bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microscopic events in β-hairpin folding from alternative unfolded ensembles
Authors: Best Robert B. , Mittal Jeetain 
Published: June 2011

We have performed the first unbiased folding simulations of the GB1 hairpin in explicit solvent, using hundreds of microsecond-long molecular dynamics simulations (total time: 0.7 ms). Our simulations are initiated from two sets of structures. Starting from an equilibrium unfolded state, we obtain single-exponential folding kinetics with rate coefficients in good agreement (
T
= 350 K) or within an order of magnitude (
T
= 300 K) of the experimental values. However, simulations initiated from unfolded configurations lacking secondary structure result in biexponential kinetics with an additional fast nanosecond kinetic mode. This mode can strongly bias the folding rate estimated from the mean first passage time, when the trials are much shorter than the folding time. We find that the mechanism of the hairpin folding is insensitive to the details of the initial unfolded ensemble and is initiated by correct formation of the turn of the hairpin, followed by the formation of the native hydrogen bonds and hydrophobic contacts, consistent with experimental
ϕ
-value analysis. Subsequent native interactions can be formed either from the turn or from the hairpin termini, helping to explain an apparent discrepancy in experimental results. From our simulations, we also obtain the transition path durations, a critical parameter for single molecule experiments aiming to resolve events along folding pathways. The lengths of transition paths span a wide range, from 50 ps to 140 ns, at 300 K.
Measurement of radon and xenon binding to a cryptophane molecular host
Authors: Jacobson David R. , Khan Najat S. , Collé Ronald , Fitzgerald Ryan , Laureano-Pérez Lizbeth , Bai Yubin , Dmochowski Ivan J. 
Published: June 2011

Xenon and radon have many similar properties, a difference being that all 35 isotopes of radon (
195
Rn–
229
Rn) are radioactive. Radon is a pervasive indoor air pollutant believed to cause significant incidence of lung cancer in many geographic regions, yet radon affinity for a discrete molecular species has never been determined. By comparison, the chemistry of xenon has been widely studied and applied in science and technology. Here, both noble gases were found to bind with exceptional affinity to tris-(triazole ethylamine) cryptophane, a previously unsynthesized water-soluble organic host molecule. The cryptophane–xenon association constant,
K
a
= 42,000 ± 2,000 M
-1
at 293 K, was determined by isothermal titration calorimetry. This value represents the highest measured xenon affinity for a host molecule. The partitioning of radon between air and aqueous cryptophane solutions of varying concentration was determined radiometrically to give the cryptophane–radon association constant
K
a
= 49,000 ± 12,000 M
-1
at 293 K.
RIP: the regulatory interaction predictor—a machine learning-based approach for predicting target genes of transcription factors
Authors: Bauer Tobias , Eils Roland , König Rainer 
Published: June 2011

Abstract
Motivation: Understanding transcriptional gene regulation is essential for studying cellular systems. Identifying genome-wide targets of transcription factors (TFs) provides the basis to discover the involvement of TFs and TF cooperativeness in cellular systems and pathogenesis.
Results: We present the regulatory interaction predictor (RIP), a machine learning approach that inferred 73 923 regulatory interactions (RIs) for 301 human TFs and 11 263 target genes with considerably good quality and 4516 RIs with very high quality. The inference of RIs is independent of any specific condition. Our approach employs support vector machines (SVMs) trained on a set of experimentally proven RIs from a public repository (TRANSFAC). Features of RIs for the learning process are based on a correlation meta-analysis of 4064 gene expression profiles from 76 studies, in silico predictions of transcription factor binding sites (TFBSs) and combinations of these employing knowledge about co-regulation of genes by a common TF (TF-module). The trained SVMs were applied to infer new RIs for a large set of TFs and genes. In a case study, we employed the inferred RIs to analyze an independent microarray dataset. We identified key TFs regulating the transcriptional response upon interferon alpha stimulation of monocytes, most prominently interferon-stimulated gene factor 3 (ISGF3). Furthermore, predicted TF-modules were highly associated to their functionally related pathways.
Conclusion: Descriptors of gene expression, TFBS predictions, experimentally verified binding information and statistical combination of this enabled inferring RIs on a genome-wide scale for human genes with considerably good precision serving as a good basis for expression profiling studies.
Contact: r.koenig@dkfz.de
Supplementary information: Supplementary data are available at Bioinformatics online.
Management of the Elderly Person After Myocardial Infarction
Authors: Aronow Wilbert S. 
Published: June 2011

