| 1341. |
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| 1342. |
- Leblond, Claire S, et al.
(författare)
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Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.
- 2014
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
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| 1343. |
- Leclere, David, et al.
(författare)
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Bending the curve of terrestrial biodiversity needs an integrated strategy
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 585:7826, s. 551-556
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Tidskriftsartikel (refereegranskat)abstract
- Increased efforts are required to prevent further losses to terrestrial biodiversity and the ecosystem services that it provides(1,2). Ambitious targets have been proposed, such as reversing the declining trends in biodiversity(3); however, just feeding the growing human population will make this a challenge(4). Here we use an ensemble of land-use and biodiversity models to assess whether-and how-humanity can reverse the declines in terrestrial biodiversity caused by habitat conversion, which is a major threat to biodiversity(5). We show that immediate efforts, consistent with the broader sustainability agenda but of unprecedented ambition and coordination, could enable the provision of food for the growing human population while reversing the global terrestrial biodiversity trends caused by habitat conversion. If we decide to increase the extent of land under conservation management, restore degraded land and generalize landscape-level conservation planning, biodiversity trends from habitat conversion could become positive by the mid-twenty-first century on average across models (confidence interval, 2042-2061), but this was not the case for all models. Food prices could increase and, on average across models, almost half (confidence interval, 34-50%) of the future biodiversity losses could not be avoided. However, additionally tackling the drivers of land-use change could avoid conflict with affordable food provision and reduces the environmental effects of the food-provision system. Through further sustainable intensification and trade, reduced food waste and more plant-based human diets, more than two thirds of future biodiversity losses are avoided and the biodiversity trends from habitat conversion are reversed by 2050 for almost all of the models. Although limiting further loss will remain challenging in several biodiversity-rich regions, and other threats-such as climate change-must be addressed to truly reverse the declines in biodiversity, our results show that ambitious conservation efforts and food system transformation are central to an effective post-2020 biodiversity strategy. To promote the recovery of the currently declining global trends in terrestrial biodiversity, increases in both the extent of land under conservation management and the sustainability of the global food system from farm to fork are required.
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| 1344. |
- Lécuyer, Lucie, et al.
(författare)
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Associations between dietary inflammatory scores and biomarkers of inflammation in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
- 2023
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Ingår i: Clinical Nutrition. - : Elsevier. - 0261-5614 .- 1532-1983. ; 42:7, s. 1115-1125
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Tidskriftsartikel (refereegranskat)abstract
- Background: Since the first version of the dietary inflammatory index (DII®) developed in the past decade, several other versions have been developed. However, to date no study has attempted to compare these versions with respect to their associations with biomarkers of inflammation.Objective: We aimed to investigate the relationship between four dietary inflammatory scores [DII, two energy-adjusted derivatives (E-DII and E-DIIr), and the Inflammatory Score of the Diet (ISD)], and circulating levels of several inflammatory markers and adipokines.Methods: This study included 17 637 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with at least one marker of inflammation measured in blood. Associations between the four scores and C-reactive protein (CRP), interleukin (IL)6, IL10, IL1RA, tumor necrosis factor-α (TNFα), soluble tumor necrosis factor receptor-1 (sTNFR1), sTNFR2, leptin, soluble leptin receptor (sLeptin R), adiponectin, and High Molecular Weight (HMW) adiponectin were evaluated using multivariable linear regressions adjusted for potential confounders.Results: Positive associations were observed between the four dietary inflammatory scores and levels of CRP, IL6, sTNFR1, sTNFR2 and leptin. However, only the DII and the ISD were positively associated with IL1RA levels and only the DII and the E-DIIr were positively associated with TNFα levels. The proportion of variance of each biomarker explained by the scores was lower than 2%, which was equivalent to the variance explained by smoking status but much lower than that explained by body mass index.Conclusions: Our results suggest that the four dietary inflammatory scores were associated with some biomarkers of inflammation and could be used to assess the inflammatory potential of diet in European adults but are not sufficient to capture the inflammatory status of an individual. These findings can help to better understand the inflammatory potential of diet, but they need to be replicated in studies with repeated dietary measurements.
