bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced cell-surface stability of rescued ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) by pharmacological chaperones
Authors: Varga Karoly , Goldstein Rebecca F. , Jurkuvenaite Asta , Chen Lan , Matalon Sadis , Sorscher Eric J. , Bebok Zsuzsa , Collawn James F. 
Published: February 2008

Misfolded proteins destined for the cell surface are recognized and degraded by the ERAD [ER (endoplasmic reticulum) associated degradation] pathway. TS (temperature-sensitive) mutants at the permissive temperature escape ERAD and reach the cell surface. In this present paper, we examined a TS mutant of the CFTR [CF (cystic fibrosis) transmembrane conductance regulator], CFTR ΔF508, and analysed its cell-surface trafficking after rescue [rΔF508 (rescued ΔF508) CFTR]. We show that rΔF508 CFTR endocytosis is 6-fold more rapid (∼30% per 2.5 min) than WT (wild-type, ∼5% per 2.5 min) CFTR at 37 °C in polarized airway epithelial cells (CFBE41o−). We also investigated rΔF508 CFTR endocytosis under two further conditions: in culture at the permissive temperature (27 °C) and following treatment with pharmacological chaperones. At low temperature, rΔF508 CFTR endocytosis slowed to WT rates (20% per 10 min), indicating that the cell-surface trafficking defect of rΔF508 CFTR is TS. Furthermore, rΔF508 CFTR is stabilized at the lower temperature; its half-life increases from &lt;2 h at 37 °C to &gt;8 h at 27 °C. Pharmacological chaperone treatment at 37 °C corrected the rΔF508 CFTR internalization defect, slowing endocytosis from ∼30% per 2.5 min to ∼5% per 2.5 min, and doubled ΔF508 surface half-life from 2 to 4 h. These effects are ΔF508 CFTR-specific, as pharmacological chaperones did not affect WT CFTR or transferrin receptor internalization rates. The results indicate that small molecular correctors may reproduce the effect of incubation at the permissive temperature, not only by rescuing ΔF508 CFTR from ERAD, but also by enhancing its cell-surface stability.
Tocopherols Modulate Extraplastidic Polyunsaturated Fatty Acid Metabolism inArabidopsisat Low Temperature
Authors: Maeda Hiroshi , Sage Tammy L. , Isaac Giorgis , Welti Ruth , DellaPenna Dean 
Published: February 2008

AbstractTocopherols (vitamin E) are synthesized in plastids and have long been assumed to have essential functions restricted to these organelles. We previously reported that the vitamin e-deficient2 (vte2) mutant of Arabidopsis thaliana is defective in transfer cell wall development and photoassimilate transport at low temperature (LT). Here, we demonstrate that LT-treated vte2 has a distinct composition of polyunsaturated fatty acids (PUFAs): lower levels of linolenic acid (18:3) and higher levels of linoleic acid (18:2) compared with the wild type. Enhanced 18:3 oxidation was not involved, as indicated by the limited differences in oxidized lipid species between LT-treated vte2 and the wild type and by a lack of impact on the LT-induced vte2 phenotype in a vte2 fad3 fad7 fad8 quadruple mutant deficient in 18:3. PUFA changes in LT-treated vte2 occur primarily in phospholipids due to reduced conversion of dienoic to trienoic fatty acids in the endoplasmic reticulum (ER) pathway. Introduction of the ER fatty acid desaturase mutation, fad2, and to a lesser extent the plastidic fad6 mutation into the vte2 background suppressed the LT-induced vte2 phenotypes, including abnormal transfer cell wall development. These results provide biochemical and genetic evidence that plastid-synthesized tocopherols modulate ER PUFA metabolism early in the LT adaptation response of Arabidopsis.
Susceptibility of Snark‐deficient mice to azoxymethane‐induced colorectal tumorigenesis and the formation of aberrant crypt foci
Authors: Tsuchihara Katsuya , Ogura Tsutomu , Fujioka Rumi , Fujii Satoshi , Kuga Wataru , Saito Marie , Ochiya Takahiro , Ochiai Atsushi , Esumi Hiroyasu 
Published: February 2008

