| 42311. |
- Köhler, S.J., et al.
(författare)
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Climate's control of intra-annual and interannual variability of total organic carbon concentration and flux in two contrasting boreal landscape elements
- 2008
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Ingår i: Journal of Geophysical Research - Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953 .- 2169-8961. ; 113:G3
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Tidskriftsartikel (refereegranskat)abstract
- [1] Large spatial and temporal variations in stream total organic carbon (TOC) concentration and export occurred during an 11-year observation period (1993-2003) in a boreal headwater catchment. TOC flux and concentration patterns from mire- and forest-dominated subcatchments differed ( mean annual flux 8.2 g m(-2)a(-1) versus 5.8 g m(-2) a(-1)). Temporal variations in stream TOC concentrations in both landscape types were primarily driven by variations in streamflow, with the mire stream generally diluting by half with increased runoff during spring flood and TOC from the forested landscape increasing during runoff peaks irrespective of season. Average TOC concentration in the mire stream in the snow-free season increased with increased seasonal precipitation from around 20 to 40 mg L-1 but then dropped to around 35 mg L-1 during very wet years. Average snow-free season TOC concentration at the forested site remained stable when summer precipitation was below average but then increased from 10 to around 25 mg L-1 during exceptionally wet years. For both the forested subcatchment and the whole catchment, TOC concentrations increased during the warm summer months during wet years, but no such increase occurred during dry years. Interannual variations in TOC flux were primarily driven by variations during the snow-free period. Wet years decreased the relative TOC export from the mire and favored the relative export of TOC from areas dominated by forest, an observation that also held true on a larger scale when similar landscape types were considered. Predicted climate change in rainfall and temperature patterns will affect the amount and character of TOC exported downstream from boreal landscapes with a mix of forest and mire.
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| 42312. |
- Köhler, Stephan, et al.
(författare)
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Landscape types and pH control organic matter mediated mobilization of Al, Fe, U and La in boreal catchments
- 2014
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Ingår i: Geochimica et Cosmochimica Acta. - : Elsevier BV. - 0016-7037 .- 1872-9533 .- 0046-564X. ; 135, s. 190-202
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Tidskriftsartikel (refereegranskat)abstract
- In this study we present data from a seven-year time series from 15 nested streams within a 68 km(2) catchment, covering a pH gradient of almost three units. We demonstrate that the two landscape types, forest and wetlands, control the relative mobilization of Al and Fe in this boreal landscape. The La/U ratio is almost constant across the whole catchment despite large variations in pH, Al/Fe and TOC, whereas U and La mobilization increases with increasing contribution of deeper soils and groundwater further downstream. High Al/TOC ratios in the forested catchments suggest that Al originates from the underlying mineral soils, and low Al/TOC ratios derive from wetlands where Al is retained. We observe a competition effect on the binding to TOC between Al and La and also that the relationship between TOC, Al and La changes from the smaller (0.05-2 km(2)) catchments to larger (3-68 km(2)) downstream locations. As pH increase downstream, Al and Fe are gradually removed from the aqueous phase by precipitation of particulate gibbsite-like phases and ferrihydrite. This selective removal of Al and Fe from TOC binding sites results in higher La, and U concentrations downstream. Observed element patterns (U, La) and the range of upper continental crust normalized (La/Nd)(UCC) and (La/Yb)(UCC) in the near stream, riparian zone were very similar to the observed ratios across the whole catchment. The rising (La/Nd)(UCC) over (La/Yb)(UCC) may be due to a selective removal of REE binding to ferrihydrate in the riparian soil, the result of two distinctly different end-members but most probably not due to the in-stream precipitation of ferrihydrate or gibbsite-like phases.
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| 42313. |
- Köhn, Linda, 1979-, et al.
(författare)
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Breakpoint characterization of a novel ~59 kb genomic deletion on 19q13.42 in autosomal dominant retinitis pigmentosa with reduced penetrance
- 2009
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Ingår i: European Journal of Human Genetics. - : Nature publishing group. - 1018-4813 .- 1476-5438. ; 17:5, s. 651-655
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.
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| 42314. |
- Köhn, Linda, et al.
(författare)
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Breakpoint characterization of a novel approximately 59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance.
