bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fractal Geometry and the Pharmacometrics of Micafungin in Overweight, Obese, and Extremely Obese People
Authors: Hall Ronald G. , Swancutt Mark A. , Gumbo Tawanda 
Published: August 2011

ABSTRACT

The majority of Americans are overweight, and the incidence of obesity continues to increase. This trend predisposes people to a number of deleterious consequences, including the metabolic syndrome and other conditions that lead to a greater number of hospital admissions. Invasive candidiasis is an important nosocomial infection that results from these admissions. Echinocandins such as micafungin are indicated for treatment. We have previously demonstrated that overweight patients exhibit higher micafungin systemic clearance (SCL) than leaner patients. We hypothesized that obese and extremely obese people would show even higher SCL than merely overweight patients. To test this, we performed a prospective study of 36 adult volunteers randomized to receive a single dose of either 100 mg or 300 mg of micafungin whose body mass index fell within one of the following categories: <25, 25 to 40, and >40 kg/m
2
. The male-to-female ratio was 1:1. The minimum weight was 43 kg, the median 97 kg, and the maximum weight 155 kg. A two-compartment model was examined using the maximum likelihood solution via the expectation-maximization algorithm. Men had a higher median SCL of 1.53 liters/h versus 1.29 liters/h (
P
= 0.01) in the Mann-Whitney U-test. The typical SCL was 1.04 liters/h but increased by a factor of (weight/66)
0.75
as weight increased above 66 kg. Thus, the relationship between micafungin SCL and weight in adults is best described by fractal-geometry-based laws. Furthermore, micafungin SCL continues to increase as weight increases, with no obvious plateau. This leads to a requirement for strategies to determine individualized dosing levels for obese and extremely obese patients.
MK-0536 Inhibits HIV-1 Integrases Resistant to Raltegravir
Authors: Métifiot Mathieu , Johnson Barry , Smith Steven , Zhao Xue Zhi , Marchand Christophe , Burke Terrence , Hughes Stephen , Pommier Yves 
Published: August 2011

ABSTRACT
With the U.S. Food and Drug Administration approval of raltegravir (RAL; MK-0518; Merck & Co.), HIV-1 integrase (IN) is the newest therapeutic target for AIDS and HIV infections. Recent structural analyses show that IN strand transfer inhibitors (INSTIs) share a common binding mode in the enzyme active site. While RAL represents a therapeutic breakthrough, the emergence of IN resistance mutations imposes the development of new INSTIs. We report here the biochemical and antiviral activities of MK-0536, a new IN inhibitor. We demonstrate that, like RAL, MK-0536 is highly potent against recombinant IN and viral replication. It is also effective against INs that carry the three main RAL resistance mutations (Y143R, N155H, and to a lesser extent G140S-Q148H) and against the G118R mutant. Modeling of IN developed from recent prototype foamy virus structures is presented to account for the differences in the drug activities of MK-0536 and RAL against the IN mutants.
Elicitation of Epithelial Cell-Derived Immune Effectors by Outer Membrane Vesicles of Nontypeable Haemophilus influenzae
Authors: Sharpe Samantha W. , Kuehn Meta J. , Mason Kevin M. 
Published: August 2011

ABSTRACTOuter membrane vesicles (OMVs) are produced by all Gram-negative microorganisms studied to date. The contributions of OMVs to biological processes are diverse and include mediation of bacterial stress responses, selective packaging and secretion of virulence determinants, modulation of the host immune response, and contributions to biofilm formation and stability. First characterized as transformasomes inHaemophilus, these membranous blebs facilitate transfer of DNA among bacteria. NontypeableHaemophilus influenzae(NTHI), an opportunistic pathogen of the upper and lower respiratory tracts, produces OMVsin vivo, but there is a paucity of information regarding both the composition and role of OMVs during NTHI colonization and pathogenesis. We demonstrated that purified NTHI vesicles are 20 to 200 nm in diameter and contain DNA, adhesin P5, IgA endopeptidase, serine protease, and heme utilization protein, suggesting a multifaceted role in virulence. NTHI OMVs can bind to human pharyngeal epithelial cells, resulting in a time- and temperature-dependent aggregation on the host cell surface, with subsequent internalization. OMVs colocalize with the endocytosis protein caveolin, indicating that internalization is mediated by caveolae, which are cholesterol-rich lipid raft domains. Upon interaction with epithelial cells, NTHI OMVs stimulate significant release of the immunomodulatory cytokine interleukin-8 (IL-8) as well as the antimicrobial peptide LL-37. Thus, we demonstrated that NTHI OMVs contain virulence-associated proteins that dynamically interact with and invade host epithelial cells. Beyond their ability to mediate DNA transfer inHaemophilus, OMV stimulation of host immunomodulatory cytokine and antimicrobial peptide release supports a dynamic role for vesiculation in NTHI pathogenesis and clinically relevant disease progression.
The Deubiquitinase Activity of the Salmonella Pathogenicity Island 2 Effector, SseL, Prevents Accumulation of Cellular Lipid Droplets
Authors: Arena Ellen T. , Auweter Sigrid D. , Antunes L. Caetano M. , Vogl A. Wayne , Han Jun , Guttman Julian A. , Croxen Matthew A. , Menendez Alfredo , Covey Scott D. , Borchers Christoph H. , Finlay B. Brett 
Published: August 2011

