bluuebunny/crossref_metadata_2025_split huggingface dataset:
Control systems for membrane fusion in the ancestral eukaryote; evolution of tethering complexes and SM proteins
Authors: Koumandou V Lila , Dacks Joel B , Coulson Richard MR , Field Mark C 
Published: February 2007

Abstract

Background
In membrane trafficking, the mechanisms ensuring vesicle fusion specificity remain to be fully elucidated. Early models proposed that specificity was encoded entirely by SNARE proteins; more recent models include contributions from Rab proteins, Syntaxin-binding (SM) proteins and tethering factors. Most information on membrane trafficking derives from an evolutionarily narrow sampling of model organisms. However, considering factors from a wider diversity of eukaryotes can provide both functional information on core systems and insight into the evolutionary history of the trafficking machinery. For example, the major Qa/syntaxin SNARE families are present in most eukaryotic genomes and likely each evolved via gene duplication from a single ancestral syntaxin before the existing eukaryotic groups diversified. This pattern is also likely for Rabs and various other components of the membrane trafficking machinery.

Results
We performed comparative genomic and phylogenetic analyses, when relevant, on the SM proteins and components of the tethering complexes, both thought to contribute to vesicle fusion specificity. Despite evidence suggestive of secondary losses amongst many lineages, the tethering complexes are well represented across the eukaryotes, suggesting an origin predating the radiation of eukaryotic lineages. Further, whilst we detect distant sequence relations between GARP, COG, exocyst and DSL1 components, these similarities most likely reflect convergent evolution of similar secondary structural elements. No similarity is found between the TRAPP and HOPS complexes and the other tethering factors. Overall, our data favour independent origins for the various tethering complexes. The taxa examined possess at least one homologue of each of the four SM protein families; since the four monophyletic families each encompass a wide diversity of eukaryotes, the SM protein families very likely evolved before the last common eukaryotic ancestor (LCEA).

Conclusion
These data further support a highly complex LCEA and indicate that the basic architecture of the trafficking system is remarkably conserved and ancient, with the SM proteins and tethering factors having originated very early in eukaryotic evolution. However, the independent origin of the tethering complexes suggests a novel pattern for increasing complexity in the membrane trafficking system, in addition to the pattern of paralogous machinery elaboration seen thus far.
APC/C – the master controller of origin licensing?
Authors: Sivaprasad Umasundari , Machida Yuichi J , Dutta Anindya 
Published: February 2007

Abstract
DNA replication must be tightly controlled to prevent initiation of a second round of replication until mitosis is complete. So far, components of the pre-replicative complex (Cdt1, Cdc6 and geminin) were considered key players in this regulation. In a new study, Machida and Dutta have shown that depletion of Emi1 caused cells to replicate their DNA more than once per cell cycle [1]. This effect was dependent on the ability of Emi1 to inhibit the APC/C. In addition to its role in regulating entry into mitosis, oscillation of APC/C activity regulates pre-RC formation: high APC/C activity in late M/G1 allows pre-RC formation and low APC/C activity in S/G2 prevents pre-RC formation for a second time thereby preventing rereplication. Each redundant pathway to prevent rereplication is dependent on regulating one of the pre-RC components, and all of the pathways are co-regulated by Emi1 through the APC/C. In this commentary we discuss how this new role of Emi1 adds to our understanding of the regulation of replication initiation. We also review the literature to analyze whether APC/C has a role in regulating endoreduplication (a normal state of polyploidy in some differentiated cells). Similarly a role of premature APC/C activation in genomic instability of tumors is discussed.
Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study
Authors: Girard Timothy D , Shintani Ayumi K , Jackson James C , Gordon Sharon M , Pun Brenda T , Henderson Melinda S , Dittus Robert S , Bernard Gordon R , Ely EWesley 
Published: February 2007

Abstract
Introduction
Post-traumatic stress disorder (PTSD) has been identified in a significant portion of intensive care unit (ICU) survivors. We sought to identify factors associated with PTSD symptoms in patients following critical illness requiring mechanical ventilation.

