bluuebunny/crossref_metadata_2025_split huggingface dataset:
An AraC-Type Transcriptional Regulator Encoded on the
Enterococcus faecalis
Pathogenicity Island Contributes to Pathogenesis and Intracellular Macrophage Survival
Authors: Coburn Phillip S. , Baghdayan Arto S. , Dolan GT , Shankar Nathan 
Published: September 2008

ABSTRACT

A gene encoding a putative AraC-type transcriptional regulator was identified on the 153-kb pathogenicity island (PAI) found among virulent
Enterococcus faecalis
strains. In an effort to understand the function of this regulator, designated PerA (for pathogenicity island-encoded regulator), we first examined the expression of the
perA
gene in the original PAI strain MMH594 and in an unrelated clinical isolate E99 by reverse transcription-PCR. Interestingly, expression analysis revealed no detectable
perA
transcript in MMH594, whereas a transcript was observed in strain E99. Nucleotide sequence analysis revealed that this altered expression between the two strains was attributable to the differential location of an IS
1191
element within the putative promoter region upstream of the
perA
gene. In order to determine the role of this putative regulator in
E. faecalis
pathogenesis, a
perA
-deficient mutant was created in strain E99, and the wild-type and mutant pair were compared for phenotypic differences. In in vitro biofilm assays, the mutant strain showed a significantly higher level of growth medium-specific biofilm formation compared to the wild type. However, in a murine intraperitoneal infection model, the mutant strain was significantly less pathogenic. The mutant was also attenuated for survival within macrophages in vitro. These findings highlight the importance of PerA as a regulator of biofilm formation and survival within macrophages and is likely a regulator controlling determinants important to pathogenesis.
Platelet Antistaphylococcal Responses Occur through P2X1and P2Y12Receptor-Induced Activation and Kinocidin Release
Authors: Trier Darin A. , Gank Kimberly D. , Kupferwasser Deborah , Yount Nannette Y. , French William J. , Michelson Alan D. , Kupferwasser Leon I. , Xiong Yan Q. , Bayer Arnold S. , Yeaman Michael R. 
Published: September 2008

ABSTRACTPlatelets (PLTs) act in antimicrobial host defense by releasing PLT microbicidal proteins (PMPs) or PLT kinocidins (PKs). Receptors mediating staphylocidal efficacy and PMP or PK release versus isogenic PMP-susceptible (ISP479C) and -resistant (ISP479R)Staphylococcus aureusstrains were examined in vitro. Isolated PLTs were incubated with ISP479C or ISP479R (PLT/S. aureusratio range, 1:1 to 10,000:1) in the presence or absence of a panel of PLT inhibitors, including P2X and P2Y receptor antagonists of increasingly narrow specificity, and PLT adhesion receptors (CD41, CD42b, and CD62P). PLT-to-S. aureusexposure ratios of ≥10:1 yielded significant reductions in the viability of both strains. Results from reversed-phase high-performance liquid chromatography indicated that staphylocidal PLT releasates contained PMPs and PKs. At ratios below 10:1, the PLT antistaphylococcal efficacy relative to the intrinsicS. aureusPMP-susceptible or -resistant phenotype diminished. Apyrase (an agent of ADP degradation), suramin (a general P2 receptor antagonist), pyridoxal 5′-phosphonucleotide derivative (a specific P2X1antagonist), and cangrelor (a specific P2Y12antagonist) mitigated the PLT staphylocidal response against both strains, correlating with reduced levels of PMP and PK release. Specific inhibition occurred in the presence and absence of homologous plasma. The antagonism of the thromboxane A2, cyclooxygenase-1/cyclooxygenase-2, or phospholipase C pathway or the hindrance of surface adhesion receptors failed to impede PLT anti-S. aureusresponses. These results suggest a multifactorial PLT anti-S. aureusresponse mechanism involving (i) a PLT-to-S. aureusratio sufficient for activation; (ii) the ensuing degranulation of PMPs, PKs, ADP, and/or ATP; (iii) the activation of P2X1/P2Y12receptors on adjacent PLTs; and (iv) the recursive amplification of PMP and PK release from these PLTs.
Preimplantation genetic diagnosis: a step by step guide to recent Italian ethical and legislative troubles
Authors: Turillazzi E , Fineschi V 
Published: September 2008