SNF‐1/5′‐AMP‐activated kinase (AMPK)‐related kinase (SNARK) is a member of the AMPK‐related kinases. Snark+/– mice exhibited mature‐onset obesity and related metabolic disorders. Obesity is regarded as a risk factor for colorectal cancer. To investigate whether Snark deficiency is involved in tumorigenesis in the large intestine, obese Snark+/– mice were treated with a chemical carcinogen, azoxymethane (AOM). The incidences of both adenomas and aberrant crypt foci (ACF) were significantly higher in Snark+/– mice than in their wild‐type counterparts 28 weeks after the completion of AOM treatment (10 mg/kg/week for 8 weeks). Furthermore, ACF formation was enhanced in Snark+/– mice treated with AOM for 2 weeks, suggesting that Snark deficiency contributed to the early phase of tumorigenesis. The total number of ACF was correlated with bodyweight in Snark+/– and Snark+/+ mice, suggesting that obesity was a risk factor for colorectal tumorigenesis in this model. However, the correlation coefficient was higher in Snark+/– mice. Moreover, AOM‐induced ACF formation was also enhanced in preobese Snark+/– mice. Together, these findings suggest that AOM‐induced tumorigenesis in Snark+/– mice was enhanced via obesity‐dependent and ‐independent mechanisms. (Cancer Sci 2008; 99: 677–682)
Sedimentation record in the Konkan–Kerala Basin: implications for the evolution of the Western Ghats and the Western Indian passive margin
Authors: Campanile D. , Nambiar C. G. , Bishop P. , Widdowson M. , Brown R. 
Published: February 2008

ABSTRACTThe Konkan and Kerala Basins constitute a major depocentre for sediment from the onshore hinterland of Western India and as such provide a valuable record of the timing and magnitude of Cenozoic denudation along the continental margin. This paper presents an analysis of sedimentation in the Konkan–Kerala Basin, coupled with a mass balance study, and numerical modelling of flexural responses to onshore denudational unloading and offshore sediment loading in order to test competing conceptual models for the development of high‐elevation passive margins. The Konkan–Kerala Basin contains an estimated 109 000 km3of Cenozoic clastic sediment, a volume difficult to reconcile with the denudation of a downwarped rift flank onshore, and more consistent with denudation of an elevated rift flank. We infer from modelling of the isostatic response of the lithosphere to sediment loading offshore and denudation onshore infer that flexure is an important component in the development of the Western Indian Margin. There is evidence for two major pulses in sedimentation: an early phase in the Palaeocene, and a second beginning in the Pliocene. The Palaeocene increase in sedimentation can be interpreted in terms of a denudational response to the rifting between India and the Seychelles, whereas the mechanism responsible for the Pliocene pulse is more enigmatic.
Fold evolution and drainage development in the Zagros mountains of Fars province, SE Iran
Authors: Ramsey Lucy A. , Walker Richard T. , Jackson James 
Published: February 2008