ABSTRACT

To cause disease,
Salmonella enterica
serovar Typhimurium requires two type III secretion systems that are encoded by
Salmonella
pathogenicity islands 1 and 2 (SPI-1 and -2). These secretion systems serve to deliver specialized proteins (effectors) into the host cell cytosol. While the importance of these effectors to promote colonization and replication within the host has been established, the specific roles of individual secreted effectors in the disease process are not well understood. In this study, we used an
in vivo
gallbladder epithelial cell infection model to study the function of the SPI-2-encoded type III effector, SseL. The deletion of the
sseL
gene resulted in bacterial filamentation and elongation and the unusual localization of
Salmonella
within infected epithelial cells. Infection with the Δ
sseL
strain also caused dramatic changes in host cell lipid metabolism and led to the massive accumulation of lipid droplets in infected cells. This phenotype was directly attributable to the deubiquitinase activity of SseL, as a
Salmonella
strain carrying a single point mutation in the catalytic cysteine also resulted in extensive lipid droplet accumulation. The excessive buildup of lipids due to the absence of a functional
sseL
gene also was observed in murine livers during
S.
Typhimurium infection. These results suggest that SseL alters host lipid metabolism in infected epithelial cells by modifying the ubiquitination patterns of cellular targets.
Next-Generation Computational Genetic Analysis: Multiple Complement Alleles Control Survival after Candida albicans Infection
Authors: Peltz Gary , Zaas Aimee K. , Zheng Ming , Solis Norma V. , Zhang Mason X. , Liu Hong-Hsing , Hu Yajing , Boxx Gayle M. , Phan Quynh T. , Dill David , Filler Scott G. 
Published: August 2011

ABSTRACTCandida albicansis a fungal pathogen that causes severe disseminated infections that can be lethal in immunocompromised patients. Genetic factors are known to alter the initial susceptibility to and severity ofC. albicansinfection. We developed a next-generation computational genetic mapping program with advanced features to identify genetic factors affecting survival in a murine genetic model of hematogenousC. albicansinfection. This computational tool was used to analyze the median survival data after inbred mouse strains were infected withC. albicans, which provides a useful experimental model for identification of host susceptibility factors. The computational analysis indicated that genetic variation within early classical complement pathway components (C1q,C1r, andC1s) could affect survival. Consistent with the computational results, serum C1 binding to this pathogen was strongly affected byC1rsalleles, as was survival of chromosome substitution strains. These results led to a combinatorial, conditional genetic model, involving an interaction betweenC5andC1r/salleles, which accurately predicted survival after infection. Beyond applicability to infectious disease, this information could increase our understanding of the genetic factors affecting susceptibility to autoimmune and neurodegenerative diseases.
Exploring the therapeutic power of narrative at the end of life: a qualitative analysis of narratives emerging in dignity therapy
Authors: Tait Glendon R , Schryer Catherine , McDougall Allan , Lingard Lorelei 
Published: August 2011