Objective:To analyse legislation and medical professionals’ position concerning the doctor’s role in assisted reproduction techniques in Italy, and to discuss the implications for physicians of preimplantation genetic diagnosis (PGD).Background:Until recently a strict interpretation of the assisted reproduction law (40/2004) and the guidelines subsequently issued, lead to denying infertile couples affected by genetic diseases the right to resort to PGD. In October 2006 the Constitutional Court ruled regarding the question of the constitutional legitimacy of the prohibition of PGD.Discussion:The Constitutional Court declared the manifest inadmissibility of the question of the constitutional legitimacy of article 13 of law 40/2004. The debate has become very animated since the ruling. After the negative sentence of the Constitutional Court, three further sentences recognised the right of couples to obtain PGD, representing a hard blow to law 40/2004 and to the ministerial guidelines; a further confirmation of the untenability of a law that violates fundamental principles such as the right to healthcare for women and the unborn child, the right to responsible motherhood and to informed consent.Conclusion:It seems that in Italy the legislative inadequacy for medically assisted procreation is reprieved by the courageous decisions of the judges, which refer to the values of the Italian Constitution, in defence of the fundamental rights of the citizens.
Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility
Authors: Szokodi István , Kerkelä Risto , Kubin Anna-Maria , Sármán Balázs , Pikkarainen Sampsa , Kónyi Attila , Horváth Iván G. , Papp Lajos , Tóth Miklós , Skoumal Réka , Ruskoaho Heikki 
Published: September 2008

Background—Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38-MAPK) have been shown to regulate various cellular processes, including cell growth, proliferation, and apoptosis in the heart. However, the function of these signaling pathways in the control of cardiac contractility is unclear. Here, we characterized the contribution of ERK1/2 and p38-MAPK to the inotropic effect of endothelin-1 (ET-1).Methods and Results—In isolated perfused rat hearts, infusion of ET-1 (1 nmol/L) for 10 minutes increased contractility and phosphorylation of ERK1/2 and their downstream target p90 ribosomal S6 kinase (p90RSK). Suppression of ERK1/2 activation prevented p90RSK phosphorylation and attenuated the inotropic effect of ET-1. Pharmacological inhibition of epidermal growth factor receptor kinase activity abolished ET-1–induced epidermal growth factor receptor transactivation and ERK1/2 and p90RSK phosphorylation and reduced ET-1–mediated inotropic response. Moreover, inhibition of the p90RSK target Na+-H+exchanger 1 attenuated the inotropic effect of ET-1. In contrast to ERK1/2 signaling, suppression of p38-MAPK activity further augmented ET-1–enhanced contractility, which was accompanied by increased phosphorylation of phospholamban at Ser-16.Conclusions—MAPKs play opposing roles in the regulation of cardiac contractility in that the ERK1/2-mediated positive inotropic response to ET-1 is counterbalanced by simultaneous activation of p38-MAPK. Hence, selective activation of ERK1/2 signaling and inhibition of p38-MAPK signaling may represent novel means to support cardiac function in disease.
Impacts of the Madden–Julian Oscillation on Australian Rainfall and Circulation
Authors: Wheeler Matthew C. , Hendon Harry H. , Cleland Sam , Meinke Holger , Donald Alexis 
Published: September 2008