Methods
Forty-three patients who were mechanically ventilated in the medical and coronary ICUs of a university-based medical center were prospectively followed during their ICU admission for delirium with the Confusion Assessment Method for the ICU. Additionally, demographic data were obtained and severity of illness was measured with the APACHE II (Acute Physiology and Chronic Health Evaluation II) score. Six months after discharge, patients were screened for PTSD symptoms by means of the Post-Traumatic Stress Syndrome 10-Questions Inventory (PTSS-10). Multiple linear regression was used to assess the association of potential risk factors with PTSS-10 scores.

Results
At follow-up, six (14%) patients had high levels of PTSD symptoms. On multivariable analysis, women had higher PTSS-10 scores than men by a margin of 7.36 points (95% confidence interval [CI] 1.62 to 13.11; p = 0.02). Also, high levels of PTSD symptoms were less likely to occur in older patients, with symptoms declining after age 50 (p = 0.04). Finally, although causation cannot be assumed, the total dose of lorazepam received during the ICU stay was associated with PTSD symptoms; for every 10-mg increase in cumulative lorazepam dose, PTSS-10 score increased by 0.39 (95% CI 0.17 to 0.61; p = 0.04). No significant relationship was noted between severity of illness and PTSD symptoms or duration of delirium and PTSD symptoms.

Conclusion
High levels of PTSD symptoms occurred in 14% of patients six months following critical illness necessitating mechanical ventilation, and these symptoms were most likely to occur in female patients and those receiving high doses of lorazepam. High levels of PTSD symptoms were less likely to occur in older patients.
Candidate Genetic Risk Factors of Stroke: Results of a Multilocus Genotyping Assay
Authors: Lalouschek Wolfgang , Endler Georg , Schillinger Martin , Hsieh Kety , Lang Wilfried , Cheng Suzanne , Bauer Peter , Wagner Oswald , Mannhalter Christine 
Published: February 2007

Abstract
Background: Epidemiological studies indicate that genetic factors play a role in the risk of stroke, particularly in younger individuals, but the role of single-nucleotide polymorphisms (SNPs) is controversial. We tested the possible association of a number of previously described SNPs with stroke risk.
Methods: We investigated the prevalence of 60 polymorphisms located in 35 genes in 450 white patients who suffered an acute stroke or transient ischemic attack before the age of 60 years and in 817 healthy control individuals by a multilocus PCR-based assay. The controls were randomly selected from attendees of a health service program. Genetic variations were detected by hybridization to nylon strips (Roche Molecular Systems) containing detection oligonucleotides for the SNPs. We used P values of &lt;0.05 for confirmatory analysis of the SNPs in the genes for APOE (allele 4), angiotensin converting enzyme, factor V, prothrombin, and methylenetetrahydrofolate reductase. To account for multiple testing we defined a P value of &lt;0.001 as statistically significant for all exploratory tests. The genes represented in the test panel by more than 1 SNP were also evaluated by haplotype analysis.
Results: Frequencies of all 60 tested SNPs among patients and controls were very similar. No SNP reached an odds ratio of 2, and no association with stroke risk was statistically significant.
Conclusions: Our results do not indicate a clinically relevant role of any of the investigated SNPs for stroke risk in individuals hospitalized for ischemic stroke/transient ischemic attack before or at 60 years of age. These results are in accordance with previous metaanalyses showing at most a very modest or no significant effect of these SNPs on stroke risk.
LC-MS/MS Quantification of Zn-α2 Glycoprotein: A Potential Serum Biomarker for Prostate Cancer
Authors: Bondar Olga P , Barnidge David R , Klee Eric W , Davis Brian J , Klee George G 
Published: February 2007

