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- Artigas Soler, María, et al.
(författare)
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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- Svensson, Gunilla, et al.
(författare)
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Evaluation of the Diurnal Cycle in the Atmospheric Boundary Layer Over Land as Represented by a Variety of Single-Column Models : The Second GABLS Experiment
- 2011
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Ingår i: Boundary-layer Meteorology. - : Springer Science and Business Media LLC. - 0006-8314 .- 1573-1472. ; 140:2, s. 177-206
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Tidskriftsartikel (refereegranskat)abstract
- We present the main results from the second model intercomparison within the GEWEX (Global Energy and Water cycle EXperiment) Atmospheric Boundary Layer Study (GABLS). The target is to examine the diurnal cycle over land in today's numerical weather prediction and climate models for operational and research purposes. The set-up of the case is based on observations taken during the Cooperative Atmosphere-Surface Exchange Study-1999 (CASES-99), which was held in Kansas, USA in the early autumn with a strong diurnal cycle with no clouds present. The models are forced with a constant geostrophic wind, prescribed surface temperature and large-scale divergence. Results from 30 different model simulations and one large-eddy simulation (LES) are analyzed and compared with observations. Even though the surface temperature is prescribed, the models give variable near-surface air temperatures. This, in turn, gives rise to differences in low-level stability affecting the turbulence and the turbulent heat fluxes. The increase in modelled upward sensible heat flux during the morning transition is typically too weak and the growth of the convective boundary layer before noon is too slow. This is related to weak modelled near-surface winds during the morning hours. The agreement between the models, the LES and observations is the best during the late afternoon. From this intercomparison study, we find that modelling the diurnal cycle is still a big challenge. For the convective part of the diurnal cycle, some of the first-order schemes perform somewhat better while the turbulent kinetic energy (TKE) schemes tend to be slightly better during nighttime conditions. Finer vertical resolution tends to improve results to some extent, but is certainly not the solution to all the deficiencies identified.
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- Ek, Weronica E, et al.
(författare)
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Germline genetic contributions to risk for esophageal adenocarcinoma, barrett's esophagus, and gastroesophageal reflux
- 2013
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 105:22, s. 1711-1718
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Tidskriftsartikel (refereegranskat)abstract
- Background Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. Methods We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h2 g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were twosided, except in the case of variance-explained estimation where one-sided tests were used. Results We estimated a statistically significant genetic variance explained for BE (h2 g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10-9) and for EA (h2 g = 25 %; SE = 5%; one-sided P = 2 × 10-7). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10-6), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. Conclusions We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases. © The Author 2013.
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- Saunders, N. R., et al.
(författare)
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Age-Dependent Transcriptome and Proteome Following Transection of Neonatal Spinal Cord of Monodelphis domestica (South American Grey Short-Tailed Opossum)
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- This study describes a combined transcriptome and proteome analysis of Monodelphis domestica response to spinal cord injury at two different postnatal ages. Previously we showed that complete transection at postnatal day 7 (P7) is followed by profuse axon growth across the lesion with near-normal locomotion and swimming when adult. In contrast, at P28 there is no axon growth across the lesion, the animals exhibit weight-bearing locomotion, but cannot use hind limbs when swimming. Here we examined changes in gene and protein expression in the segment of spinal cord rostral to the lesion at 24 h after transection at P7 and at P28. Following injury at P7 only forty genes changed (all increased expression); most were immune/inflammatory genes. Following injury at P28 many more genes changed their expression and the magnitude of change for some genes was strikingly greater. Again many were associated with the immune/inflammation response. In functional groups known to be inhibitory to regeneration in adult cords the expression changes were generally muted, in some cases opposite to that required to account for neurite inhibition. For example myelin basic protein expression was reduced following injury at P28 both at the gene and protein levels. Only four genes from families with extracellular matrix functions thought to influence neurite outgrowth in adult injured cords showed substantial changes in expression following injury at P28: Olfactomedin 4 (Olfm4, 480 fold compared to controls), matrix metallopeptidase (Mmp1, 104 fold), papilin (Papln, 152 fold) and integrin alpha 4 (Itga4, 57 fold). These data provide a resource for investigation of a priori hypotheses in future studies of mechanisms of spinal cord regeneration in immature animals compared to lack of regeneration at more mature stages.
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- Bosveld, Fred C., et al.
