| 81. |
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| 82. |
- Hansen, Eline P., et al.
(författare)
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Exploration of extracellular vesicles from Ascaris suum provides evidence of parasite-host cross talk
- 2019
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The prevalent porcine helminth, Ascaris suum, compromises pig health and reduces farm productivity worldwide. The closely related human parasite, A. lumbricoides, infects more than 800 million people representing a disease burden of 1.31 million disability-adjusted life years. The infections are often chronic in nature, and the parasites have a profound ability to modulate their hosts' immune responses. This study provides the first in-depth characterisation of extracellular vesicles (EVs) from different developmental stages and body parts of A. suum and proposes the role of these vesicles in the host-parasite interplay. The release of EVs from the third- (L3) and fourth-stage (L4) larvae and adults was demonstrated by transmission electron microscopy (TEM), and sequencing of EV-derived RNA identified a number of microRNAs (miRNAs) and transcripts of potential host immune targets, such as IL-13, IL-25 and IL-33, were identified. Furthermore, proteomics of EVs identified several proteins with immunomodulatory properties and other proteins previously shown to be associated with parasite EVs. Taken together, these results suggest that A. suum EVs and their cargo may play a role in host-parasite interactions. This knowledge may pave the way to novel strategies for helminth infection control and knowledge of their immune modulatory potential.
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| 83. |
- Higelin, Julia, et al.
(författare)
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NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons
- 2018
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Ingår i: Stem Cell Research. - : Elsevier. - 1873-5061 .- 1876-7753. ; 30, s. 150-162
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction. Motoneurons carrying a C9orf72 mutation exhibited cell specific signs of increased DNA damage. This phenotype was even more severe in NEK1c.2434A>T neurons that showed significantly increased DNA damage at basal level and impaired DDR after induction of DNA damage in an maturation-dependent manner. Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS. Therefore, our study contributes to the development of novel therapeutic strategies to reduce DNA damage accumulation in neurodegenerative diseases and ALS.
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| 84. |
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| 85. |
- Jonsson, Andreas P., et al.
(författare)
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Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis
- 2004
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 127:Pt 1, s. 73-88
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Tidskriftsartikel (refereegranskat)abstract
- Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.
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| 86. |
- Jonsson, Andreas P., et al.
(författare)
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Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1
- 2006
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Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 65:12, s. 1126-1136
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Tidskriftsartikel (refereegranskat)abstract
- Mutant human CuZn-superoxide dismutases (hSOD1s) cause amyotrophic lateral sclerosis (ALS). The most common mutation is the wild type-like D90A and to explore its properties, transgenic mice were generated and compared with mice expressing wild-type hSOD1. D90A hSOD1 was both in vivo in mice and in vitro under denaturing conditions nearly as stable as the wild-type human enzyme. It appeared less toxic than other tested mutants, but mice homozygous for the transgene insertion developed a fatal motor neuron disease. In these mice, the disease progression was slow and there were bladder disturbances similar to what is found in human ALS cases homozygous for the D90A mutation. The homozygous D90A mice accumulated detergent-resistant hSOD1 aggregates in spinal cords, and abundant hSOD1 inclusions and vacuoles were seen in the ventral horns. Mice expressing wild-type hSOD1 at a comparable rate showed similar pathologic changes but less and later. Hemizygous D90A mice showed even milder alterations. At 600 days, the wild-type hSOD1 transgenic mice had lost more ventral horn neurons than hemizygous D90A mice (38% vs 31% p < 0.01). Thus, wild-type hSOD1 shows a significant neurotoxicity in the spinal cord, that is less than equal but more than half as large as that of D90A mutant enzyme.
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| 87. |
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| 88. |
- Kliest, Tessa, et al.
(författare)
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Clinical trials in pediatric ALS: a TRICALS feasibility study
- 2022
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis Group. - 2167-8421 .- 2167-9223. ; 23:7-8, s. 481-488
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
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| 89. |
- Kotak, R., et al.
(författare)
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Dust and The Type II-Plateau Supernova 2004et
- 2009
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 704:1, s. 306-323
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Tidskriftsartikel (refereegranskat)abstract
- We present mid-infrared (MIR) observations of the Type II-plateau supernova (SN) 2004et, obtained with the Spitzer Space Telescope between 64 and 1406 days past explosion. Late-time optical spectra are also presented. For the period 300-795 days past explosion, we argue that the spectral energy distribution (SED) of SN 2004et comprises (1) a hot component due to emission from optically thick gas, as well as free-bound radiation; (2) a warm component due to newly formed, radioactively heated dust in the ejecta; and (3) a cold component due to an IR echo from the interstellar-medium dust of the host galaxy, NGC 6946. There may also have been a small contribution to the IR SED due to free-free emission from ionized gas in the ejecta. We reveal the first-ever spectroscopic evidence for silicate dust formed in the ejecta of a supernova. This is supported by our detection of a large, but progressively declining, mass of SiO. However, we conclude that the mass of directly detected ejecta dust grew to no more than a few times 10-4 M sun. We also provide evidence that the ejecta dust formed in comoving clumps of fixed size. We argue that, after about two years past explosion, the appearance of wide, box-shaped optical line profiles was due to the impact of the ejecta on the progenitor circumstellar medium and that the subsequent formation of a cool, dense shell was responsible for a later rise in the MIR flux. This study demonstrates the rich, multifaceted ways in which a typical core-collapse supernova and its progenitor can produce and/or interact with dust grains. The work presented here adds to the growing number of studies that do not support the contention that SNe are responsible for the large mass of observed dust in high-redshift galaxies.
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| 90. |
- Kuzma-Kozakiewicz, Magdalena, et al.
(författare)
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Putative founder effect in the Polish, Iranian and United States populations for the L144SSOD1mutation associated with slowly uniform phenotype of amyotrophic lateral sclerosis
- 2021
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 22:1-2, s. 80-85
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Tidskriftsartikel (refereegranskat)abstract
- Mutations inSOD1cause approximately 12-25% of familial ALS and approximate to 2% of apparently sporadic ALS cases. Clinical phenotypes linked to SOD1 mutations are heterogeneous and intra-familial variability of the clinical phenotype is frequently observed. SOD1 L144S mutation, identified also in Brazil, Iran and United States, is the second most frequent mutation among ALS patients in Poland. So far, 10 FALS pedigrees with SOD1 L144S mutation have been reported worldwide. The aim of the study was to establish the origin of SOD1 L144S mutation in geographically distinct populations. The clinical presentation of the Polish patients was compared with those from the previously reported populations (26 ever-reported patients). Clinically, L144S mutation is associated with both sporadic and familial ALS of relatively slow uniform course, a prevalent onset in the lower limbs, either classic or PMA presentation and a long survival time. Like in the case of other previously described SOD1 mutations, there was an intra-familial heterogeneity and reduced penetrance for ALS was observed. We propose that the L144S SOD1 mutation in the three studied populations has a common founder most likely of Polish origin.
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