ABSTRACTA central question in structural geology is whether, and by what mechanism, active faults (and the folds often associated with them) grow in length as they accumulate displacement. An obstacle in our understanding of these processes is the lack of examples in which the lateral growth of active structures can be demonstrated definitively, as geomorphic indicators of lateral propagation are often difficult, or even impossible to distinguish from the effects of varying lithology or non‐uniform displacement and slip histories. In this paper we examine, using the Zagros mountains of southern Iran as our example, the extent to which qualitative analysis of satellite imagery and digital topography can yield insight into the growth, lateral propagation, and interaction of individual fold segments in regions of active continental shortening. The Zagros fold‐and‐thrust belt contains spectacular whaleback anticlines that are well exposed in resistant Tertiary and Mesozoic limestone, are often >100 km in length, and which contain a large proportion of the global hydrocarbon reserves. In one example, Kuh‐e Handun, where an anticline is mantled by soft Miocene sediments, direct evidence of lateral fold propagation is recorded in remnants of consequent drainage patterns on the fold flanks that do not correspond to the present‐day topography. We suggest that in most other cases, the soft Miocene and Pliocene sediments that originally mantled the folds, and which would have recorded early stages in the growth histories, have been completely stripped away, thus removing any direct geomorphic evidence of lateral propagation. However, many of the long fold chains of the Zagros do appear to be formed from numerous segments that have coalesced. If our interpretations are correct, the merger of individual fold segments that have grown in length is a major control on the development of through‐going drainage and sedimentation patterns in the Zagros, and may be an important process in other regions of crustal shortening as well. Abundant earthquakes in the Zagros show that large seismogenic thrust faults must be present at depth, but these faults rarely reach the Earth's surface, and their relationship to the surface folding is not well constrained. The individual fold segments that we identify are typically 20–40 km in length, which correlates well with the maximum length of the seismogenic basement faults suggested from the largest observed thrusting earthquakes. This correlation between the lengths of individual fold segments and the lengths of seismogenic faults at depth suggest that it is possible, at least in some cases, that there may be a direct relationship between folding and faulting in the Zagros, with individual fold segments underlain by discrete thrusts.
Basin modelling of the Limón Back‐arc Basin (Costa Rica): burial history and temperature evolution of an island arc‐related basin‐system
Authors: Brandes C. , Astorga A. , Littke R. , Winsemann J. 
Published: February 2008

ABSTRACTThe Limón back‐arc basin belongs to the southern Central American arc‐trench system and is situated at the east coast of Costa Rica. The basin‐fill consists of Late Cretaceous to Pleistocene sedimentary rocks. A northern and a southern sub‐basin can be defined, separated by the E–W‐trending Trans Isthmic Fault System. The North Limón Basin is nearly undeformed, whereas the South Limón Basin is characterized by a fold‐and‐thrust belt. Both sub‐basins have a very similar sedimentary fill and can act as a natural laboratory for reconstructing controlling factors of arc‐related sedimentary basins as well as the influence of deformation on a basin system. Modelling focused on burial history and temperature evolution. Two‐dimensional simulations were carried out with the software PetroMod®. The geohistory curve of the North Limón Basin is overall linear, indicating continuous subsidence. The South Limón Basin is also characterized by continuous subsidence, but rates strongly increased at the beginning of the Neogene. Despite a rapid Plio‐Pleistocene deformation of the fold‐and‐thrust belt, the present‐day temperature field is not disturbed in that area. The modelling results indicate a mean heat flow of 60 mW m−2 for the North Limón Basin and 41 mW m−2 for the South Limón Basin. These values are low compared with other back‐arc basins. The lower values are attributed to the following effects: (1) underlying basaltic crust, (2) the lack of an initial rift phase, (3) the low extension rates, (4) absence of volcanic activity and (5) insulation effects of a thick sediment pile. The reasons for the locally lower heat flow in the southern sub‐basin can be found in the low‐angle subduction of the Cocos Ridge. Owing to the low subduction angle, the cool fore‐arc mantle‐wedge below the island‐arc is pushed backwards increasing the cooled area.
An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study
Authors: Hirt Déborah , Van Overmeire Bart , Treluyer Jean‐Marc , Langhendries Jean‐Paul , Marguglio Arnaud , Eisinger Mark J. , Schepens Paul , Urien Saïk 
Published: February 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Ibuprofen is a nonsteroidal anti‐inflammatory agent that induces closure of the patent ductus arteriosus in neonates.• Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age. WHAT THIS STUDY ADDS • A population pharmacokinetic study was performed on 66 neonates to characterize the concentration‐time courses of ibuprofen.• Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age.• A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced.• Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates.AIMSTo describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.METHODSSixty‐six neonates were treated with median daily doses of 10, 5 and 5 mg kg−1 of ibuprofen‐lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.RESULTSIbuprofen pharmacokinetics were described by a one‐compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h−1 (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)1.49. AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l−1 h (or AUC3D < 900 mg l−1 h) and in 91% when AUC1D > 600 mg l−1 h (or AUC3D > 900 mg l−1 h) (P = 0.006). No correlation between AUC and side‐effects could be demonstrated.CONCLUSIONSTo achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg−1 for neonates younger than 70 h, 14, 7, 7 mg kg−1 for neonates between 70 and 108 h and 18, 9, 9 mg kg−1 for neonates between 108 and 180 h.
Fluctuations in circumpolar seabird populations linked to climate oscillations
Authors: IRONS DAVID B. , ANKER‐NILSSEN TYCHO , GASTON ANTHONY J. , BYRD G. VERNON , FALK KNUD , GILCHRIST GRANT , HARIO MARTTI , HJERNQUIST MÅNS , KRASNOV YURI V. , MOSBECH ANDERS , OLSEN BERGUR , PETERSEN AEVAR , REID JAMES B. , ROBERTSON GREGORY J. , STRØM HALLVARD , WOHL KENTON D. 
Published: February 2008