AbstractBackground: Zn-α2 glycoprotein (ZAG) is a relatively abundant glycoprotein that has potential as a biomarker for prostate cancer. We present a high-flow liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for measuring serum ZAG concentrations by proteolytic cleavage of the protein and quantification of a unique peptide.Methods: We selected the ZAG tryptic peptide 147EIPAWVPEDPAAQITK162 as the intact protein for quantification and used a stable isotope-labeled synthetic peptide with this sequence as an internal standard. Standards using recombinant ZAG in bovine serum albumin, 50 g/L, and a pilot series of patient sera were denatured, reduced, alkylated, and digested with trypsin. The concentration of ZAG was calculated from a dose–response curve of the ratio of the relative abundance of the ZAG tryptic peptide to internal standard.Results: The limit of detection for ZAG in serum was 0.08 mg/L, and the limit of quantification was 0.32 mg/L with a linear dynamic range of 0.32 to 10.2 mg/L. Replicate digests from pooled sera run during a period of 3 consecutive days showed intraassay imprecision (CV) of 5.0% to 6.3% and interassay imprecision of 4.4% to 5.9%. Mean (SD) ZAG was higher in 25 men with prostate cancer [7.59 (2.45) mg/L] than in 20 men with nonmalignant prostate disease [6.21 (1.65) mg/L, P = 0.037] and 6 healthy men [3.65 (0.71) mg/L, P = 0.0007].Conclusions: This LC-MS/MS assay is reproducible and can be used to evaluate the clinical utility of ZAG as a cancer biomarker.
Asymmetric Dimethylarginine, Smoking, and Risk of Coronary Heart Disease in Apparently Healthy Men: Prospective Analysis from the Population-Based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg Study and Experimental Data
Authors: Maas Renke , Schulze Friedrich , Baumert Jens , Löwel Hannelore , Hamraz Khatera , Schwedhelm Edzard , Koenig Wolfgang , Böger Rainer H 
Published: February 2007

AbstractBackground: An increased plasma concentration of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predicts adverse clinical outcome in patients with coronary heart disease. We investigated the association between plasma concentrations of ADMA and risk in initially healthy smoking and nonsmoking men.Methods: Participants for this nested case-control study came from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study. ADMA was measured by liquid chromatography–tandem mass spectrometry in 88 men with incident coronary events (fatal and nonfatal myocardial infarction and sudden cardiac death) and 254 age-matched controls, with a median (interquartile range) follow-up of 6.2 (3.3–7.9) years.Results: After adjustment for potential confounders, the relative risk for a future coronary event was 2.00 [95% confidence interval (CI) 1.27–3.16; P = 0.003] for smokers compared with nonsmokers and 1.35 (95% CI 0.78–2.33; P = 0.282) for the top vs the bottom tertile of the ADMA distribution. In cases and controls, lower ADMA plasma concentrations were observed in smokers. Analysis of ADMA-associated risk in smokers and nonsmokers separately revealed substantial differences: the adjusted relative risk for future coronary events (top vs bottom tertile of the ADMA distribution) was 0.48 (95% CI 0.16–1.46; P = 0.198) in smokers and 2.40 (95% CI 1.14–5.08; P = 0.021) in nonsmokers. Exposure of human endothelium-derived EAhy 926 cells to tobacco smoke enhanced expression of the ADMA metabolizing enzyme dimethylarginine dimethylaminohydrolase 2 and reduced ADMA concentration.Conclusions: In apparently healthy men, increased ADMA predicts the risk for coronary events in nonsmokers, but not in smokers. This may be explained in part by an alteration of ADMA metabolism by tobacco smoke.
Statins and the Risk of Pneumonia: A Population‐Based, Nested Case‐Control Study
Authors: Schlienger Raymond G. , Fedson David S. , Jick Susan S. , Jick Hershel , Meier Christoph R. 
Published: February 2007