Abstract
Impacts of the Madden–Julian oscillation (MJO) on Australian rainfall and circulation are examined during all four seasons. The authors examine circulation anomalies and a number of different rainfall metrics, each composited contemporaneously for eight MJO phases derived from the real-time multivariate MJO index. Multiple rainfall metrics are examined to allow for greater relevance of the information for applications. The greatest rainfall impact of the MJO occurs in northern Australia in (austral) summer, although in every season rainfall impacts of various magnitude are found in most locations, associated with corresponding circulation anomalies. In northern Australia in all seasons except winter, the rainfall impact is explained by the direct influence of the MJO’s tropical convective anomalies, while in winter a weaker and more localized signal in northern Australia appears to result from the modulation of the trade winds as they impinge upon the eastern coasts, especially in the northeast. In extratropical Australia, on the other hand, the occurrence of enhanced (suppressed) rainfall appears to result from induced upward (downward) motion within remotely forced extratropical lows (highs), and from anomalous low-level northerly (southerly) winds that transport moisture from the tropics. Induction of extratropical rainfall anomalies by remotely forced lows and highs appears to operate mostly in winter, whereas anomalous meridional moisture transport appears to operate mainly in the summer, autumn, and to some extent in the spring.
Observations of Ekman Currents in the Southern Ocean
Authors: Lenn Yueng-Djern , Chereskin Teresa K. 
Published: September 2008

Abstract
Largely zonal winds in the Southern Ocean drive an equatorward Ekman transport that constitutes the shallowest limb of the meridional overturning circulation of the Antarctic Circumpolar Current (ACC). Despite its importance, there have been no direct observations of the open ocean Ekman balance in the Southern Ocean until now. Using high-resolution repeat observations of upper-ocean velocity in Drake Passage, a mean Ekman spiral is resolved and Ekman transport is computed. The mean Ekman currents decay in amplitude and rotate anticyclonically with depth, penetrating to ∼100-m depth, above the base of the annual mean mixed layer at 120 m. The rotation depth scale exceeds the e-folding scale of the speed by about a factor of 3, resulting in a current spiral that is compressed relative to predictions from Ekman theory. Transport estimated from the observed currents is mostly equatorward and in good agreement with the Ekman transport computed from four different gridded wind products. The mean temperature of the Ekman layer is not distinguishable from temperature at the surface. Turbulent eddy viscosities inferred from Ekman theory and a direct estimate of the time-averaged stress were O(102–103) cm2 s−1. The latter calculation results in a profile of eddy viscosity that decreases in magnitude with depth and a time-averaged stress that is not parallel to the time-averaged vertical shear. The compression of the Ekman spiral and the nonparallel shear–stress relation are likely due to time averaging over the cycling of the stratification in response to diurnal buoyancy fluxes, although the action of surface waves and the oceanic response to high-frequency wind variability may also contribute.
Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3
Authors: Nelson Erik A. , Walker Sarah R. , Kepich Alicia , Gashin Laurie B. , Hideshima Teru , Ikeda Hiroshi , Chauhan Dharminder , Anderson Kenneth C. , Frank David A. 
Published: September 2008

Abstract
Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival.
Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology
Authors: Baenziger Stefan , Heikenwalder Mathias , Johansen Pål , Schlaepfer Erika , Hofer Ursula , Miller Regina C. , Diemand Simone , Honda Kenya , Kundig Thomas M. , Aguzzi Adriano , Speck Roberto F. 
Published: September 2008

AbstractChronic immune activation is a major cause for progressive immunodeficiency in human immunodeficiency virus type-1 (HIV) infection. The underlying trigger, however, remains largely unknown. HIV single-stranded RNA is a potent immune activator by triggering Toll-like receptor (TLR) 7/8. Thus, we hypothesized that sustained TLR7 triggering induces chronic immune activation and thereby contributes to progressive immunodeficiency. We used the synthetic compound R848 or a mixture of uridine-rich HIV single-stranded (ss) RNA oligonucleotides—both are potent TLR7/8 agonists—to explore the effects of sustained TLR7 triggering on the murine lymphoid system. Sustained TLR7 triggering induced an immunopathology reminiscent of progressive lymphoid destruction in HIV disease; we observed lymphopenia, elevated proinflammatory cytokines, splenomegaly, contracted lymphoid subsets, and lymphoid microarchitecture alteration with reduced marginal zone B-lymphocytes. Upon exposure to inactivated vesiculo-stomatitis virus, antibody production was abolished, although splenic lymphocytes were activated and total IgG was elevated. Our data imply that HIV itself may directly contribute to immune activation and dysfunction by stimulating TLR7. Thus, manipulation of TLR7 signaling may be a potential strategy to reduce chronic hyper-immune activation and, thereby, disease progression in HIV infection.
Critical role of scavenger receptor-BI–expressing bone marrow–derived endothelial progenitor cells in the attenuation of allograft vasculopathy after human apo A-I transfer
Authors: Feng Yingmei , van Eck Miranda , Van Craeyveld Eline , Jacobs Frank , Carlier Vincent , Van Linthout Sophie , Erdel Martin , Tjwa Marc , De Geest Bart 
Published: September 2008