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| 1345. |
- Lee, Ho-Hsien, et al.
(författare)
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Expression, purification and crystallization of CTB-MPR, a candidate mucosal vaccine component against HIV-1
- 2014
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Ingår i: IUCrJ. - 2052-2525. ; 1:5, s. 305-317
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Tidskriftsartikel (refereegranskat)abstract
- CTB-MPR is a fusion protein between the B subunit of cholera toxin (CTB) andthe membrane-proximal region of gp41 (MPR), the transmembrane envelopeprotein ofHuman immunodeficiency virus 1(HIV-1), and has previously beenshown to induce the production of anti-HIV-1 antibodies with antiviralfunctions. To further improve the design of this candidate vaccine, X-raycrystallography experiments were performed to obtain structural informationabout this fusion protein. Several variants of CTB-MPR were designed,constructed and recombinantly expressed inEscherichia coli. The first variantcontained a flexible GPGP linker between CTB and MPR, and yielded crystalsthat diffracted to a resolution of 2.3 A ̊, but only the CTB region was detectedin the electron-density map. A second variant, in which the CTB was directlyattached to MPR, was shown to destabilize pentamer formation. A thirdconstruct containing a polyalanine linker between CTB and MPR proved tostabilize the pentameric form of the protein during purification. The purificationprocedure was shown to produce a homogeneously pure and monodispersesample for crystallization. Initial crystallization experiments led to pseudo-crystals which were ordered in only two dimensions and were disordered inthe third dimension. Nanocrystals obtained using the same precipitant showedpromising X-ray diffraction to 5 A ̊resolution in femtosecond nanocrystallo-graphy experiments at the Linac Coherent Light Source at the SLAC NationalAccelerator Laboratory. The results demonstrate the utility of femtosecondX-ray crystallography to enable structural analysis based on nano/microcrystalsof a protein for which no macroscopic crystals ordered in three dimensions havebeen observed before.
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| 1346. |
- Lee, Justin H., et al.
(författare)
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MMS Measurements and Modeling of Peculiar Electromagnetic Ion Cyclotron Waves
- 2019
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Ingår i: Geophysical Research Letters. - : AMER GEOPHYSICAL UNION. - 0094-8276 .- 1944-8007.
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Tidskriftsartikel (refereegranskat)abstract
- Orbiting Earth's dayside outer magnetosphere on 29 September 2015, the Magnetospheric Multiscale (MMS) satellites measured plasma composition, simultaneous electromagnetic ion cyclotron waves, and intermittent fast plasma flows consistent with ultralow frequency waves or convection. Such flows can accelerate typically unobservable low-energy plasma into a measurable energy range of spacecraft plasma instrumentation. We exploit the flow occurrence to ensure measurement of cold ion species alongside the hot particles-consisting of ionospheric heavy ions and solar wind He++-during a subinterval of wave emissions with spectral properties previously described as peculiar. Through application of the composition and multisatellite wave vector data to linear theory, we demonstrate the emissions are in fact consistent with theory, growing naturally in the He++ band with sufficient free energy.
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| 1347. |
- Lenz, Tobias L., et al.
(författare)
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Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
- 2015
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Ingår i: Nature Genetics. - : Macmillan Publishers Ltd.. - 1061-4036 .- 1546-1718. ; 47:9, s. 1085-1090
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Tidskriftsartikel (refereegranskat)abstract
- Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (n(cases) = 5,337), type 1 diabetes (T1D; n(cases) = 5,567), psoriasis vulgaris (n(cases) = 3,089), idiopathic achalasia (n(cases) = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 x 10(-12); T1D, P = 2.4 x 10(-10); psoriasis, P = 5.9 x 10(-6); celiac disease, P = 1.2 x 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 x 10(-3); T1D, P = 8.6 x 10(-27); celiac disease, P = 6.0 x 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.
