bluuebunny/crossref_metadata_2025_split huggingface dataset:
Timing of Toll-Like Receptor 9 Agonist Administration in Pneumococcal Vaccination Impacts Both Humoral and Cellular Immune Responses as Well as Nasopharyngeal Colonization in Mice
Authors: Jensen Katrine M. , Melchjorsen Jesper , Dagnaes-Hansen Frederik , Sørensen Uffe B. S. , Laursen Rune R. , Østergaard Lars , Søgaard Ole S. , Tolstrup Martin 
Published: February 2012

ABSTRACTSynthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs, CpG ODN, are Toll-like receptor 9 agonists (TLR9a), which have been used as adjuvants in pneumococcal vaccines to improve antibody responses in immunodeficient patients. Here, we examined whether the coadministration of TLR9a with pneumococcal CRM197-conjugate vaccine enhances protection against pneumococcal colonization, the levels of antipolysaccharide antibodies, and the CD4+T-cell responses. Wild-type BALB/c mice and B-cell-deficient BALB/c Igh-Jtm1Dhumice were immunized twice with the following: (i) PCV alone; (ii) simultaneous PCV and TLR9a; (iii) PCV and then TLR9a, after a 48-h delay; (iv) TLR9a alone; and (v) phosphate-buffered saline. Nasopharyngeal protection, serum antibodies, CD4+T-cell responses, and clearance of bacteremia after intraperitoneal challenge withStreptococcus pneumoniae6B were evaluated. We found decreased nasopharyngeal protection againstS. pneumoniae6B colonization after simultaneous immunization with PCV and TLR9a compared to immunization with PCV alone in wild-type BALB/c mice (P= 0.037). A similar trend was observed in B-cell-deficient BALB/c Igh-Jtm1Dhumice. Simultaneous administration did not enhance antibody levels and lowered the CRM197-specific cytokine release of gamma interferon, interleukin-2 (IL-2), IL-5 and IL-13. Immunization with PCV and then TLR9a, after a 48-h delay, significantly improved nasopharyngeal protection compared to simultaneous administration (P= 0.011). Furthermore, delaying TLR9a delivery increased antibody titers compared to both simultaneous administration (P= 0.001) and PCV immunization alone (P= 0.026). In conclusion, the immunological and clinical impact of adjuvanting a pneumococcal conjugate vaccine (Prevnar; Pfizer) with a TLR9a is highly depended on timing of the adjuvant administration. Thus, careful timing of adjuvant administration may improve novel vaccine formulations.
Characterization of the Structurally Diverse N-Linked Glycans of Campylobacter Species
Authors: Jervis Adrian J. , Butler Jonathan A. , Lawson Andrew J. , Langdon Rebecca , Wren Brendan W. , Linton Dennis 
Published: March 2012

ABSTRACTThe Gram-negative bacteriumCampylobacter jejuniencodes an extensively characterized N-linked protein glycosylation system that modifies many surface proteins with a heptasaccharide glycan. InC. jejuni, the genes that encode the enzymes required for glycan biosynthesis and transfer to protein are located at a singlepglgene locus. Similar loci are also present in the genome sequences of all otherCampylobacterspecies, although variations in gene content and organization are evident. In this study, we have demonstrated that onlyCampylobacterspecies closely related toC. jejuniproduce glycoproteins that interact with both aC. jejuniN-linked-glycan-specific antiserum and a lectin known to bind to theC. jejuniN-linked glycan. In order to further investigate the structure ofCampylobacterN-linked glycans, we employed anin vitropeptide glycosylation assay combined with mass spectrometry to demonstrate thatCampylobacterspecies produce a range of structurally distinct N-linked glycans with variations in the number of sugar residues (penta-, hexa-, and heptasaccharides), the presence of branching sugars, and monosaccharide content. These data considerably expand our knowledge of bacterial N-linked glycan structure and provide a framework for investigating the role of glycosyltransferases and sugar biosynthesis enzymes in glycoprotein biosynthesis with practical implications for synthetic biology and glycoengineering.
Prevalence and risk factors for forced or coerced sex among school-going youth: national cross-sectional studies in 10 southern African countries in 2003 and 2007
Authors: Andersson Neil , Paredes-Solís Sergio , Milne Deborah , Omer Khalid , Marokoane Nobantu , Laetsang Ditiro , Cockcroft Anne 
Published: March 2012