AbstractAllograft vasculopathy is the leading cause of death in patients with heart transplantation. Accelerated endothelial regeneration mediated by enhanced endothelial progenitor cell (EPC) incorporation may attenuate the development of allograft vasculopathy. We investigated the hypothesis that modulation of EPC biology and attenuation of allograft vasculopathy by increased high-density lipoprotein cholesterol after human apo A-I (AdA-I) transfer requires scavenger receptor (SR)–BI expression in bone marrow–derived EPCs. After AdA-I transfer, the number of circulating EPCs increased 2.0-fold (P < .001) at different time points in C57BL/6 mice transplanted with SR-BI+/+ bone marrow but remained unaltered in mice with SR-BI−/− bone marrow. The effect of high-density lipoprotein on EPC migration in vitro requires signaling via SR-BI and extracellular signal-regulated kinases and is dependent on increased nitric oxide (NO) production in EPCs. Human apo A-I transfer 2 weeks before paratopic artery transplantation reduced intimal area at day 21 3.7-fold (P < .001) in mice with SR-BI+/+ bone marrow but had no effect in mice with SR-BI−/− bone marrow. AdA-I transfer potently stimulated EPC incorporation and accelerated endothelial regeneration in chimeric SR-BI+/+ mice but not in chimeric SR-BI−/− mice. In conclusion, human apo A-I transfer accelerates endothelial regeneration mediated via SR-BI expressing bone marrow–derived EPCs, thereby preventing allograft vasculopathy.
iRefIndex: A consolidated protein interaction database with provenance
Authors: Razick Sabry , Magklaras George , Donaldson Ian M 
Published: September 2008

Abstract

Background
Interaction data for a given protein may be spread across multiple databases. We set out to create a unifying index that would facilitate searching for these data and that would group together redundant interaction data while recording the methods used to perform this grouping.

Results
We present a method to generate a key for a protein interaction record and a key for each participant protein. These keys may be generated by anyone using only the primary sequence of the proteins, their taxonomy identifiers and the Secure Hash Algorithm. Two interaction records will have identical keys if they refer to the same set of identical protein sequences and taxonomy identifiers. We define records with identical keys as a redundant group. Our method required that we map protein database references found in interaction records to current protein sequence records. Operations performed during this mapping are described by a mapping score that may provide valuable feedback to source interaction databases on problematic references that are malformed, deprecated, ambiguous or unfound. Keys for protein participants allow for retrieval of interaction information independent of the protein references used in the original records.

Conclusion
We have applied our method to protein interaction records from BIND, BioGrid, DIP, HPRD, IntAct, MINT, MPact, MPPI and OPHID. The resulting interaction reference index is provided in PSI-MITAB 2.5 format at http://irefindex.uio.no. This index may form the basis of alternative redundant groupings based on gene identifiers or near sequence identity groupings.
Gene conversion and purifying selection of a placenta-specific ERV-V envelope gene during simian evolution
Authors: Kjeldbjerg Anders L , Villesen Palle , Aagaard Lars , Pedersen Finn Skou 
Published: September 2008

Abstract

Background
Most human endogenous retroviruses (HERVs) invaded our genome at least 25 million years ago. The majority of the viral genes are degenerated, since no selection preserves them within the genome. However, a few intact and very old HERV genes exist, and likely are beneficial for the host. We here address evolutionary aspects of two HERV-V envelope genes, ENVV1 and ENVV2, located in tandem and containing a long open reading frame.