Study Objective. To determine if the use of statins affects pneumonia‐related outpatient visits, hospitalizations with survival, and deaths.Design. Population‐based, retrospective, nested case‐control analysis.Data Source. United Kingdom‐based General Practice Research Database.Participants. The study population (134,262 patients aged > 30 yrs) consisted of 55,118 patients who took statins and/or fibrates, 29,144 patients with hyperlipidemia not taking lipid‐lowering agents, and 50,000 randomly selected patients without hyperlipidemia and without lipid‐lowering treatment.Measurements and Main Results. We identified 1253 patients with pneumonia and matched them with 4838 control subjects based on age, sex, general practice, and index date. After adjusting for comorbidity and frequency of visits to general practitioners, we calculated the risks (odds ratios with 95% confidence intervals) of uncomplicated pneumonia, hospitalization for pneumonia with survival, and fatal pneumonia in participants who used statins compared with those who did not. Current statin users had a significantly reduced risk of fatal pneumonia (adjusted odds ratio 0.47, 95% confidence interval 0.25–0.88) and slightly but not significantly reduced risks of uncomplicated pneumonia and pneumonia hospitalization with survival. Recent or past statin use and fibrate use at any time were not associated with a reduced risk of pneumonia.
Adjunctive Dexmedetomidine Therapy in the Intensive Care Unit: A Retrospective Assessment of Impact on Sedative and Analgesic Requirements, Levels of Sedation and Analgesia, and Ventilatory and Hemodynamic Parameters
Authors: MacLaren Robert , Forrest Laurel K. , Kiser Tyree H. 
Published: February 2007

Study Objective. To determine if adjunctive dexmedetomidine therapy in intensive care patients alters requirements for and levels of sedation and analgesia, and to describe hemodynamic and ventilatory parameters.Design. Retrospective, noncontrolled, descriptive study of clinical practice.Setting. Four intensive care units (ICUs; medical, surgical, neurosurgical, or burn) in a university‐affiliated medical center.Patients. Forty patients who were already receiving sustained use of propofol, lorazepam, or fentanyl when dexmedetomidine was started.Measurements and Main Results. Medical records were identified by searching the pharmacy database for patients who had received continuous‐infusion dexmedetomidine from January 2000‐January 2003 while in one of the four ICUs. Primary end points were discontinuation or dosage reduction of other sedatives or fentanyl from the hour before to 6 hours after starting dexmedetomidine. Other outcomes included levels of sedation and analgesia before and after dexmedetomidine and description of ventilatory and hemodynamic parameters. The initial dexmedetomidine rate of 0.4 ± 0.25 μg/kg/hour changed minimally through 47.4 ±61.1 infusion hours. At 6 hours, 11 of 13 patients receiving propofol, 14 of 23 receiving lorazepam, and 4 of 30 receiving fentanyl had the respective agent discontinued. With dexmedetomidine, the hourly rates and cumulative daily doses were reduced only for propofol. Adequate sedation occurred at rates of 64.6% and 47.9% during the 24‐hour periods before and after dexmedetomidine was started, respectively (p=0.001). Four and 12 patients had severe agitation before and after, respectively (p=0.05). One and 12 patients had severe pain before and after, respectively (p=0.02). Nine patients experienced hypotension or bradycardia. Twenty‐two patients were successfully extubated within 24 hours of starting dexmedetomidine.Conclusions. Adjunctive dexmedetomidine reduces sedative requirements but does not alter analgesic requirements. However, dexmedetomidine was associated with enhanced agitation, severe pain, and hemodynamic compromise. Transitioning to dexmedetomidine from other sedatives and analgesics may not provide optimal sedation and analgesia. Future studies are needed to evaluate dexmedetomidine as a bridge to extubation.
Amiodarone Prophylaxis for Atrial Fibrillation After Cardiac Surgery: Meta‐Analysis of Dose Response and Timing of Initiation
Authors: Buckley Mitchell S. , Nolan Paul E. , Slack Marion K. , Tisdale James E. , Hilleman Daniel E. , Copeland Jack G. 
Published: February 2007

