inventory falls to zero (rises to S), the controller expedites (curtails) shipments to return it to q (Q). Employing apparently new techniques based on methods of Lagrangian relaxation, we show that this type of policy is optimal even with constraints on the size of adjustments and on the maximum inventory level. We also extend these results to the discounted cost problem.
Multilevel Monte Carlo Path Simulation
Authors: Giles Michael B.
Published: July 2008

We show that multigrid ideas can be used to reduce the computational complexity of estimating an expected value arising from a stochastic differential equation using Monte Carlo path simulations. In the simplest case of a Lipschitz payoff and a Euler discretisation, the computational cost to achieve an accuracy of O(ϵ) is reduced from O(ϵ−3) to O(ϵ−2 (log ϵ)2). The analysis is supported by numerical results showing significant computational savings.
A Static Approximation for Dynamic Demand Substitution with Applications in a Competitive Market
Authors: Hopp Wallace J. , Xu Xiaowei
Published: July 2008

We propose a static approximation of dynamic demand substitution behavior based on a fluid network model and a service-inventory mapping. This approximation greatly enhances our ability to analyze the interdependent inventory/service, price, and product assortment decisions in noncompetitive and competitive scenarios with demand substitution. We demonstrate that the approximation is well behaved and then apply it to two previously intractable applications. First, we study a price and service competition between single-product retailers. After establishing a unique pure-strategy Nash equilibrium, we find that competition results in lower price, higher demand, and a higher level of inventory. We also observe that the aggregate profit and inventory level increase to positive constants as the number of retailers goes to infinity. Second, we study a duopolistic competition on price, service, and product assortment. We establish a pure-strategy Nash equilibrium for the product assortment competition and identify a condition for uniqueness. We find that competition on both price and product assortment results in lower price and less variety for each competitor, but the total number of products and the aggregate inventory level in a duopoly market are both likely to be higher than in a monopolistic market.
The Extinctive Effect of Promissory Estoppel
Authors: Capper David
Published: July 2008

It is said that promissory estoppel has merely a suspensory effect on a payment obligation. In the context of periodic payments this makes sense. The payer pays less or nothing at all for a period of time or while a set of circumstances exist and when this time or those circumstances end the obligation to pay in full is reinstated. In the context of liquidated debts promissory estoppel is said to give only time to pay because any ‘forgiveness' of the debt would be incompatible with the decision of the House of Lords in Foakes v Beer. In late 2007 the Court of Appeal gave some support to the notion that a creditor's promise to accept part of a liquidated debt, followed by the debtor's actual payment of that amount, would of itself discharge the original debt. This article argues that this goes too far but supports the Court of Appeal to the extent that where all the elements of promissory estoppel are satisfied a liquidated debt is extinguished and the right to receive payment not merely suspended. Some suggestions are also made about the wider implications of this thesis for contractual renegotiations in general.