AbstractWe found that synchronous fluctuations of two congeneric seabird species across the entire Arctic and sub‐Arctic regions were associated with changes in sea surface temperatures (SST) that were linked to two climate shifts, in 1977 and again in 1989. As the SST changes linked to climate shifts were congruent at the scale of ocean basins, fluctuations of these species occurred similarly at continental or basin scale. Changes in colony sizes were examined for a decade following climate shifts. The magnitude of the SST shift was more important than its direction in determining the subsequent rate of population change. Seabirds declined when the SST shift was large and increased when the shift was small, although the effect differed between the Arctic‐breeding species and the more temperate‐breeding congener. The Arctic species, Thick‐billed Murre (Uria lomvia) increased most rapidly when SST warmed slightly, while the temperate species, Common Murre (Uria aalge) showed most rapid increase with moderate cooling. Both showed negative trends with large temperature shifts in either direction. This pattern was replicated during both climate oscillations. Negative population trends in seabirds presumably indicate the alteration of underlying food webs. Hence, similar widespread fluctuations in response to climate shifts are likely for other ecosystem components (marine mammals, fish, and invertebrates).
Effects of vegetation control on ecosystem water use efficiency within and among four grassland ecosystems in China
Authors: HU ZHONGMIN , YU GUIRUI , FU YULING , SUN XIAOMIN , LI YINGNIAN , SHI PEILI , WANG YANFEN , ZHENG ZEMEI 
Published: February 2008

AbstractThrough 2–3‐year (2003–2005) continuous eddy covariance measurements of carbon dioxide and water vapor fluxes, we examined the seasonal, inter‐annual, and inter‐ecosystem variations in the ecosystem‐level water use efficiency (WUE, defined as the ratio of gross primary production, GPP, to evapotranspiration, ET) at four Chinese grassland ecosystems in the Qinghai‐Tibet Plateau and North China. Representing the most prevalent grassland types in China, the four ecosystems are an alpine swamp meadow ecosystem, an alpine shrub‐meadow ecosystem, an alpine meadow‐steppe ecosystem, and a temperate steppe ecosystem, which illustrate a water availability gradient and thus provide us an opportunity to quantify environmental and biological controls on ecosystem WUE at different spatiotemporal scales. Seasonally, WUE tracked closely with GPP at the four ecosystems, being low at the beginning and the end of the growing seasons and high during the active periods of plant growth. Such consistent correspondence between WUE and GPP suggested that photosynthetic processes were the dominant regulator of the seasonal variations in WUE. Further investigation indicated that the regulations were mainly due to the effect of leaf area index (LAI) on carbon assimilation and on the ratio of transpiration to ET (T/ET). Besides, except for the swamp meadow, LAI also controlled the year‐to‐year and site‐to‐site variations in WUE in the same way, resulting in the years or sites with high productivity being accompanied by high WUE. The general good correlation between LAI and ecosystem WUE indicates that it may be possible to predict grassland ecosystem WUE simply with LAI. Our results also imply that climate change‐induced shifts in vegetation structure, and consequently LAI may have a significant impact on the relationship between ecosystem carbon and water cycles in grasslands.
Dependence of surface monoclonal antibody binding on dynamic changes in FcγRIIb expression
Authors: Walker Jennifer A. , Smith Kenneth G. C. 
Published: February 2008