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| 1348. |
- Leon-Ferre, Roberto A., et al.
(författare)
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Automated mitotic spindle hotspot counts are highly associated with clinical outcomes in systemically untreated early-stage triple-negative breast cancer
- 2024
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Ingår i: npj Breast Cancer. - : NATURE PORTFOLIO. - 2374-4677. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Operable triple-negative breast cancer (TNBC) has a higher risk of recurrence and death compared to other subtypes. Tumor size and nodal status are the primary clinical factors used to guide systemic treatment, while biomarkers of proliferation have not demonstrated value. Recent studies suggest that subsets of TNBC have a favorable prognosis, even without systemic therapy. We evaluated the association of fully automated mitotic spindle hotspot (AMSH) counts with recurrence-free (RFS) and overall survival (OS) in two separate cohorts of patients with early-stage TNBC who did not receive systemic therapy. AMSH counts were obtained from areas with the highest mitotic density in digitized whole slide images processed with a convolutional neural network trained to detect mitoses. In 140 patients from the Mayo Clinic TNBC cohort, AMSH counts were significantly associated with RFS and OS in a multivariable model controlling for nodal status, tumor size, and tumor-infiltrating lymphocytes (TILs) (p < 0.0001). For every 10-point increase in AMSH counts, there was a 16% increase in the risk of an RFS event (HR 1.16, 95% CI 1.08-1.25), and a 7% increase in the risk of death (HR 1.07, 95% CI 1.00-1.14). We corroborated these findings in a separate cohort of systemically untreated TNBC patients from Radboud UMC in the Netherlands. Our findings suggest that AMSH counts offer valuable prognostic information in patients with early-stage TNBC who did not receive systemic therapy, independent of tumor size, nodal status, and TILs. If further validated, AMSH counts could help inform future systemic therapy de-escalation strategies.
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| 1349. |
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| 1350. |
- Leta, Tesfaye H., et al.
(författare)
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The use of antibiotic-loaded bone cement and systemic antibiotic prophylactic use in 2,971,357 primary total knee arthroplasties from 2010 to 2020: an international register-based observational study among countries in Africa, Europe, North America, and Oceania
- 2023
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Ingår i: Acta Orthopaedica. - 1745-3674 .- 1745-3682. ; 94, s. 416-425
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose — Antibiotic-loaded bone cement (ALBC) and systemic antibiotic prophylaxis (SAP) have been used to reduce periprosthetic joint infection (PJI) rates. We investigated the use of ALBC and SAP in primary total knee arthroplasty (TKA). Patients and methods — This observational study is based on 2,971,357 primary TKAs reported in 2010–2020 to national/regional joint arthroplasty registries in Australia, Den-mark, Finland, Germany, Italy, the Netherlands, New Zealand, Norway, Romania, South Africa, Sweden, Switzerland, the UK, and the USA. Aggregate-level data on trends and types of bone cement, antibiotic agents, and doses and duration of SAP used was extracted from participating registries. Results — ALBC was used in 77% of the TKAs with variation ranging from 100% in Norway to 31% in the USA. Palacos R+G was the most common (62%) ALBC type used. The primary antibiotic used in ALBC was gentamicin (94%). Use of ALBC in combination with SAP was common practice (77%). Cefazolin was the most common (32%) SAP agent. The doses and duration of SAP used varied from one single preoperative dosage as standard practice in Bolzano, Italy (98%) to 1-day 4 doses in Norway (83% of the 40,709 TKAs reported to the Norwegian arthroplasty register). Conclusion — The proportion of ALBC usage in primary TKA varies internationally, with gentamicin being the most common antibiotic. ALBC in combination with SAP was common practice, with cefazolin the most common SAP agent. The type of ALBC and type, dose, and duration of SAP varied among participating countries.
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