Abstract
Elderly persons after myocardial infarction should have their modifiable coronary artery risk factors intensively treated. Hypertension should be treated with beta blockers and angiotensin-converting enzyme inhibitors. The blood pressure should be reduced to &lt;140/85 mmHg and to ≥130/80 mmHg in persons with diabetes or renal insufficiency. The serum low-density lipoprotein cholesterol should be reduced to &lt;100 mg/dl with statins if necessary. Aspirin or clopidogrel, beta blockers, and angiotensin-converting enzyme inhibitors should be given indefinitely unless contraindications exist to the use of these drugs. Long-acting nitrates are effective antianginal and antiischemic drugs. There are no Class I indications for the use of calcium channel blockers after myocardial infarction. Postinfarction patients should not receive Class I antiarrhythmic drugs, sotalol, or amiodarone. An automatic implantable cardioverter-defibrillator should be implanted in postinfarction patients at very high risk for sudden cardiac death. Hormonal therapy should not be used in postmenopausal women after myocardial infarction. The two indications for coronary revascularization are prolongation of life and relief of unacceptable symptoms despite optimal medical management.
Media Portrayals and Health Inequalities: A Case Study of Characterizations of Gene × Environment Interactions
Authors: Horwitz Allan V. 
Published: June 2011

Objectives. This article examines how genetic and environmental interactions associated with health inequalities are constructed and framed in the presentation of scientific research.
Methods. It uses the example of a major article about depression in a longitudinal study of young adults that appeared in Science in 2003.
Results. This portrayal of findings related to health inequalities uses a genetic lens that privileges genetic influences and diminishes environmental ones.
Discussion. The emphasis on the genetic side of Gene × Environment interactions can serve to deflect attention away from the important impact of social inequalities on health.
Economic Status Over the Life Course and Racial Disparities in Health
Authors: Kahn Joan R. , Fazio Elena M. 
Published: June 2011

Objectives. Racial and socioeconomic disparities in health have become a prominent feature of American society, though our understanding of the processes leading to such persistent disparities is still relatively limited. In this study, we focus on the impact of social and economic advantages and disadvantages over the life course on health disparities at older ages. In particular, we look at the roles of both cumulative and current financial resources and financial strains as determinants of a range of subjective and objective health assessments of physical conditions, functional impairment, and mental health.
Methods. Our data come from the 2001 Aging, Stress, and Health Study, which interviewed over 1,100 White and African American adults aged 65 years and older living in the Washington, D.C., metropolitan area.
Results and Discussion. Our results show that although racial and socioeconomic disparities in health do not follow a simple explanation, we do provide strong support for the fundamental importance of social and economic resources. Unlike previous studies that emphasize the role of financial resources such as income and wealth, we show that the lack of these resources, as indicated by high levels of financial strain, provides an important clue to how economic resources influence health.
Mental Health Disparities Across Education and Sex: A Prospective Analysis Examining How They Persist Over the Life Course
Authors: Miech Richard A. , Eaton William W. , Brennan Kathleen 
Published: June 2011

Objectives. Higher levels of psychopathology among people with lower socioeconomic status and among women persist as cohorts age. In this analysis, we examine whether the persistence of these disparities as a cohort ages results from (a) a single set of people within a disadvantaged group who have chronic psychopathology or (b) continually changing sets of people within a disadvantaged group who have psychopathology of short duration.
Methods. Data for this analysis come from the Epidemiologic Catchment Area Study, which includes two psychological assessments (depressive syndrome and psychological distress) in a population sample of adults in Baltimore, Maryland, collected 13 years apart.
Results and Discussion. Results indicate that the persistence of disparities across education resulted primarily from one single set of respondents with chronic psychopathology over the 13 years of the survey, while the persistence of disparities across sex involved new sets of women as the cohort aged. We discuss implications of these results for theory and policy.
Significance of Molecular Testing for Congenital Chloride Diarrhea
Authors: Lechner Silvia , Ruemmele Frank M , Zankl Andreas , Lausch Ekkehart , Huber Wolf‐Dietrich , Mihatsch Walter , Phillips Alan D , Lewindon Peter , Querfeld Uwe , Heinz‐Erian Peter , Müller Thomas , Janecke Andreas R 
Published: June 2011