ObjectivesTo study prevalence at two time points and risk factors for experience of forced or coerced sex among school-going youth in 10 southern African countries.DesignCross-sectional surveys, by facilitated self-administered questionnaire, of in-school youth in 2003 and 2007.SettingSchools serving representative communities in eight countries (Botswana, Lesotho, Malawi, Mozambique, Namibia, Swaziland, Zambia and Zimbabwe) in 2003 and with Tanzania and South Africa added in 2007.ParticipantsStudents aged 11–16 years present in the school classes.Main outcome measuresExperience of forced or coerced sex, perpetration of forced sex.ResultsIn 2007, 19.6% (4432/25 840) of female students and 21.1% (4080/21 613) of male students aged 11–16 years reported they had experienced forced or coerced sex. Rates among 16-year-olds were 28.8% in females and 25.4% in males. Comparing the same schools in eight countries, in an analysis age standardised on the 2007 Botswana male sample, there was no significant decrease between 2003 and 2007 among females in any country and inconsistent changes among males. In multilevel analysis using generalised linear mixed model, individual-level risk factors for forced sex among female students were age over 13 years and insufficient food in the household; school-level factors were a lower proportion of students knowing about child rights and higher proportions experiencing or perpetrating forced sex; and community-level factors were a higher proportion of adults in favour of transactional sex and a higher rate of intimate partner violence. Male risk factors were similar. Some 4.7% of female students and 11.7% of male students reported they had perpetrated forced sex. Experience of forced sex was strongly associated with perpetration and other risk factors for perpetration were similar to those for victimisation.ConclusionsForced or coerced sex remained common among female and male youth in 2007. Experience of sexual abuse in childhood is recognised to increase the risk of HIV infection. The association the authors found between forced sex and school-level factors suggests preventive interventions in schools could help to tackle the HIV epidemic in southern Africa.
Hypnotics' association with mortality or cancer: a matched cohort study
Authors: Kripke Daniel F , Langer Robert D , Kline Lawrence E 
Published: February 2012

ObjectivesAn estimated 6%–10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality.SettingA large integrated health system in the USA.DesignLongitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.SubjectsSubjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007.Main outcome measuresData were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity.ResultsAs predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4–18, 18–132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose–response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.ConclusionsReceiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.
Defining impact of a rapid response team: qualitative study with nurses, physicians and hospital administrators
Authors: Benin Andrea L , Borgstrom Christopher P , Jenq Grace Y , Roumanis Sarah A , Horwitz Leora I 
Published: March 2012

ObjectiveThe objective of this study was to qualitatively describe the impact of a Rapid Response Team (RRT) at a 944-bed, university-affiliated hospital.MethodsWe analysed 49 open-ended interviews with administrators, primary team attending physicians, trainees, RRT attending hospitalists, staff nurses, nurses and respiratory technicians.ResultsThemes elicited were categorised into the domains of (1) morale and teamwork, (2) education, (3) workload, (4) patient care, and (5) hospital administration. Positive implications beyond improved care for acutely ill patients were: increased morale and empowerment among nurses, real-time redistribution of workload for nurses (reducing neglect of non-acutely ill patients during emergencies), and immediate access to expert help. Negative implications were: increased tensions between nurses and physician teams, a burden on hospitalist RRT members, and reduced autonomy for trainees.ConclusionsThe RRT provides advantages that extend well beyond a reduction in rates of transfers to intensive care units or codes but are balanced by certain disadvantages. The potential impact from these multiple sources should be evaluated to understand the utility of any RRT programme.
Time and temperature effects on geomembrane strain from a gravel particle subjected to sustained vertical force
Authors: Sabir A. , Brachman R.W.I. 
Published: February 2012