- 2009
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 17:5, s. 651-655
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.
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| 42315. |
- Köhn, Linda, 1979-, et al.
(författare)
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Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1
- 2008
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology. - 0146-0404 .- 1552-5783. ; 49:7, s. 3172-3177
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Bothnia dystrophy (BD) is an autosomal recessive retinitis pigmentosa (arRP) associated with the c.700C>T mutation in the RLBP1 gene. Testing of patients with BD has revealed the c.700C>T mutation on one or both alleles. The purpose of this study was to elucidate the underlying genetic mechanisms along with a clinical evaluation of the heterozygous patients with BD.Methods: Patients with BD heterozygous for the RLBP1 c.700C>T were tested for 848 mutations by arrayed primer-extension technology. Further mutation detection was performed by PCR-restriction fragment length polymorphism (RFLP), sequencing, denaturing (d)HLPC and allelic discrimination. The ophthalmic examinations were performed in all c.700C>T heterozygotes.Results: The clinical findings in 10 BD heterozygotes were similar to those in the homozygotes. The presence of a second mutation, c.677T>A, corresponding to p.M226K was detected in all 10 cases. Segregation analysis showed that the mutations were allelic, and the patients were compound heterozygotes [c.677T>A]+[c.700C>T]. One of those patients was also a carrier of the c.40C>T corresponding to the p.R14W change in carbonic anhydrase IV (CAIV) associated with autosomal dominant RP, RP17. His mother, a carrier of the identical change was declared healthy after ophthalmic examination. This sequence variant was found in 6 of 143 tested blood donors.Conclusions: The high frequency of arRP in northern Sweden is due to two mutations in the RLBP1 gene: c.677T>A and c.700C>T. BD is caused by the loss of CRALBP function due to changed physical features and impaired activity of retinoid binding. The CAIV p.R14W sequence variant found in one of the patients with a BD phenotype is a benign polymorphism in a population of northern Sweden.
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| 42316. |
- Köhn, Linda, 1979-
(författare)
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Genetic mapping of retinal degenerations in Northern Sweden
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inherited retinal degenerations are a group of disorders characterised by great genetic heterogeneity. Clinically, they can be divided into two large groups of diseases, those associated with night blindness, e.g. retinitis pigmentosa (RP), and those with macular malfunction, e.g. cone/cone-rod dystrophy (COD/CORD). This thesis is focused on finding the genetic basis of disease in families with autosomal dominant COD, autosomal dominant RP, and Bothnia dystrophy (BD), a regional variant of RP. A variant of COD was previously mapped to 17p12-p13 in a family from northern Sweden. One additional family originating from the same geographical area was included in fine mapping of this chromosome region. Using 12 microsatellite markers in linkage and haplotype analysis, the region was refined from 26.9 to 14.3 cM. A missense mutation, Q626H, in an evolutionarily conserved region of PITPNM3, phosphatidylinositol transfer membrane-associated protein, was identified. The mutation segregated with the disease in both families and was absent from normal control chromosomes. PITPNM3 is a human homologue of the Drosophila retinal degeneration (rdgB) protein, which is highly expressed in the retina and has been proposed to be required for membrane turnover of photoreceptor cells. With the intention of establishing the global impact that PITPNM3 has on retinal degenerations 165 DNA samples from COD and CORD patients were obtained from Denmark, Germany, the UK, and USA and screened for mutations. The Q626H mutation found in the Swedish families was also found in one British family and a novel Q342P variant was detected in a German patient. In addition, two intronic variants were identified: c.900+60C>T and c.901-45G>A. Thus, we concluded that mutations in PITPNM3 represent a rare cause of COD worldwide. In two large families from northern Sweden showing autosomal dominant RP with reduced penetrance, the disease locus was mapped using genome-wide linkage analysis to 19q13.42 (RP11). Since mutation screening of eight genes on 19q13.42 revealed no mutations, multiplex ligation-dependent probe amplification (MLPA) was used to screen for large genomic abnormalities in PRPF31, RHO, RP1, RPE65, and IMPDH1. A large deletion spanning 11 exons of PRPF31 and three genes upstream was identified. Using long-range PCR, the breakpoints of the deletion were identified and the size of the deletion was determined to encompass almost 59 kb. BD is an autosomal recessive type of RP with high prevalence in northern Sweden. The disease is associated with a c.700C>T mutation in RLBP1. In a screening of recessive RP in northern Sweden, 67 patients were found to be homozygous for c.700C>T and 10 patients were heterozygous. An evaluation with arrayed primer extension (APEX) technology revealed a second mutation, c.677T>A, in RLBP1 giving rise to compound heterozygosity in these patients. In addition, a c.40C>T exchange in CAIV was detected in a patient with BD and in 143 healthy blood donors. The c.40C>T substitution in CAIV has been reported to cause autosomal dominant RP in South African families with European ancestry. However, in the population of northern Sweden it appears to be a benign polymorphism. In summary, a first mutation in PITPNM3, encoding a human homologue of the Drosophila retinal degeneration protein, was detected in two large families with COD. A large deletion in PRPF31 was discovered in two families with autosomal dominant RP showing reduced penetrance and in 10 patients BD was shown to be caused by two allelic mutations in RLBP1.