ObjectiveTo understand the therapeutic effect of a narrative intervention, specifically dignity therapy, in patients at the end-of-life. To examine the thematic dimensions and shared narrative features of the stories that emerge in dignity therapy and theorise their relationship to the intervention's clinical impact.DesignResident physicians, as part of an educational intervention, co-administered the dignity therapy protocol with the principal investigator. Interviews were transcribed, edited, and then, within a week, read back to the patient and provided as a document for the patient to keep. A constant comparative approach was taken to identify narratives and thematic patterns.Participants12 Patients at the end-of-life were administered dignity interviews by 12 resident physicians, accompanied by the principal investigator.SettingPalliative care settings in two University of Toronto academic hospitals.ResultsThree narrative types emerged, each containing several themes. Evaluation narratives create a life lived before illness, with an overarching theme of overcoming adversity. Transition narratives describe a changing health situation and its meanings, including impact on family and on one's world view. Legacy narratives discuss the future without the patient and contain the parables and messages to be left for loved ones.ConclusionsWhile the interview protocol guides patients' responses, the commonality of narrative structures across interviews suggests that patients draw on experiences with two familiar genres: the eulogy and the medical interview, to create a narrative order during the chaos of dying. The dignity interview's resonance with these genres appears to facilitate a powerful, and perhaps unexpected sense of agency.
Pressure–temperature evolution and thermal regimes in the Barrovian zones, Scotland
Authors: Vorhies Sarah H. , Ague Jay J. 
Published: August 2011

Abstract:

We constrain the
P
–
T
evolution of the Barrovian metamorphic zones from the southwestern to the northeastern coasts of Scotland using thermobarometry and pseudosection analysis based on mineral composition data, garnet zoning profiles and 2D garnet maps. Twenty-five samples were investigated from the garnet to the sillimanite zones. In the western half of the field area there was relatively high-
P
metamorphism (0.9–1.1 GPa) followed by near-isothermal decompression. In and around the Barrovian type area of Glen Clova maximum pressures were also high (
c
. 0.8–0.9 GPa); however, peak-
T
conditions were driven by a brief (of the order of 1 Ma or less) thermal pulse or pulses during exhumation at
c
. 0.6 GPa. Pressures at peak-
T
conditions along the eastern coast were the lowest observed,
c
. 0.4–0.5 GPa. These rocks were probably affected by the same thermal pulse activity evident around Glen Clova. All three regions initially developed during regional metamorphism associated with thermal relaxation of tectonically overthickened crust. The eastern part of the sequence, including Glen Clova, is fundamentally different from the western part because it required additional advective heat input to achieve peak thermal conditions. This heat was probably supplied by synorogenic magmas (e.g. Newer Gabbros) and the associated elevated crustal heat flow.

Supplementary material:

Electron microprobe methods, mineral and rock analyses, mineral activity–composition relations, criteria for identifying prograde mineral compositions, pseudosection and diffusion modelling methods, and profiles of
X
Alm
and
X
Prp
from garnets in Figures
7
,
8
,
9
,
10
are available at
http://www.geolsoc.org.uk/SUP18491
.
Effects of melt percolation on platinum group elements and Re–Os systematics of peridotites from the Tan-Lu fault zone, eastern North China Craton
Authors: Xiao Yan , Zhang Hong-Fu 
Published: August 2011

Abstract:

Concentrations of platinum group elements (PGE) and Re–Os isotopic compositions were determined for a suite of peridotite xenoliths from Cenozoic Beiyan volcanoes within the Tan-Lu fault zone, eastern North China Craton (NCC). Previous petrographic and geochemical data indicate the existence of considerable modification by melt–peridotite interaction for these xenoliths. Thus, this suite of xenoliths provides an unusual opportunity to examine the effects of melt percolation on PGE abundances and Re–Os isotopes. Our data show that most of the Beiyan peridotites have flat chondrite-normalized PGE patterns whereas a considerable variation in total PGE abundances has been observed in lherzolites to highly fertile cpx-rich lherzolites and wehrlites. Their total PGE contents range between 0.97 and 61.4 ppb and their PGE relative abundances from 0.1 to 0.0001 × CI-chondrites, respectively. In these rocks, the total PGE budget was reduced by more than 90% from lherzolite to cpx-rich lherzolite and to wehrlite, probably because intergranular sulphides were completely removed by silicate melt. However, Beiyan peridotites have low and variable Re (0.0002–0.5118 ppb) and Os (0.194–10.4 ppb) abundances and high
187
Os/
188
Os (0.12167–0.14978) ratios. The
187
Os/
188
Os ratios in some wehrlites are much higher than the value for the primitive mantle. The high
187
Os/
188
Os ratios have also been observed in peridotites found in other localities within the Tan-Lu fault zone such as Shanwang and Nüshan. This could be the result of the addition of radiogenic Os during the melt percolation. Extremely low Os abundances in Beiyan peridotites suggest that Os may behave as an incompatible element during melt percolation and could mobilize with the dissolution of sulphides. The suprachondritic
187
Os/
188
Os ratios in peridotites within the Tan-Lu fault zone relative to those away from it indicate that the Tan-Lu fault zone played an important role as a melt infiltrating channel in the radiogenic Os enrichment induced by melt percolation. This could be the reason for the Os isotopic heterogeneity observed in the eastern NCC. This study also confirms that Os isotopes and PGE appear to be mobile during massive melt percolation.
Age and composition of crystalline basement rocks on the Norwegian continental margin: offshore extension and continuity of the Caledonian–Appalachian orogenic belt
Authors: Slagstad Trond , Davidsen Børre , Daly J.Stephen 
Published: August 2011

