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- Ogishi, M, et al.
(författare)
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Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency
- 2022
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:10
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Tidskriftsartikel (refereegranskat)abstract
- Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
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- Zhang, Q, et al.
(författare)
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Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia
- 2022
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:8
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Tidskriftsartikel (refereegranskat)abstract
- Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5–13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10−11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.
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- Golosio, B., et al.
(författare)
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The FIRST experiment for nuclear fragmentation measurements at GSI
- 2011
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Ingår i: Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC), 2011 IEEE. ; , s. 2277-2280
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Konferensbidrag (refereegranskat)abstract
- Nuclear fragmentation processes are relevant in different fields of physics concerning both basic research and applications. FIRST (Fragmentation of Ions Relevant for Space and Therapy) is an experiment aimed at the measurement of double differential cross sections (DDCS), with respect to kinetic energy and scattering polar angle, of nuclear fragmentation processes relevant for hadron therapy and for space radiation protection applications, in the energy range between 100 and 1000 MeV/u. The experiment was mounted at the GSI laboratories of Darmstadt, in Germany. A first data taking was performed in August 2011, using 400 MeV/u 12C on carbon and gold targets. In this work we present a description of the experimental apparatus and some figures from the data acquisition and from the preliminary work on data analysis
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| 10. |
- Komatsu, Kimberly J., et al.
(författare)
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Global change effects on plant communities are magnified by time and the number of global change factors imposed
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:36, s. 17867-17873
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Tidskriftsartikel (refereegranskat)abstract
- Accurate prediction of community responses to global change drivers (GCDs) is critical given the effects of biodiversity on ecosystem services. There is consensus that human activities are driving species extinctions at the global scale, but debate remains over whether GCDs are systematically altering local communities worldwide. Across 105 experiments that included over 400 experimental manipulations, we found evidence for a lagged response of herbaceous plant communities to GCDs caused by shifts in the identities and relative abundances of species, often without a corresponding difference in species richness. These results provide evidence that community responses are pervasive across a wide variety of GCDs on long-term temporal scales and that these responses increase in strength when multiple GCDs are simultaneously imposed.Global change drivers (GCDs) are expected to alter community structure and consequently, the services that ecosystems provide. Yet, few experimental investigations have examined effects of GCDs on plant community structure across multiple ecosystem types, and those that do exist present conflicting patterns. In an unprecedented global synthesis of over 100 experiments that manipulated factors linked to GCDs, we show that herbaceous plant community responses depend on experimental manipulation length and number of factors manipulated. We found that plant communities are fairly resistant to experimentally manipulated GCDs in the short term (<10 y). In contrast, long-term (≥10 y) experiments show increasing community divergence of treatments from control conditions. Surprisingly, these community responses occurred with similar frequency across the GCD types manipulated in our database. However, community responses were more common when 3 or more GCDs were simultaneously manipulated, suggesting the emergence of additive or synergistic effects of multiple drivers, particularly over long time periods. In half of the cases, GCD manipulations caused a difference in community composition without a corresponding species richness difference, indicating that species reordering or replacement is an important mechanism of community responses to GCDs and should be given greater consideration when examining consequences of GCDs for the biodiversity–ecosystem function relationship. Human activities are currently driving unparalleled global changes worldwide. Our analyses provide the most comprehensive evidence to date that these human activities may have widespread impacts on plant community composition globally, which will increase in frequency over time and be greater in areas where communities face multiple GCDs simultaneously.
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- Zechel, S, et al.
(författare)
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Expression and functions of fibroblast growth factor 2 (FGF-2) in hippocampal formation
- 2010
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Ingår i: The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. - : SAGE Publications. - 1089-4098. ; 16:4, s. 357-373
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Tidskriftsartikel (refereegranskat)abstract
- Among the 23 members of the fibroblast growth factor (FGF) family, FGF-2 is the most abundant one in the central nervous system. Its impact on neural cells has been profoundly investigated by in vitro and in vivo studies as well as by gene knockout analyses during the past 2 decades. Key functions of FGF-2 in the nervous system include roles in neurogenesis, promotion of axonal growth, differentiation in development, and maintenance and plasticity in adulthood. From a clinical perspective, its prominent role for the maintenance of lesioned neurons (e.g., ischemia and following transection of fiber tracts) is of particular relevance. In the unlesioned brain, FGF-2 is involved in synaptic plasticity and processes attributed to learning and memory. The focus of this review is on the expression of FGF-2 and its receptors in the hippocampal formation and the physiological and pathophysiological roles of FGF-2 in this region during development and adulthood.