SummaryReceptors for the Fc region of immunoglobulin G (FcγRs) are expressed on a broad range of haematopoietic cell types and are responsible for regulating antibody production and linking the humoral and effector responses. In response to a number of stimuli, such as cytokine signals or inflammation, FcγR expression at the cell surface is dynamically regulated. On B cells, we observed what appeared to be a correlation between CD22 expression and FcγRIIb expression when the latter was varied in a number of models. Further investigation revealed that this was specific to a particular anti‐CD22 monoclonal antibody, which appeared to require stabilization by interaction with FcγRIIb for optimal binding to CD22. Since alterations in the regulation of FcγR expression are important in controlling immune responses and have been associated with a number of immune‐mediated disease states, we suggest that it might be prudent to confirm the expression of cell surface markers by two independent methods. Furthermore, because the efficacy of therapeutic antibodies may depend upon their interaction with FcγRs, our results are relevant to their design and assessment.
Distinct in vivo roles of CD80 and CD86 in the effector T‐cell responses inducing antigen‐induced arthritis
Authors: Odobasic Dragana , Leech Michelle T. , Xue Jin R. , Holdsworth Stephen R. 
Published: February 2008

SummaryCD80 and CD86 play a critical role in the initiation of T‐cell responses. However, their role in the in vivo effector CD4+ T‐cell responses has been less extensively investigated. The current studies have examined the functional relevance of CD80 and CD86 in the effector CD4+ T‐cell responses inducing antigen‐induced arthritis. Arthritis was induced in C57BL/6 mice by sensitization to methylated bovine serum albumin (mBSA) on day 0, booster immunization (day 7) and intra‐articular injection of mBSA (day 21). Control or anti‐CD80 and/or anti‐CD86 monoclonal antibodies were administered from day 21 to day 28. Arthritis severity and immune responses were assessed on day 28. The development of arthritis was significantly suppressed by inhibition of CD80 or CD86. Blockade of both CD80 and CD86 caused a trend towards reduced disease severity compared to control antibody‐treated mice. Neutralization of CD80 attenuated accumulation of CD4+ T cells in joints and enhanced splenocyte production and circulating levels of interleukin‐4. Inhibition of CD86 or both CD80 and CD86 reduced T‐cell accumulation in joints without affecting T helper type 1/type 2 (Th1/Th2) differentiation or antibody levels. Blockade of CD86, and not CD80, significantly suppressed splenocyte interleukin‐17 (IL‐17) production. These results provide further in vivo evidence that CD80 and CD86 play important pathogenic roles in effector T‐cell responses. CD80 exacerbates arthritis by downregulating systemic levels of IL‐4 and increasing T‐cell accumulation in joints without affecting IL‐17 production. CD86 enhances disease severity by upregulating IL‐17 production and increasing the accumulation of effector T cells in joints without affecting Th1/Th2 development.
Spatial pattern formation facilitates eradication of infectious diseases
Authors: Eisinger Dirk , Thulke Hans‐Hermann 
Published: February 2008

Summary

Control of animal‐born diseases is a major challenge faced by applied ecologists and public health managers. To improve cost‐effectiveness, the effort required to control such pathogens needs to be predicted as accurately as possible. In this context, we reviewed the anti‐rabies vaccination schemes applied around the world during the past 25 years.
We contrasted predictions from classic approaches based on theoretical population ecology (which governs rabies control to date) with a newly developed individual‐based model. Our spatially explicit approach allowed for the reproduction of pattern formation emerging from a pathogen's spread through its host population.
We suggest that a much lower management effort could eliminate the disease than that currently in operation. This is supported by empirical evidence from historic field data. Adapting control measures to the new prediction would save one‐third of resources in future control programmes.
The reason for the lower prediction is the spatial structure formed by spreading infections in spatially arranged host populations. It is not the result of technical differences between models.
Synthesis and applications. For diseases predominantly transmitted by neighbourhood interaction, our findings suggest that the emergence of spatial structures facilitates eradication. This may have substantial implications for the cost‐effectiveness of existing disease management schemes, and suggests that when planning management strategies consideration must be given to methods that reflect the spatial nature of the pathogen–host system.