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| 42317. |
- Köhn, Linda, et al.
(författare)
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Liquid biopsies in lung cancer : time to implement research technologies in routine care?
- 2017
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Ingår i: Annals of Translational Medicine. - : AME Publishing Company. - 2305-5839 .- 2305-5847. ; 5:13
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Forskningsöversikt (refereegranskat)abstract
- Lung cancer is the leading cause of cancer mortality. A substantial progress in the understanding of lung cancer biology has resulted in several promising targeted therapies for advanced disease. Druggable targets today include point mutations such as EGFR, BRAF and re-arrangements in genes such as ALK and ROS1. Liquid biopsies collecting e.g., circulating tumor DNA (ctDNA) reflects overall tumor information and is not biased by analyzing of only a small fraction of the tumor and is always accessible in contrast to the lung cancer tissue. Technological advances in detection of low frequency mutation variants in ctDNA have made it the dominating liquid biopsy platform in terms of utility and sensitivity. Circulating DNA or RNA may possible be used to define populations with higher risk of developing lung cancer, thus reducing screening cohorts and increasing the positive predictive value of screening. Blood based-tests may also aid to identify genetic alterations several weeks prior to radiologically verified recurrence and may be of great value in the follow-up of lung cancer patients. Besides being an alternative to invasive biopsies in selected cases, liquid biopsies offer a unique possibility to monitor treatment response following medical treatment as well as treatment response and resistance development after targeted therapy, giving a possibility to modify the treatment after the genetic profile of the tumor. Ideally, genetic alterations found in ctDNA could be tracked in real-time discriminating between fast-growing life-threatening tumors from more indolent slow growing tumors or premalignant growth that are of no concern for the wellbeing of the patient. This review focuses on future perspectives of liquid biopsies in lung cancer care for different clinical settings and present current technological platforms for further discussion of possible strategies for implementation of liquid biopsies in lung cancer.
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| 42318. |
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| 42319. |
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| 42320. |
- Köhn, Linda, 1979-, et al.
(författare)
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Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families
- 2007
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Ingår i: European Journal of Human Genetics. - : Nature publishing group. - 1018-4813 .- 1476-5438. ; 15:6, s. 664-671
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal dominant cone dystrophy (CORD5) (MIM 600977) is a rare disease predominantly affecting cone photoreceptors. Here we refine the CORD5 locus previously mapped to 17p13 from 27 to 14.3 cM and identified a missense mutation, Q626H in the phosphatidylinositol transfer (PIT) membrane-associated protein (PITPNM3) (MIM 608921) in two Swedish families. PITPNM3, known as a human homologue of the Drosophila retinal degeneration B (rdgB), lacks the N-terminal PIT domain needed for transport of phospholipids, renewal of photoreceptors membrane and providing the electroretinogram (ERG) response to light. In our study, the mutation causing CORD5 is located in the C-terminal region interacting with a member of nonreceptor protein tyrosine kinases, PYK2. Our finding on the first mutation in the human homologue of Drosophila rdgB indicates novel pathways and a potential important role of the PITPNM3 in mammalian phototransduction.
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