(författare)
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The Third GABLS Intercomparison Case for Evaluation Studies of Boundary-Layer Models. Part B : Results and Process Understanding
- 2014
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Ingår i: Boundary-layer Meteorology. - : Springer Science and Business Media LLC. - 0006-8314 .- 1573-1472. ; 152:2, s. 157-187
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Tidskriftsartikel (refereegranskat)abstract
- We describe and analyze the results of the third global energy and water cycle experiment atmospheric boundary layer Study intercomparison and evaluation study for single-column models. Each of the nineteen participating models was operated with its own physics package, including land-surface, radiation and turbulent mixing schemes, for a full diurnal cycle selected from the Cabauw observatory archive. By carefully prescribing the temporal evolution of the forcings on the vertical column, the models could be evaluated against observations. We focus on the gross features of the stable boundary layer (SBL), such as the onset of evening momentum decoupling, the 2-m minimum temperature, the evolution of the inertial oscillation and the morning transition. New process diagrams are introduced to interpret the variety of model results and the relative importance of processes in the SBL; the diagrams include the results of a number of sensitivity runs performed with one of the models. The models are characterized in terms of thermal coupling to the soil, longwave radiation and turbulent mixing. It is shown that differences in longwave radiation schemes among the models have only a small effect on the simulations; however, there are significant variations in downward radiation due to different boundary-layer profiles of temperature and humidity. The differences in modelled thermal coupling to the land surface are large and explain most of the variations in 2-m air temperature and longwave incoming radiation among models. Models with strong turbulent mixing overestimate the boundary-layer height, underestimate the wind speed at 200 m, and give a relatively large downward sensible heat flux. The result is that 2-m air temperature is relatively insensitive to turbulent mixing intensity. Evening transition times spread 1.5 h around the observed time of transition, with later transitions for models with coarse resolution. Time of onset in the morning transition spreads 2 h around the observed transition time. With this case, the morning transition appeared to be difficult to study, no relation could be found between the studied processes, and the variation in the time of the morning transition among the models.
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- Liddelow, S. A., et al.
(författare)
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Mechanisms That Determine the Internal Environment of the Developing Brain: A Transcriptomic, Functional and Ultrastructural Approach
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- We provide comprehensive identification of embryonic (E15) and adult rat lateral ventricular choroid plexus transcriptome, with focus on junction-associated proteins, ionic influx transporters and channels. Additionally, these data are related to new structural and previously published permeability studies. Results reveal that most genes associated with intercellular junctions are expressed at similar levels at both ages. In total, 32 molecules known to be associated with brain barrier interfaces were identified. Nine claudins showed unaltered expression, while two claudins (6 and 8) were expressed at higher levels in the embryo. Expression levels for most cytoplasmic/regulatory adaptors (10 of 12) were similar at the two ages. A few junctional genes displayed lower expression in embryos, including 5 claudins, occludin and one junctional adhesion molecule. Three gap junction genes were enriched in the embryo. The functional effectiveness of these junctions was assessed using blood-delivered water-soluble tracers at both the light and electron microscopic level: embryo and adult junctions halted movement of both 286Da and 3kDa molecules into the cerebrospinal fluid (CSF). The molecular identities of many ion channel and transporter genes previously reported as important for CSF formation and secretion in the adult were demonstrated in the embryonic choroid plexus (and validated with immunohistochemistry of protein products), but with some major age-related differences in expression. In addition, a large number of previously unidentified ion channel and transporter genes were identified for the first time in plexus epithelium. These results, in addition to data obtained from electron microscopical and physiological permeability experiments in immature brains, indicate that exchange between blood and CSF is mainly transcellular, as well-formed tight junctions restrict movement of small water-soluble molecules from early in development. These data strongly indicate the brain develops within a well-protected internal environment and the exchange between the blood, brain and CSF is transcellular and not through incomplete barriers.
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- Olshammar, M, et al.
(författare)
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Fallstudie — Avgiftssystem fosfor och kväve för kommunala avloppsreningsverk
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I denna studie undersöks effekter av ett avgiftssystem för utsläpp av kväve och fosfor från avloppsreningsverk som bygger på samma principer som det svenska NOx-systemet för förbränningsanläggningar, vilket innebär att en avgift tas ut per kg utsläppt fosfor och kväve. Pengar betalas sedan tillbaka till avloppsreningsverken utifrån en återföringsnyckel.Avgiftssystemet utvärderades i Mälarens och Mörrumsåns avrinningsområden, samt vid utvalda avloppsreningsverk. Studien baseras till största delen på kontakter med ett 20-tal kommunala avloppsreningsverk där frågor om verkens teknik och aktuella data diskuterades. Ett syfte har varit att teoretiskt jämföra effekten av avgiftssystemet vid olika avgiftsnivåer med Baltic Sea Action Plan-betinget för Sveriges havsbassänger genom att skala upp resultaten inom Norra Östersjöns vattendistrikt. Resultaten i studien talar för att en avgift på 200 kr/kg kväve med bred marginal skulle uppfylla BSAP-målet att minska belastningen på havet med 3 000 ton årligen. Kostnaden för detta skulle emellertid bli likartad ett system med generella reningskrav och denna avgiftsnivå skulle innebära stora investeringar för många reningsverk. Vid en avgift på 75 kr/kg N skulle en kvävereduktion på ca 2 100 ton kväve/år kunna nås — dvs. ca 70 % av målet. I kombination med omprövningar av tillstånd som ändå kommer att ske för vissa reningsverk, för att klara vattenförvaltningens krav på god ekologisk status i recipienterna, är sannolikt ett system med en avgift på 75 kg/kg N ett kostnadseffektivt sätt att uppnå såväl BSAP som övriga miljömål. För fosfor är det troligt att man redan idag utan ytterligare åtgärder kommer att klara det uppsatta målet att minska utsläppen med minst 15 ton/år.