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| 13. |
- Bohlen, S, et al.
(författare)
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Physical therapy in Huntington's disease : towards objective assessments?
- 2013
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 20:2, s. 389-393
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Tidskriftsartikel (refereegranskat)abstract
- Background and purposePhysical therapy is recommended for the treatment of Huntington's disease, but reliable studies investigating its efficacy are almost non-existent. This may in part be due to the lack of suitable outcome measures. Therefore, we investigated the applicability of novel quantitative and objective assessments of motor dysfunction in the evaluation of physical therapy interventions aimed at improving gait and posture.MethodsTwelve patients with Huntington disease received a predefined twice-weekly intervention focusing on posture and gait over 6 weeks. The GAITRite mat and a force plate were used for objective and quantitative assessments. The Unified Huntingtons Disease Rating Scale Total Motor Score, the timed Up &Go test, and the Berg Balance Scale were used as clinical outcome measures.ResultsSignificant improvements were seen in GAITRite measures after therapy. Improvements were also seen in the Up & Go test and Berg Balance Scale, whereas force plate measures and Total Motor Scores did not change.ConclusionsThe results suggest that physical therapy has a positive effect on gait in Huntington's disease. The study shows that objective and quantitative measures of gait and posture may serve as endpoints in trials assessing the efficacy of physical therapy. They should be explored further in larger trials applying a randomized controlled setting.
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- Oltmanns, J., et al.
(författare)
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Development of a novel scoring system for identifying emerging chemical risks in the food chain
- 2018
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Ingår i: Environmental Science. - : Royal Society of Chemistry (RSC). - 2050-7887 .- 2050-7895. ; 20:2, s. 340-353
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Tidskriftsartikel (refereegranskat)abstract
- The European Food Safety Authority (EFSA) is responsible for risk assessment of all aspects of food safety, including the establishment of procedures aimed at the identification of emerging risks to food safety. Here, a scoring system was developed for identifying chemicals registered under the European REACH Regulation that could be of potential concern in the food chain using the following parameters: (i) environmental release based on maximum aggregated tonnages and environmental release categories; (ii) biodegradation in the environment; (iii) bioaccumulation and in vivo and in vitro toxicity. The screening approach was tested on 100 data-rich chemicals registered under the REACH Regulation at aggregated volumes of at least 1000 tonnes per annum. The results show that substance-specific data generated under the REACH Regulation can be used to identify potential emerging risks in the food chain. After application of the screening procedure, priority chemicals can be identified as potentially emerging risk chemicals through the integration of exposure, environmental fate and toxicity. The default approach is to generate a single total score for each substance using a predefined weighting scenario. However, it is also possible to use a pivot table approach to combine the individual scores in different ways that reflect user-defined priorities, which enables a very flexible, iterative definition of screening criteria. Possible applications of the approaches are discussed using illustrative examples. Either approach can then be followed by in-depth evaluation of priority substances to ensure the identification of substances that present a real emerging chemical risk in the food chain.
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| 16. |
- Peel, Jessica N., et al.
(författare)
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Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals
- 2024
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Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 134:8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Weakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODS. This study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTS. We found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSION. These findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.
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| 17. |
- Ramstein, B, et al.