Study Objective. To investigate a possible dose‐response relationship between amiodarone and reduction in incidence of postoperative atrial fibrillation, and to determine whether pre‐ or postoperative initiation of amiodarone is superior.Design. Meta‐analysis of randomized controlled trials.Data Source. MEDLINE and EMBASE databases and the Cochrane Central Register of Controlled Trials for English‐language reports published between 1966 and December 2005.Measurements and Main Results. Of 23 identified randomized controlled trials of amiodarone prophylaxis of postoperative atrial fibrillation, 14 were included in the final analysis. These studies enrolled a total of 2864 patients. For each study, the total administered amiodarone dose—categorized as low (< 3000 mg), medium (3000–5000 mg), or high (> 5000 mg)—and preoperative versus postoperative initiation were aggregated by using meta‐analytic techniques. The incidence of postoperative atrial fibrillation was significantly reduced by amiodarone compared with placebo (p<0.001). Although the odds of developing atrial fibrillation appeared to be somewhat higher in the low‐dose group, no significant differences were noted in the odds ratios (ORs) of developing atrial fibrillation among the low‐, medium‐, and high‐dose groups: OR 0.58, 95% confidence interval (CI) 0.44–0.77; OR 0.45, 95% CI 0.30–0.69; and OR 0.44, 95% CI 0.33–0.58; respectively (p=0.238). In addition, the ORs for atrial fibrillation development associated with preoperative and postoperative initiation of amiodarone were not significantly different (OR 0.50, 95% CI 0.39–0.63; and OR 0.48, 95% CI 0.37–0.63; respectively, p=0.862).Conclusion. Total amiodarone doses of 3000 mg or higher may be more effective than lower doses in reducing the rate of postoperative atrial fibrillation after cardiac surgery. Preoperative initiation of amiodarone appears to be unnecessary. These findings require confirmation in prospective, randomized trials.
Generation of Cardiac and Endothelial Cells from Neonatal Mouse Testis-Derived Multipotent Germline Stem Cells
Authors: Baba Shiro , Heike Toshio , Umeda Katsutsugu , Iwasa Toru , Kaichi Shinji , Hiraumi Yoshimi , Doi Hiraku , Yoshimoto Momoko , Kanatsu-Shinohara Mito , Shinohara Takashi , Nakahata Tatsutoshi 
Published: February 2007

Abstract
Multipotent germline stem (mGS) cells have been established from neonatal mouse testes. Here, we compared mGS, embryonic stem (ES), and embryonic germ (EG) cells with regard to their ability to differentiate into mesodermal cells, namely, cardiomyocytes and endothelial cells. The in situ morphological appearances of undifferentiated mGS, ES, and EG cells were similar, and 4 days after being induced to differentiate, approximately 30%–40% of each cell type differentiated into Flk1+ cells. The sorted Flk1+ cells differentiated efficiently into cardiomyocytes and endothelial cells. By day 10 after differentiation induction, the three cell types generated equal number of endothelial colonies. However, by day 13 after differentiation induction, the Flk1+ mGS cells generated more contractile colonies than did the Flk1+ ES cells, whereas the Flk1+ EG cells generated equivalent numbers as the Flk1+ mGS cells. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis of differentiation markers such as Rex1, FGF-5, GATA-4, Brachyury, and Flk1 revealed that mGS cells expressed these markers more slowly during days 0–4 after differentiation induction than did ES cells, but that this mGS cell pattern was similar to that of the EG cells. RT-PCR analysis also revealed that the three differentiation cell types expressed various cardiac markers. Moreover, immunohistochemical analysis revealed that the contractile colonies derived from Flk1+ mGS cells express mature cardiac cell-specific markers. In conclusion, mGS cells are phenotypically similar to ES and EG cells and have a similar potential to differentiate into cardiomyocytes and endothelial cells.
Disclosure of potential conflicts of interest is found at the end of this article.
Conditional Gene Expression in Human Embryonic Stem Cells
Authors: Vallier Ludovic , Alexander Morgan , Pedersen Roger 
Published: February 2007

Abstract
Human embryonic stem cells (hESCs) possess unique properties for studying mechanisms controlling cell fate commitment during early mammalian development. Gain of function is a common strategy to study the function of specific genes involved in these mechanisms. However, transgene toxicity can be a major limitation, especially with factors influencing proliferation or differentiation. Here, we describe an efficient method based on the inducible recombinase Cre-ERT2 for conditional gene expression in hESCs and their differentiated derivatives. Using this approach, we have established several hESC sublines inducible for the expression of the enhanced green fluorescent protein and the transforming growth factor β family member Nodal. Together, these results demonstrate that Cre-ERT2 can be used to control gene expression in undifferentiated and differentiated cells, thereby providing the first conditional transgene expression system that works effectively in hESCs.
Disclosure of potential conflicts of interest is found at the end of this article.