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- Su, Zhan, et al.
(författare)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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- Ek, C. Joakim, et al.
(författare)
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Barriers in the developing brain and Neurotoxicology
- 2012
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X. ; 33:3, s. 586-604
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Tidskriftsartikel (refereegranskat)abstract
- The brain develops and grows within a well-controlled internal environment that is provided by cellular exchange mechanisms in the interfaces between blood, cerebrospinal fluid and brain. These are generally referred to by the term "brain barriers": blood-brain barrier across the cerebral endothelial cells and blood-CSF barrier across the choroid plexus epithelial cells. An essential component of barrier mechanisms is the presence of tight junctions between the endothelial and epithelial cells of these interfaces. This review outlines historical evidence for the presence of effective barrier mechanisms in the embryo and newborn and provides an up to date description of recent morphological, biochemical and molecular data for the functional effectiveness of these barriers. Intercellular tight junctions between cerebral endothelial cells and between choroid plexus epithelial cells are functionally effective as soon as they differentiate. Many of the influx and efflux mechanisms are not only present from early in development, but the genes for some are expressed at much higher levels in the embryo than in the adult and there is physiological evidence that these transport systems are functionally more active in the developing brain. This substantial body of evidence supporting the concept of well developed barrier mechanisms in the developing brain is contrasted with the widespread belief amongst neurotoxicologists that "the" blood-brain barrier is immature or even absent in the embryo and newborn. A proper understanding of the functional capacity of the barrier mechanisms to restrict the entry of harmful substances or administered therapeutics into the developing brain is critical. This knowledge would assist the clinical management of pregnant mothers and newborn infants and development of protocols for evaluation of risks of drugs used in pregnancy and the neonatal period prior to their introduction into clinical practice. (c) 2011 Elsevier Inc. All rights reserved.
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| 39. |
- Ek, C. Joakim, et al.
(författare)
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Pathological Changes in the White Matter after Spinal Contusion Injury in the Rat
- 2012
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- It has been shown previously that after spinal cord injury, the loss of grey matter is relatively faster than loss of white matter suggesting interventions to save white matter tracts offer better therapeutic possibilities. Loss of white matter in and around the injury site is believed to be the main underlying cause for the subsequent loss of neurological functions. In this study we used a series of techniques, including estimations of the number of axons with pathology, immunohistochemistry and mapping of distribution of pathological axons, to better understand the temporal and spatial pathological events in white matter following contusion injury to the rat spinal cord. There was an initial rapid loss of axons with no detectable further loss beyond 1 week after injury. Immunoreactivity for CNPase indicated that changes to oligodendrocytes are rapid, extending to several millimetres away from injury site and preceding much of the axonal loss, giving early prediction of the final volume of white matter that survived. It seems that in juvenile rats the myelination of axons in white matter tracts continues for some time, which has an important bearing on interpretation of our, and previous, studies. The amount of myelin debris and axon pathology progressively decreased with time but could still be observed at 10 weeks after injury, especially at more distant rostral and caudal levels from the injury site. This study provides new methods to assess injuries to spinal cord and indicates that early interventions are needed for the successful sparing of white matter tracts following injury.
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- Tiblad, E, et al.
(författare)
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Procedure-related complications and perinatal outcome after intrauterine transfusions in red cell alloimmunization in Stockholm
- 2011
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Ingår i: Fetal diagnosis and therapy. - : S. Karger AG. - 1421-9964 .- 1015-3837. ; 30:4, s. 266-273
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Tidskriftsartikel (refereegranskat)abstract
- <i>Introduction:</i> We present a review of all cases of intravascular transfusions in red cell alloimmunization over a time span of 20 years in Stockholm. The aim of the study is to compare our results with published results from larger centers and to identify areas that can be further improved. <i>Material and Methods:</i> A retrospective cohort study was conducted of all women treated with intrauterine transfusions due to erythrocyte immunization in our hospital between June 1990 and June 2010. Primary outcome variables were fetal and neonatal survival, procedure-related complications and gestational age at delivery. <i>Results:</i> A total of 284 intrauterine transfusions were performed in 84 pregnancies, with an overall survival rate of 91.8%. Procedure-related and fatal complications occurred in the present study in 4.9 and 1.4% of fetuses or neonates, respectively. Procedure-related complications were significantly more common in free-loop transfusions than in transfusions in the intrahepatic part of the umbilical vein (OR: 5.4, p = 0.025). There was no significant difference between the intrahepatic and the placental cord insertion route (p = 0.83). Gestational age at first transfusion was significantly associated with an increased risk of a procedure-related complication (OR: 0.8, p = 0.019). Of the live-born infants, 24% of the neonates were born before gestational week 34. <i>Discussion:</i> Our study confirms previous studies demonstrating favorable results with intravascular transfusions.
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