(författare)
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H-2(He-3, t)2p reaction at 2 GeV
- 2003
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Ingår i: European Physical Journal A. Hadrons and Nuclei. - : Springer Science and Business Media LLC. - 1434-6001. ; 16:4, s. 583-597
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Tidskriftsartikel (refereegranskat)abstract
- The exclusive H-2 (He-3, t)2p reaction has been studied at 2 GeV for energy transfers up to 500 MeV and triton angles up to 3.4degrees. The protons were measured in the large acceptance magnetic detector DIOGENE, in coincidence with the forward tritons detected in a dedicated magnetic arm. The energy transfer spectra extend well above the pion threshold. However, in the region of Delta excitation, the yield is less than 10% of the inclusive H-2(He-3, t) cross-section, which indicates the small contribution of the DeltaN --> NN process. The angular distributions of the two protons in their center of mass have been analysed as a function of energy transfer and triton angle and a Legendre polynomial decomposition has been achieved. These data have been compared to a model based on a coupled-channel approach for describing the NN and NDelta systems.
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| 18. |
- Wei, Xin-Feng, et al.
(författare)
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Microplastics generated from a biodegradable plastic in freshwater and seawater
- 2021
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Ingår i: Water Research. - : Elsevier BV. - 0043-1354 .- 1879-2448. ; 198
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Tidskriftsartikel (refereegranskat)abstract
- Biodegradable polymers have been regarded as a promising solution to tackle the pollutions caused by the wide use of conventional polymers. However, during the biodegradation process, the material fragmentation leads to microplastics. In this work, the formation of microplastics from biodegradable poly (butylene adipate-co-terephthalate) (PBAT) in different aquatic environments was investigated and compared with the common non-biodegradable low-density polyethylene (LDPE). The results showed that a much larger quantity of plastic fragments/particles were formed in all aquatic environments from PBAT than from LDPE. In addition, UV-A pretreatment, simulating the exposure to sunlight, increased the rate of PBAT microplastic formation significantly. The size distribution and shapes of the formed microplastics were systematically studied, along with changes in the polymer physicochemical properties such as molecular weight, thermal stability, crystallinity, and mechanical properties, to reveal the formation process of microplastics. This study shows that the microplastic risk from biodegradable polymers is high and needs to be further evaluated with regards to longer timeframes, the biological fate of intermediate products, and final products in freshwater, estuarine and seawater natural habitats. Especially, considering that these microplastics may have good biodegradability in warmer 20 & ndash; 25 degrees water but will most likely be highly persistent in the world & rsquo;s cold deep seas.
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| 19. |
- Wei, Xin-Feng, et al.
(författare)
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Visualizing undyed microplastic particles and fibers with plasmon-enhanced fluorescence
- 2022
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Ingår i: Chemical Engineering Journal. - : Elsevier B.V.. - 1385-8947 .- 1873-3212. ; 442
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Tidskriftsartikel (refereegranskat)abstract
- Despite widespread awareness that enormous consumption of plastics is not sustainable, the global production and use of plastics continue to grow. This generates vast amounts of plastic waste and microplastics, ending up e.g., in the marine environment. There are serious challenges in detecting and measuring microplastics, especially in highly diluted natural samples. Here, a new alternative microplastic detection method based on plasmon-enhanced fluorescence (PEF) was developed and tested using fluorescence microscopy. In particular, gold nanopillar-based substrates, displaying (i) high electromagnetic field enhancement, and (ii) surface superhydrophobicity and high adhesion properties, were utilized to enhance the fluorescence emission signal from microplastics in water samples. The fluorescence microscopy imaging revealed remarkable fluorescence enhancement by the PEF substrates on the microplastic particles and fibers with different sizes of both conventional, low-density polyethylene, and biodegradable poly (butylene adipate-co-terephthalate). The limit of detection and quantification by this method was estimated to be as low as 0.35 and 1.2 femtograms, respectively. The observed fluorescence enhancement of the gold nanopillar substrates for the microplastics was ca. 70 times greater than the case of having the microplastics on a glass substrate. Additionally, 3D FEM simulations were performed to further investigate the system's electromagnetic field distribution near the nanostructures. This new method makes undyed microplastics visible in fluorescence microscopy, even particles and fibres too small to be imaged with conventional light microscopy. This can be a great tool for microplastic research, helping us to detect, study, understand microplastic dynamics in water based systems. © 2022 The Authors
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