| 1. |
- Cossee, Mireille, et al.
(författare)
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Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes
- 1999
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Ingår i: Annals of Neurology. - 0364-5134 .- 1531-8249. ; 45:2, s. 200-206
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Tidskriftsartikel (refereegranskat)abstract
- Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.
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| 2. |
- Elenkov, Angel, et al.
(författare)
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Impact of SARS-CoV-2 and Other Upper Respiratory Tract Viral Infections on Reproductive Parameters in Young Healthy Men with Mild Symptoms of Disease
- 2023
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Ingår i: Andrologia. - 0303-4569. ; 2023
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Tidskriftsartikel (refereegranskat)abstract
- Data regarding excretion of SARS-CoV-2 in semen are inconclusive and counseling regarding risk of sexual transmission is still challenging. Our knowledge on the effect of upper respiratory tract infections (URTI) on male reproductive system is also scarce. Apart from negative effect of fever on spermatogenesis virtually no study has been able to compare reproductive parameters in men with COVID-19 or other URTI with predisease data. Eleven men who developed symptoms of URTI during the first and second wave of COVID-19 pandemic and who had preexistent fertility and hormonal data, participated in the study leaving sperm and blood samples. Three additional subjects were recruited among proven SARS-CoV-2 positive male hospital workers (without previous data). SARS-CoV-2 RNA was present in the ejaculate from 2 of 5 (40%) young men with mild COVID-19. In one of them viral particles could be detected in the semen sample 2 weeks after the first sampling. Men with any URTI showed higher LH (p=0.02), lower sperm concentration (p=0.047), and free testosterone (p=0.008) when compared to their samples delivered 10 years earlier. When SARS-CoV-2 positive subjects were compared to subjects with other URTIs, no difference in levels of reproductive parameters or inflammatory markers was seen. In conclusion, SARS-CoV-2 RNA can be present in the ejaculate but does not seem to affect reproductive parameters any more than other viruses. However, mild URTI was shown to affect the sperm concentration, LH, and free testosterone negatively.
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| 3. |
- Westerlund, Annie M., et al.
(författare)
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Markov state modelling reveals heterogeneous drug-inhibition mechanism of Calmodulin
- 2022
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 18:10
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Tidskriftsartikel (refereegranskat)abstract
- Calmodulin (CaM) is a calcium sensor which binds and regulates a wide range of target-proteins. This implicitly enables the concentration of calcium to influence many downstream physiological responses, including muscle contraction, learning and depression. The antipsychotic drug trifluoperazine (TFP) is a known CaM inhibitor. By binding to various sites, TFP prevents CaM from associating to target-proteins. However, the molecular and state-dependent mechanisms behind CaM inhibition by drugs such as TFP are largely unknown. Here, we build a Markov state model (MSM) from adaptively sampled molecular dynamics simulations and reveal the structural and dynamical features behind the inhibitory mechanism of TFP-binding to the C-terminal domain of CaM. We specifically identify three major TFP binding-modes from the MSM macrostates, and distinguish their effect on CaM conformation by using a systematic analysis protocol based on biophysical descriptors and tools from machine learning. The results show that depending on the binding orientation, TFP effectively stabilizes features of the calcium-unbound CaM, either affecting the CaM hydrophobic binding pocket, the calcium binding sites or the secondary structure content in the bound domain. The conclusions drawn from this work may in the future serve to formulate a complete model of pharmacological modulation of CaM, which furthers our understanding of how these drugs affect signaling pathways as well as associated diseases. Author summary Calmodulin (CaM) is a calcium-sensing protein which makes other proteins dependent on the surrounding calcium concentration by binding to these proteins. Such protein-protein interactions with CaM are vital for calcium to control many physiological pathways within the cell. The antipsychotic drug trifluoperazine (TFP) inhibits CaM's ability to bind and regulate other proteins. Here, we use molecular dynamics simulations together with Markov state modeling and machine learning to understand the structural and dynamical features by which TFP bound to the one domain of CaM prevents association to other proteins. We find that TFP encourages CaM to adopt a conformation that is like the one stabilized in absence of calcium: depending on the binding orientation of TFP, the drug indeed either affects the CaM hydrophobic binding pocket, the calcium binding sites or the secondary structure content in the domain. Understanding TFP binding is a first step towards designing better drugs targeting CaM.
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