Abstract:
Twenty-two wells on the Norwegian continental margin have penetrated underlying basement. We present U–Pb zircon, whole-rock geochemical, and Sm–Nd and Rb–Sr isotopic data from nine wells in the North Sea and Norwegian Sea with relevance to the offshore continuation of the Norwegian Caledonides, and their correlation throughout the Caledonian–Appalachian orogenic belt. Palaeozoic magmatism in the North Sea can be divided into two groups. The older group consists of 460 Ma calc-alkaline granites with evolved isotopic compositions, correlative with similar rocks in the Uppermost Allochthon. The younger group consists of a 430 Ma dacite and a 421 Ma leucogabbro, with less evolved isotopic compositions. In the Norwegian Sea, isotopically evolved granitic magmatism at 437 Ma and more juvenile dioritic magmatism at 447 Ma are correlative with magmatism in the Bindal and Smøla–Hitra Batholiths in the Uppermost Allochthon. Metasedimentary basement rocks from the North Sea and Norwegian Sea, dominated by Late Palaeoproterozoic and Mesoproterozoic grains, resemble rocks found in the Caledonides of Scotland, Greenland and Svalbard. The new data, along with studies elsewhere along the belt, suggest that similar rocks may exist along much of the orogen.

Supplementary material:

U–Pb isotopic data are available at
http://www.geolsoc.org.uk/SUP18471
.
Provenance and geotectonic setting of the Palaeoproterozoic Zhongtiao Group and implications for assembly of the North China Craton: whole-rock geochemistry and detrital zircon data
Authors: Li Q. , Liu S. , Wang Z. , Shen Y. , Zhang L. , Zhang J. 
Published: August 2011

Abstract:

Geochemical data reveal the contrasting geochemical characteristics of the metasediments in the Jiepailiang and Bizigou formations of the Palaeoproterozoic Zhongtiao Group, North China Craton. High Zr/Sc and SiO
2
/Al
2
O
3
values and especially the evolved and uniform nature of
ε
Nd
(
t
) values plus detrital zircon U–Pb ages and Hf isotopic signatures for the former are consistent with derivation from an evolved felsic source with sedimentary recycling signs. However, lower values of SiO
2
/Al
2
O
3
and Zr/Sc, and higher contents of Fe
2
O
3
* and MgO for the latter indicate input of more mafic components. These geochemical characteristics, combined with the wide range of
ε
Nd
(
t
) values, suggest that these rocks were derived in part from old continental material, dominated by felsic rocks of magmatic origin, and in part from a continental island arc, which accounts for the variable mixture of mafic components. These results suggest that the Zhongtiao Group was deposited after
c
. 2110 Ma, in a back-arc basin, behind an eastward-directed subduction system. Subsequent deformation and metamorphism reflect closure of the oceanic basin between the Eastern and Western blocks of the North China Craton, along the Trans-North China Orogen, contributing to amalgamation of the supercontinental Columbia.

Supplementary material:

Data are available at
http://www.geolsoc.org.uk/SUP18478
.
Turbidite pathways, pore-fluid pressures and productivity in the Central Wales Orefield
Authors: James David M.D. 
Published: August 2011

Abstract:
Lodes in the Central Wales Orefield are mineralized oblique-slip normal faults that postdate the regional joints. They developed shortly after the (Acadian) deformation of the Welsh Basin in the late Early Devonian and many were reactivated with further mineralization in the early Carboniferous. Although orefield extent is clearly centred on the structural culmination around the Plynlimon Dome the major areas of lead–zinc production are strongly off-centered. These areas lie on the depositional pathways of three horizons of late Ordovician–early Silurian massive turbidite sandstones. It is argued that these basin-floor sand bodies are preferential sites of lode nucleation and that their distribution controls the size and abundance of the lodes and hence their chances to link laterally and at depth. This in turn controls their ability to capture and transmit mineralizing fluids and thus their chances of hosting large ore deposits. The prime cause of high fluid pressure gradients during the first phase of mineralization was rapid uplift of ‘tight' rock with dehydration fluids from Acadian metamorphism. Second phase fluids probably originated as seawater and were driven by convective overturn at essentially hydrostatic pressures. The stratigraphic control of lode productivity has implications for mineral exploration in such terranes.
Did shortening in thick crust cause rapid Late Cenozoic uplift in the northern Bolivian Andes?
Authors: Lamb Simon 
Published: August 2011