ABSTRACTObjectives:Autosomal recessive, congenital chloride diarrhea (CLD) is a form of persistent secretory diarrhea, presenting with polyhydramnios and intractable diarrhea from birth. CLD is caused by mutations in the SLC26A3 gene, encoding a Na+‐independent Cl−/HCO3‐ exchanger. The diagnosis is generally made on the basis of high fecal chloride concentration in patients with serum electrolyte homoeostasis corrected by salt substitution. We aimed to evaluate the role of diagnostic genetic testing in CLD.Patients and Methods:Clinical and laboratory data were collected from 8 unrelated children diagnosed as having or suspected to have CLD. The evaluation included physical examination, routine clinical chemistry, and SLC26A3 mutation analysis by direct sequencing of DNA extracted from buccal swabs or peripheral leukocytes.Results:CLD was initially diagnosed on high fecal chloride concentrations in 7 patients, and by mutation analysis in 1 patient. In 3 of these patients the correct diagnosis was made more than 6 months after birth. We identified SLC26A3 mutations on both alleles in all 8 patients with CLD, including 3 novel missense and 4 novel truncating mutations. We present a compilation of reported SLC26A3 mutations and polymorphisms.Conclusions:The diagnosis and therapy of CLD were considerably delayed in 3 of 8 patients from this series, highlighting the potential of misdiagnosing CLD. We add 7 novel mutations, including 3 missense changes of highly conserved residues to a total of 41 mutations in this gene.Molecular analysis is efficient and should be considered as a means of early diagnosis of CLD, especially if the clinical diagnosis remains uncertain.
Leukocytapheresis in Pediatric Patients With Ulcerative Colitis
Authors: Tomomasa Takeshi , Tajiri Hitoshi , Kagimoto Seiichi , Shimizu Toshiaki , Yoden Atsushi , Ushijima Kosuke , Uchida Keiichi , Kaneko Hiroaki , Abukawa Daiki , Konno Mutsuko , Maisawa Shun‐ichi , Kohsaka Takao , Kobayashi Akio ,   Japanese Study Group for Pediatric Ulcerative Colitis
Published: June 2011

ABSTRACTObjective:Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open‐label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC.Patients and Methods:Twenty‐three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid‐resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half‐volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements.Results:The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration.Conclusions:The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.
Two‐day Bowel Preparation With Polyethylene Glycol 3350 and Bisacodyl: A New, Safe, and Effective Regimen for Colonoscopy in Children
Authors: Phatak Uma P , Johnson Susanne , Husain Sohail Z , Pashankar Dinesh S 
Published: June 2011

ABSTRACTObjectives:To assess the safety, efficacy, and acceptance of a 2‐day bowel preparation with polyethylene glycol (PEG) 3350 without electrolytes and bisacodyl for colonoscopy in children.Patients and Methods:In a prospective study, 111 children of mean age 11.9 years were given 2 g/kg of PEG and a 5‐mg tablet of bisacodyl daily for 2 days before colonoscopy. Stool frequency, consistency, and adverse effects were monitored for the duration of the bowel preparation. Compliance and quality of colonic preparation were assessed on the day of the colonoscopy.Results:The average daily stool frequency increased from a baseline of 2, to 4* on day 1, and 6.5* on day 2 of the bowel preparation (*P < 0.001 for difference vs baseline). The colonic preparations were rated as excellent or good in 92% and 93% of the patients in the right and left colon, respectively. Adverse effects were mild nausea (19%), abdominal pain (11%), and vomiting (4%). The compliance was rated as excellent in 95% of the patients.Conclusions:A 2‐day bowel preparation with PEG and bisacodyl is safe, effective, and well accepted for colonoscopy in children without any major adverse effects.
Evaluation of a novel needle guide for ultrasound‐guided phantom vessel cannulation*
Authors: Luyet C. , Hartwich V. , Urwyler N. , Schumacher P. M. , Eichenberger U. , Vogt A. 
Published: June 2011