Results
The ENVV2 gene is preserved with an intact reading frame during simian evolution, but none of the ENVV genes are found in the prosimian species tested. While we observe many transposon insertions in the gag and pol regions of the ERV-V2 provirus, the ENVV2 genes have escaped transposon crossfire in all species tested. Additional analysis of nucleotide substitutions provides further strong evidence of purifying selection on the ENVV2 gene during primate evolution. The other copy, ENVV1, seems to be involved in gene conversion of the major part of the envelope. Furthermore, ENVV1 and ENVV2 show placenta-specific expression in human and a baboon species.

Conclusion
Our analyses show that ERV-V entered our genome after the split between simian and prosimian primates. Subsequent purifying selection and gene conversion have preserved two copies of the ENVV envelope gene in most species. This is the first case of gene conversion involving long open reading frames in HERVs. Together with the placenta-specific expression of the human and baboon ENVV1 and ENVV2 envelope genes, these data provide strong evidence of a beneficial role for the host.
Host immunity in the protective response to vaccination with heat-killed Burkholderia mallei
Authors: Whitlock Gregory C , Lukaszewski Roman A , Judy Barbara M , Paessler Slobodan , Torres Alfredo G , Estes D Mark 
Published: September 2008

Abstract

Background
We performed initial cell, cytokine and complement depletion studies to investigate the possible role of these effectors in response to vaccination with heat-killed Burkholderia mallei in a susceptible BALB/c mouse model of infection.

Results
While protection with heat-killed bacilli did not result in sterilizing immunity, limited protection was afforded against an otherwise lethal infection and provided insight into potential host protective mechanisms. Our results demonstrated that mice depleted of either B cells, TNF-α or IFN-γ exhibited decreased survival rates, indicating a role for these effectors in obtaining partial protection from a lethal challenge by the intraperitoneal route. Additionally, complement depletion had no effect on immunoglobulin production when compared to non-complement depleted controls infected intranasally.

Conclusion
The data provide a basis for future studies of protection via vaccination using either subunit or whole-organism vaccine preparations from lethal infection in the experimental BALB/c mouse model. The results of this study demonstrate participation of B220+ cells and pro-inflammatory cytokines IFN-γ and TNF-α in protection following HK vaccination.
Is there a need for a GP consultant at a university hospital?
Authors: Mulder J , Groenier KH , Dekker JH , Berendsen AJ , Schuling J 
Published: September 2008

Abstract

Background
Patients in hospital can develop complaints unrelated to the condition they are admitted for. The treating specialist will then call upon a co-specialist who is specialized in the clinical picture associated with the new complaint. For such a complaint, the GP is usually the first contact, when the patient is not in hospital. Normally specialists only encounter patients GPs have selected for referral. The risk of the specialist overestimating the predictive value of 'unselected' complaints and symptoms of a serious condition is high. This may lead to an overuse of diagnostic treatments. Such treatments weigh more heavily on the patient, cause inadequate use of hospital facilities and, as a consequence, generate higher costs.
Because of these considerations, we wished to investigate if there is a need for the GP as a consultant for new complaints during hospital admittance.

Method
The files of a random sample of patients who had an interdisciplinary consultation during their stay in hospital were judged by an expertpanel whether the consultation fitted the expertise of a GP.

Results
In 28 out of 84 files the consultation fitted the expertise of a GP; most cases concerned a specific condition that is not part of the specialist's expertise, most frequently dermatological problems. In a minority of cases the specialist is confronted with a clinical problem with symptoms of which the cause is not clear, for example fever.

Conclusion
Generally, the consultations concern serious, often very complex conditions, i.e. cases that should be assessed by a specialist. Nevertheless, the expert panel's judgment of the interdisciplinary consultations shows that in more than half of the dermatological cases and in a limited number of consultations by a specialist of internal medicine and geriatrics the problems fit the GP's expertise.
Given the morbidity in academic hospitals we suppose that the results of a similar study in a peripheral hospital might even show more perspective for a GP consultant. These results offer sufficient arguments to start a pilotstudy into the role of a GP consultant in hospital.