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- Lundtoft, Christian, et al.
(författare)
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Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjogren's Syndrome
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:11, s. 1842-1850
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Tidskriftsartikel (refereegranskat)abstract
- Objective Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjogren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 x 10(-9)) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Conclusion We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.
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- Analatos, Apostolos, et al.
(författare)
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Tension-free mesh versus suture-alone cruroplasty in antireflux surgery : a randomized, double-blind clinical trial
- 2020
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Ingår i: British Journal of Surgery. - : John Wiley & Sons. - 0007-1323 .- 1365-2168. ; 107:13, s. 1731-1740
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAntireflux surgery is effective for the treatment of gastro-oesophageal reflux disease (GORD) but recurrence of hiatal hernia remains a challenge. In other types of hernia repair, use of mesh is associated with reduced recurrence rates. The aim of this study was to compare the use of mesh versus sutures alone for the repair of hiatal hernia in laparoscopic antireflux surgery.MethodsPatients undergoing laparoscopic Nissen fundoplication for GORD between January 2006 and December 2010 were allocated randomly to closure of the diaphragmatic hiatus with crural sutures or non-absorbable polytetrafluoroethylene mesh (CruraSoft®). The primary outcome was recurrence of hiatal hernia, as determined by barium swallow study 12 months after surgery. Secondary outcomes were: intraoperative and postoperative complications, use of antireflux medication, postoperative oesophageal acid exposure, quality of life, dysphagia and duration of hospital stay.ResultsSome 77 patients were randomized to the suture technique and 82 patients underwent mesh repair. At 1 year, the hiatal hernia had recurred in six of 64 patients (9 per cent) in the mesh group and two of 64 (3 per cent) in the suture group (P = 0·144). Reflux symptoms, use of proton pump inhibitors and oesophageal acid exposure did not differ between the groups. At 3 years, recurrence rates were 13 and 10 per cent in the mesh and suture groups respectively (P = 0·692). Dysphagia scores decreased in both groups, but more patients had dysphagia for solid food after mesh closure (P = 0·013). Quality-of-life scores were comparable between the groups.ConclusionTension-free crural repair with non-absorbable mesh does not reduce the incidence of recurrent hiatal hernia compared with use of sutures alone in patients undergoing laparoscopic fundoplication. NCT03730233 (http://www.clinicaltrials.gov).
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- Berggren, Elin, et al.
(författare)
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Charge Transfer in the P(g42T-T) : BBL Organic Polymer Heterojunction Measured with Core-Hole Clock Spectroscopy
- 2023
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Ingår i: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 127:49, s. 23733-23742
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Tidskriftsartikel (refereegranskat)abstract
- The conductivity of organic polymer heterojunction devices relies on the electron dynamics occurring along interfaces between the acceptor and donor moieties. To investigate these dynamics with chemical specificity, spectroscopic techniques are employed to obtain localized snapshots of the electron behavior at selected interfaces. In this study, charge transfer in blends (by weight 10, 50, 90, and 100%) of p-type polymer P(g(4)2T-T) (bithiophene-thiophene) and n-type polymer BBL (poly(benzimidazo-benzo-phenanthroline)) was measured by resonant Auger spectroscopy. Electron spectra emanating from the decay of core-excited states created upon X-ray absorption in the donor polymer P(g(4)2T-T) were measured in the sulfur KL2,3L2,3 Auger kinetic energy region as a function of the excitation energy. By tuning the photon energy across the sulfur K-absorption edge, it is possible to differentiate between decay paths in which the core-excited electron remained on the atom with the core-hole and those where it tunneled away. Analyzing the competing decay modes of these localized and delocalized (charge-transfer) processes facilitated the computation of charge-transfer times as a function of excitation energy using the core-hole clock method. The electron delocalization times derived from the measurements were found to be in the as/fs regime for all polymer blends, with the fastest charge transfer occurring in the sample with an equal amount of donor and acceptor polymer. These findings highlight the significance of core-hole clock spectroscopy as a chemically specific tool for examining the local charge tunneling propensity, which is fundamental to understanding macroscopic conductivity. Additionally, the X-ray absorption spectra near the sulfur K-edge in the P(g(4)2T-T) polymer for different polymer blends were analyzed to compare molecular structure, orientation, and ordering in the polymer heterojunctions. The 50% donor sample exhibited the most pronounced angular dependence of absorption, indicating a higher level of ordering compared to the other weight blends. Our studies on the electron dynamics of this type of all-polymer donor-acceptor systems, in which spontaneous ground-state electron transfer occurs, provide us with critical insights to further advance the next generation of organic conductors with mixed electron-hole conduction characteristics suitable for highly stable electrodes of relevance for electronic, electrochemical, and optoelectronic applications.
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- Brancalion, L., et al.
(författare)
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Roan, ticked and clear coat patterns in the canine are associated with three haplotypes near usherin on CFA38
- 2021
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Ingår i: Animal Genetics. - : Wiley. - 0268-9146 .- 1365-2052. ; 52:2, s. 198-207
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Tidskriftsartikel (refereegranskat)abstract
- White coat patterning is a feature of many dog breeds and is known to be coded primarily by the gene micropthalmia-associated transcription factor (MITF). This patterning in the coat can be modified by other factors to produce the attractive phenotypes termed ‘ticked’ and ‘roan’ that describe the presence of flecks of color that vary in distribution and intensity within otherwise ‘clear’ white markings. The appearance of the pigment in the white patterning caused by ticking and roaning intensifies in the weeks after birth. We applied genome-wide association to compare English Cocker Spaniels of roan phenotype (N = 34) with parti-color (non-roan) English Cocker Spaniels (N = 9) and identified an associated locus on CFA 38, CFA38:11 057 040 (Praw = 8.9 × 10−10, Pgenome = 2.7 × 10−5). A local case–control association in English Springer Spaniels comparing 11 ticked and six clear dogs identified indicative association with a different haplotype, CFA38:11 122 467G>T (Praw = 1.7 × 10−5) and CFA38:11 124 294A>C (Praw = 1.7 × 10−5). We characterize three haplotypes in Spaniels according to their putative functional variant profiles at CFA38:11 111 286C>T (missense), CFA38:11 131 841–11 143 239DUP.insTTAA (using strongly linked marker CFA38:11 143 243C>T) and CFA38:11 156 425T>C (splice site). In Spaniels, the haplotypes work as an allelic series including alleles (t, recessive clear; T, dominant ticked/parti-color; and TR, incomplete dominant roan) to control the appearance of pigmented spots or flecks in otherwise white areas of the canine coat. In Spaniels the associated haplotypes are t (CCT), T (TCC) and TR (TTT) for SNP markers on CFA38 at 11 111 286C>T, 11 143 243C>T and 11 156 425T>C respectively. It is likely that other alleles exist in this series and together the haplotypes result in a complex range of patterning that is only visible when dogs have white patterning resulting from the epistatic gene Micropthalmia-associated transcription factor (the S-locus).
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- Christmas, Matthew, et al.
(författare)
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Evolutionary constraint and innovation across hundreds of placental mammals
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643
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Tidskriftsartikel (refereegranskat)abstract
- Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (similar to 10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.
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