SummaryWe evaluated a novel, sled‐mounted needle guide for ultrasound‐guided vessel cannulation. Fifty medical students were randomly assigned to use ultrasound with the sled (sled group, n = 23) or ultrasound without the sled (control group, n = 27) for vessel cannulation in a phantom. For each of 15 attempts we recorded cannulation time and designated a successful cannulation as 1 and a failure as 0. Our primary outcome was the mean overall success rate. The median (IQR [range]) number of successes in the sled group and control group were 15.0 (13.0–15.0 [11.0–15.0]) and 11.0 (9.0–13.0 [6.0–15.0]), respectively (p < 0.001). Cannulation time decreased from the first to the last attempt in the sled group from 7.0 s (6.0–10.0 [4.0–16]) s to 4.0 s (3.0–4.0 [1.0–6.0]) s and in the control group from 35.0 s (27.0–35.0 [11.0–35.0]) s to 7.0 s (5.0–10.0 [3.0–25.0]) s. The sled group demonstrated a shorter cannulation time at each attempt (p < 0.001). The novel sled improved the success rate and efficiency of ultrasound‐guided phantom vessel cannulation.
Ideal versus corrected body weight for dosage of sugammadex in morbidly obese patients
Authors: Van Lancker P. , Dillemans B. , Bogaert T. , Mulier J. P. , De Kock M. , Haspeslagh M. 
Published: June 2011

SummaryTo date, the dosing of sugammadex is based on real body weight without taking fat content into account. We compared the reversal of profound rocuronium‐induced neuromuscular blockade in morbidly obese patients using doses of sugammadex based on four different weight corrections. One hundred morbidly obese patients, scheduled for laparoscopic bariatric surgery under propofol‐sufentanil anaesthesia, were randomly assigned four groups: ideal body weight; ideal body weight + 20%; ideal body weight + 40%; and real body weight. Patients received sugammadex 2 mg.kg−1, when adductor pollicis monitoring showed two responses. The primary endpoint was full decurarisation. Secondary endpoints were the ability to get into bed independently on arrival to the post‐anaesthetic care unit and clinical signs of residual paralysis. There was no residual paralysis in any patient. Morbidly obese patients can safely be decurarised from rocuronium‐induced neuromuscular blockade T1‐T2 with sugammadex dosed at 2 mg.kg−1 ideal body weight + 40% (p < 0.0001).
Postoperative hypothermia and patient outcomes after elective cardiac surgery
Authors: Karalapillai D. , Story D. , Hart G. K. , Bailey M. , Pilcher D. , Cooper D. J. , Bellomo R. 
Published: June 2011