Experimental data is reported that quantifies how time (up to 10 000 h) and temperature (from 22 to 85 °C) impact tensile strains in a 1.5 mm thick high-density polyethylene geomembrane — with a compressible clay liner beneath it — that are induced by an overlying gravel particle when subjected to a sustained vertical force. At an average applied stress of 250 kPa and clay water content of 16%, tensile strains were found to increase by 1.25 times as the temperature was increased from 22 to 55 °C after 1000 h. Similarly, strains were found to increase by factors between 1.2 to 1.3 as time was increased from 10 to 1000 h. Based on the measured data, time–temperature superposition (tTS) was then used to develop an approach to predict long-term geomembrane strains from gravel indentations. The tTS approach was validated against independent experiments conducted for 10 000 h (1.14 years) as it was found that the predicted strain of 19% was very close to the measured strain of 18%. Provided that the physical properties of the geomembrane do not decrease abruptly, the results suggest that the tTS approach developed can be used to provide estimates of long-term geomembrane strains.
Lower-bound calculations of the bearing capacity of eccentrically loaded footings in cohesionless soil
Authors: Krabbenhoft Sven , Damkilde Lars , Krabbenhoft Kristian 
Published: February 2012

Lower-bound calculations based on the finite element method are used to determine the bearing capacity of a strip foundation subjected to a vertical, eccentric load on cohesionless soil with varying surcharges. The soil is assumed perfectly plastic following the Mohr–Coulomb failure criterion. The results are reported as tables and graphs showing the bearing capacity as a function of the eccentricity and surcharge. Normalised interaction diagrams in the vertical force versus moment plane have been produced. The results from the analysis are in reasonable agreement with existing methods for smaller eccentricities, whereas for greater eccentricities (e > 0.25B–0.3B, where B is the width of the foundation), the lower-bound values in general — and especially for greater surcharges — are considerably smaller than the bearing capacities predicted by existing methods. For the special case of no surcharge, the results are in very good agreement with results obtained by the effective-width approach originally proposed by Meyerhof.
Hydrogeological support to United States military operations, 1917–2010
Authors: Gellasch Christopher A. 
Published: February 2012

Abstract
Over the past 100 years, hydrogeology has played a role in most military operations undertaken by the USA. The first significant application by US forces took place during World War I, on the Western Front. America's entry into World War II highlighted the need for military hydrogeologists once again, and a combination of civilian and uniformed hydrogeologists provided valuable support to the war effort, notably by terrain analysis. During the Cold War, the United States Geological Survey Military Geology Branch conducted military hydrogeological studies, and in 1985 the US Army Corps of Engineers created the Water Detection Response Team (WDRT) to provide hydrogeological expertise to military well-drilling units. During the Persian Gulf War of 1990–1991, groundwater was important for sustaining troops living in the northern Saudi Arabian desert. Operations in Bosnia and Kosovo later in that decade required the assistance of the WDRT in obtaining adequate groundwater supplies for base camps. Current military operations in Afghanistan rely on groundwater as a significant source for most US bases. In combination, uniformed and civilian geologists serving in a variety of roles to support American troops have located water supplies essential to the success of US military operations around the globe.
Hydrogeology of British military sites: Project Aquatrine
Authors: McCaffrey Lewis , Bullock Colin 
Published: February 2012