Abstract:

This study explores the role of crustal shortening as a mechanism for Late Cenozoic surface uplift in the northern Bolivian Andes between
c
. 16°S and
c
. 19°S, based on new geological cross-sections across the Corque–Corocoro basin in the Altiplano (
c
. 60 km thick crust today), and published radiometric ages of volcanic rocks, in the context of a simple 2D crustal balancing model. Deformation since
c
. 10 Ma (mainly between 10 and 6 Ma) involved 28 ± 7 km of shortening across the Corque–Corocoro basin, with a wider zone of lower crustal strain, and a total of
c
. 70 km of underthrusting in the Subandes. The uplift model is supported by dynamical analyses and is identical within 2σ error to published palaeo-elevation proxies, with 2.5 ± 0.5 km of surface uplift in the Corque–Corocoro basin since
c
. 10 Ma (1.8 ± 0.5 km between 10 and 6 Ma), and 1.6 ± 0.5 km outside the basin. In this way, the Late Cenozoic palaeo-elevation record in the northern Bolivian Andes can be explained within error entirely in terms of the Late Cenozoic crustal thickening expected for the observed history of crustal shortening.
Late Cretaceous–Palaeocene continental rifting in the High Arctic: U–Pb geochronology of the Kap Washington Group volcanic sequence, North Greenland
Authors: Thorarinsson Sigurjon B. , Holm Paul M. , Tappe Sebastian , Heaman Larry M. , Tegner Christian 
Published: August 2011

Abstract:

The Kap Washington Group volcanic sequence is exposed on the north coast of Greenland. The sequence was erupted in a continental rift setting during the opening of the Arctic Ocean and provides important geological constraints on the timing of this event. In this study we present the first isotope dilution thermal ionization mass spectrometry U–Pb zircon ages from 10 samples of trachytic to rhyolitic composition. Samples from Lockwood Island (
n
= 4) gave concordant ages between 67.2 ± 0.5 and 61.0 ± 0.3 Ma (2σ). Lavas from Kap Kane (
n
= 5) yielded concordant ages between 70.5 ± 0.3 and 69.7 ± 0.2 Ma. An ignimbrite from the Kap Washington peninsula yielded a concordant age of 68.5 ± 0.3 Ma. The Kap Washington Group sequence and similar occurrences on Ellesmere Island record a prolonged period of continental rift volcanism lasting from 92 to 58 Ma. We propose that this volcanism occurred along the margins of a nascent Eurasia Basin undergoing east–west extension linked to rifting in the Labrador Sea–Baffin Bay system.
Borehole evidence for wing-like clastic intrusion complexes on the western Norwegian margin
Authors: Jackson Christopher A.-L. , Sømme Tor O. 
Published: August 2011

Abstract:
Data from a borehole on the Norwegian margin indicate that a strata-concordant amplitude anomaly within the Upper Cretaceous succession represents a 15 m thick sandbody that was either intruded in the subsurface or extruded on the palaeo-seabed. This observation implies that spatially related, strata-discordant anomalies are the seismic expression of sandstone dykes, thereby supporting previous geometry-based interpretations of the origin of these amplitude anomalies. Furthermore, this study indicates that thickness of an intrusion may be overestimated if based solely on seismic reflection mapping, and that this may lead to erroneous calculation of the ratio between depositional and intruded sandstone.
Leveraging reconfigurability in the hardware/software codesign process
Authors: Shannon Lesley , Chow Paul 
Published: August 2011

Current technology allows designers to implement complete embedded computing systems on a single FPGA. Using an FPGA as the implementation platform introduces greater flexibility into the design process and allows a new approach to embedded system design. Since there is no cost to reprogramming an FPGA, system performance can be measured on-chip in the runtime environment and the system's architecture can be altered based on an evaluation of the data to meet design requirements.
In this article, we discuss a new hardware/software codesign methodology tailored to reconfigurable platforms and a design infrastructure created to incorporate on-chip design tools. This methodology utilizes the FPGA's reconfigurability during the design process to profile and verify system performance, thereby reducing system design time. Our current design infrastructure includes: a system specification tool, two on-chip profiling tools, and an on-chip system verification tool.