SummaryHypothermia after elective cardiac surgery is an important physiological abnormality and is associated with increased morbidity and mortality. The Australian and New Zealand intensive care adult patient database was studied to obtain the lowest and highest temperature in the first 24 h after surgery. Hypothermia was defined as core temperature < 36 °C; transient hypothermia as temperature < 36 °C that was corrected within 24 h; and persistent hypothermia as hypothermia that was not corrected within 24 h. Hypothermia occurred in 28 587 out of a total of 43 158 consecutive patients (66%) and was persistent in 111 (0.3%). Transient hypothermia was not independently associated with increased hospital mortality (OR = 0.9, 95% CI 0.8–1.1), whereas persistent hypothermia was associated with markedly increased risk of death (OR = 6.3, 95% CI = 3.3–12.0). Hypothermia is common in postoperative cardiac surgery patients during the first 24 h after ICU admission but, if transient, is not independently associated with an increased risk of death.
Use of modelling and simulation techniques to support decision making on the progression of PF‐04878691, a TLR7 agonist being developed for hepatitis C
Authors: Jones Hannah M. , Chan Phylinda L. S. , van der Graaf Piet H. , Webster Robert 
Published: June 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• While several clinical studies have been published on toll‐like receptor 7 (TLR7) agonists, there is no information on the quantitative link between 2′,5′‐oligoadenylate synthetase (OAS) and antiviral efficacy (viral load).WHAT THIS STUDY ADDS• This study provides the only quantitative dynamic clinical relationship between the pharmacokinetics (PK) of PF‐04878691 and OAS and lymphocyte levels, together with the only published clinical relationship between markers of anti‐viral pharmacology (OAS) and antiviral efficacy (viral load). This study highlights how modelling and simulation can be used to impact compound progression decisions in clinical development.AIMTo use non‐linear mixed effects modelling and simulation techniques to predict whether PF‐04878691, a toll‐like receptor 7 (TLR7) agonist, would produce sufficient antiviral efficacy while maintaining an acceptable side effect profile in a ‘proof of concept’ (POC) study in chronic hepatitis C (HCV) patients.METHODSA population pharmacokinetic–pharmacodynamic (PKPD) model was developed using available ‘proof of pharmacology’ (POP) clinical data to describe PF‐04878691 pharmacokinetics (PK) and its relationship to 2′,5′‐oligoadenylate synthetase (OAS; marker of pharmacology) and lymphocyte levels (marker of safety) following multiple doses in healthy subjects. A second model was developed to describe the relationship between change from baseline OAS expressed as fold change and HCV viral RNA concentrations using clinical data available in HCV patients for a separate compound, CPG‐10101 (ACTILON™), a TLR9 agonist. Using these models the antiviral efficacy and safety profiles of PF‐04878691 were predicted in HCV patients.RESULTSThe population PKPD models described well the clinical data as assessed by visual inspection of diagnostic plots, visual predictive checks and precision of the parameter estimates. Using these relationships, PF‐04878691 exposure and HCV viral RNA concentration was simulated in HCV patients receiving twice weekly administration for 4 weeks over a range of doses. The simulations indicated that significant reductions in HCV viral RNA concentrations would be expected at doses >6 mg. However at these doses grade ≥3 lymphopenia was also predicted.CONCLUSIONSThe model simulations indicate that PF‐04878691 is unlikely to achieve POC criteria and support the discontinuation of this compound for the treatment of HCV.
A functional promoter polymorphism of the human IL18 gene is associated with aspirin-induced urticaria
Authors: Kim S-H. , Son J.K. , Yang E-M. , Kim J-E. , Park H-S. 
Published: June 2011

Summary
Background Urticaria is the commonest cutaneous reaction caused by aspirin or other nonsteroidal anti-inflammatory drugs. The pathogenesis of aspirin-induced urticaria (AIU) is not fully understood, but appears to involve mast cell activation and neutrophil infiltration.
Objectives To investigate the genetic contribution of interleukin (IL)-18, which can amplify acute inflammation by promoting mast cell activation, neutrophil migration and cytokine production, to the pathogenesis of AIU.
Methods A case–control association study was performed using 275 patients with AIU and 196 normal healthy controls in a Korean population. Two promoter polymorphisms of the IL18 gene (−607A/C and −137G/C) were genotyped using the primer extension method. The functional effect of the IL18 gene promoter polymorphism was investigated through in vitro studies including a luciferase reporter assay and electrophoretic mobility shift assays (EMSAs) and ex vivo studies involving neutrophil chemotaxis assays.
Results A significant association was detected between both AIU in general and the aspirin-intolerant acute urticaria (AIAU) phenotype and the IL18 promoter polymorphism −607A/C. Patients with AIAU showed higher frequencies of the C−607G−137 haplotype, ht1 [CG], compared with controls (P =0·02). Moreover, ht1 [CG] showed a high transcript haplotype by the luciferase activity assay, and EMSAs identified a −607C allele-specific DNA-binding protein as CREB2. Neutrophil chemotactic activity was highest in subjects with AIU exhibiting the high transcript haplotype, ht1 [CG] (P =0·019).
Conclusions The high transcript haplotype ht1 [CG] of the IL18 gene may contribute to the development of acute cutaneous inflammation sensitive to aspirin, leading to the clinical presentation of AIAU.