Abstract
Project Aquatrine was the UK Ministry of Defence's Private Finance Initiative project to transfer responsibility for water supply and waste water removal to private companies. Britain was split into three geographical areas, with Package A approximately covering the area to the west of a line between the Mersey and Southampton, Package C covering the rest of England, and Package B covering Scotland. Hydrogeology was a major factor in the models used to produce financial forecasts for Package A, upon which the winning bid was based. Reconnaissance-level understanding of aquifers, water demand and the Environment Agency's view of licensing possibilities were used to produce a list of sites where water resources could be developed to replace the incumbent water suppliers. Several sites have been developed successfully, but a number of possible abstractions have failed to be realized because of hydrogeological (quality, quantity) and other causes. In the operational phase of Aquatrine, hydrogeology was used to understand the data produced by a new network of telemetred groundwater level loggers, to constrain the location of new sewage treatment works and to apply for appropriate abstraction licences when Crown Immunity under the Water Resources Act 1991 is finally lost.
Examples of the influence of groundwater on British military mining in Flanders, 1914–1917
Authors: Doyle Peter 
Published: February 2012

Abstract
The success of military mining is inherently controlled by subsurface conditions. Military mining may be offensive (i.e. intended to breach enemy fortifications at the ground surface by explosive detonation), defensive (counter-mining to destroy enemy mine galleries) or passive (to provide troops with underground protection from bombardment). The geology of the British Sector of the Western Front in World War I varied from the Palaeogene–Neogene sediments of the Flanders Plain in Belgium to the late Cretaceous chalks of Picardy and Artois in northern France, all with intermittent Quaternary cover. In Flanders, British mining operations commenced in late 1914. Passive mining created shallow dugouts and isolated shelters, and offensive mines also tended to be shallow, rapidly dug, and of low engineering impact. By 1915, with the war above ground now largely in stalemate, the impetus for more extensive mining grew, leading to the high point of offensive mine warfare with detonations that initiated the Battle of Messines on 7 June 1917. Development of mine warfare required engineering innovations such as ‘tubbing’ to deal with major groundwater problems presented by variation in the permeability of the sediments, as can be illustrated by two examples from the battleground of Ypres (Ieper).
Expression of a Truncated Active Form of VDAC1 in Lung Cancer Associates with Hypoxic Cell Survival and Correlates with Progression to Chemotherapy Resistance
Authors: Brahimi-Horn M. Christiane , Ben-Hail Danya , Ilie Marius , Gounon Pierre , Rouleau Matthieu , Hofman Véronique , Doyen Jérôme , Mari Bernard , Shoshan-Barmatz Varda , Hofman Paul , Pouysségur Jacques , Mazure Nathalie M. 
Published: March 2012

AbstractResistance to chemotherapy-induced apoptosis of tumor cells represents a major hurdle to efficient cancer therapy. Although resistance is a characteristic of tumor cells that evolve in a low oxygen environment (hypoxia), the mechanisms involved remain elusive. We observed that mitochondria of certain hypoxic cells take on an enlarged appearance with reorganized cristae. In these cells, we found that a major mitochondrial protein regulating metabolism and apoptosis, the voltage-dependent anion channel 1 (VDAC1), was linked to chemoresistance when in a truncated (VDAC1-ΔC) but active form. The formation of truncated VDAC1, which had a similar channel activity and voltage dependency as full-length, was hypoxia-inducible factor-1 (HIF-1)-dependent and could be inhibited in the presence of the tetracycline antibiotics doxycycline and minocycline, known inhibitors of metalloproteases. Its formation was also reversible upon cell reoxygenation and associated with cell survival through binding to the antiapoptotic protein hexokinase. Hypoxic cells containing VDAC1-ΔC were less sensitive to staurosporine- and etoposide-induced cell death, and silencing of VDAC1-ΔC or treatment with the tetracycline antibiotics restored sensitivity. Clinically, VDAC1-ΔC was detected in tumor tissues of patients with lung adenocarcinomas and was found more frequently in large and late-stage tumors. Together, our findings show that via induction of VDAC1-ΔC, HIF-1 confers selective protection from apoptosis that allows maintenance of ATP and cell survival in hypoxia. VDAC1-ΔC may also hold promise as a biomarker for tumor progression in chemotherapy-resistant patients. Cancer Res; 72(8); 2140–50. ©2012 AACR.
Combinations of BRAF, MEK, and PI3K/mTOR Inhibitors Overcome Acquired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated byNRASorMEKMutations
Authors: Greger James G. , Eastman Stephen D. , Zhang Vivian , Bleam Maureen R. , Hughes Ashley M. , Smitheman Kimberly N. , Dickerson Scott H. , Laquerre Sylvie G. , Liu Li , Gilmer Tona M. 
Published: March 2012

AbstractRecent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAFV600E and the YUSIT1 BRAFV600K melanoma cell lines. These clones also showed reduced sensitivity to the allosteric mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibitor GSK1120212 (trametinib). Genetic characterization of these clones identified an in-frame deletion in MEK1 (MEK1K59del) or NRAS mutation (NRASQ61K and/or NRASA146T) with and without MEK1P387S in the BRAFV600E background and NRASQ61K in the BRAFV600K background. Stable knockdown of NRAS with short hairpin RNA partially restored GSK2118436 sensitivity in mutant NRAS clones, whereas expression of NRASQ61K or NRASA146T in the A375 parental cells decreased sensitivity to GSK2118436. Similarly, expression of MEK1K59del, but not MEK1P387S, decreased sensitivity of A375 cells to GSK2118436. The combination of GSK2118436 and GSK1120212 effectively inhibited cell growth, decreased ERK phosphorylation, decreased cyclin D1 protein, and increased p27kip1 protein in the resistant clones. Moreover, the combination of GSK2118436 or GSK1120212 with the phosphoinositide 3-kinase/mTOR inhibitor GSK2126458 enhanced cell growth inhibition and decreased S6 ribosomal protein phosphorylation in these clones. Our results show that NRAS and/or MEK mutations contribute to BRAF inhibitor resistance in vitro, and the combination of GSK2118436 and GSK1120212 overcomes this resistance. In addition, these resistant clones respond to the combination of GSK2126458 with GSK2118436 or GSK1120212. Clinical trials are ongoing or planned to test these combinations. Mol Cancer Ther; 11(4); 909–20. ©2012 AACR.
Procoagulant activity of erythrocytes and platelets through phosphatidylserine exposure and microparticles release in patients with nephrotic syndrome
Authors: Gao Chunyan , Xie Rui , Yu Chengyuan , Wang Qin , Shi Fangfang , Yao Chunying , Zhou Jin , Gilbert Gary E. , Xie Rujuan , Shi Jialan 
Published: February 2012

SummaryRecent studies showed that an imbalance of prothrombotic and antithrombotic factors and impaired thrombolytic activity contribute to the thrombophilia of the nephrotic syndrome (NS). However, it is not clear whether blood cell injury and/or activation is involved in hypercoagulability in NS patients. Our objectives were to study the increase in microparticle (MP) release and phosphatidylserine (PS) exposure on the outer membrane of MP-origin cells in NS patients, and to evaluate their procoagulant activity (PCA). The subjects were patients with membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS) and healthy controls. Analyses of MPs and PS exposure were performed using a flow cytometer. PCA was determined by clotting time and purified coagulation complex assays. We found that lactadherin+ MPs, which derived from red blood cells (RBC), platelet and endothelial cell, increased in NS patients. Moreover, PS exposure on RBCs and platelets in each NS group, especially in MN, are higher than that in controls. MP shedding and PS exposure of RBCs/platelets were highly procoagulant in NS patients. However, blockade of PS with lactadherin inhibited over 90% of PCA while an anti-tissue factor antibody had no significant inhibition effect. Our results demonstrate that the thrombophilic susceptibility of NS may be partly ascribed to MP release and PS exposure of RBCs, platelets and endothelial cells. Lactadherin is a sensitive probe for PS that has high anticoagulant activity.