sv.
- MeSH
- Psychoanalysis MeSH
- Publication type
- Periodical MeSH
- Conspectus
- Psychologie
- NML Fields
- psychologie, klinická psychologie
Nonhomologous end joining (NHEJ) is a DNA repair mechanism that religates double-strand DNA breaks to maintain genomic integrity during the entire cell cycle. The Ku70/80 complex recognizes DNA breaks and serves as an essential hub for recruitment of NHEJ components. Here, we describe intramolecular interactions of the Ku70 C-terminal domain, known as the SAP domain. Using single-particle cryo-electron microscopy, mass spectrometric analysis of intermolecular cross-linking and molecular modelling simulations, we captured variable positions of the SAP domain depending on DNA binding. The first position was localized at the DNA aperture in the Ku70/80 apo form but was not observed in the DNA-bound state. The second position, which was observed in both apo and DNA-bound states, was found below the DNA aperture, close to the helical arm of Ku70. The localization of the SAP domain in the DNA aperture suggests a function as a flexible entry gate for broken DNA. DATABASES: EM maps have been deposited in EMDB (EMD-11933). Coordinates have been deposited in Protein Data Bank (PDB 7AXZ). Other data are available from corresponding authors upon a request.
- MeSH
- Humans MeSH
- Dental Restoration, Permanent methods MeSH
- Dental Amalgam MeSH
- Dental Instruments MeSH
- Check Tag
- Humans MeSH
[1. vyd.] Nestr. : obr. ; 17 cm
[1. vyd.] Nestr. : fot. ; 17 cm
- MeSH
- Research Support as Topic MeSH
- Humans MeSH
- Lysosomal Storage Diseases diagnosis physiopathology MeSH
- Infant, Newborn MeSH
- Saposins diagnostic use deficiency MeSH
- Lipid Metabolism, Inborn Errors diagnosis physiopathology MeSH
- Rare Diseases congenital MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Anti-Arrhythmia Agents pharmacokinetics pharmacology MeSH
- Antihypertensive Agents pharmacokinetics pharmacology MeSH
- Electrophysiological Phenomena MeSH
- Animal Experimentation statistics & numerical data MeSH
- Financing, Organized MeSH
- Ventricular Function, Right physiology drug effects MeSH
- Gallopamil pharmacokinetics pharmacology MeSH
- Guinea Pigs MeSH
- Myocardium MeSH
- Papillary Muscles physiology drug effects MeSH
- Verapamil pharmacokinetics pharmacology MeSH
- Animals MeSH
- Check Tag
- Guinea Pigs MeSH
- Animals MeSH
Chlorinated ethenes (CE) are among the most frequent contaminants of soil and groundwater in the Czech Republic. Because conventional methods of subsurface contamination investigation are costly and technically complicated, attention is directed on alternative and innovative field sampling methods. One promising method is sampling of tree cores (plugs of woody tissue extracted from a host tree). Volatile organic compounds can enter into the trunks and other tissues of trees through their root systems. An analysis of the tree core can thus serve as an indicator of the subsurface contamination. Four areas of interest were chosen at the experimental site with CE groundwater contamination and observed fluctuations in groundwater concentrations. CE concentrations in groundwater and tree cores were observed for a 1-year period. The aim was to determine how the CE concentrations in obtained tree core samples correlate with the level of contamination of groundwater. Other factors which can affect the transfer of contaminants from groundwater to wood were also monitored and evaluated (e.g., tree species and age, level of groundwater table, river flow in the nearby Ploučnice River, seasonal effects, and the effect of the remediation technology operation). Factors that may affect the concentration of CE in wood were identified. The groundwater table level, tree species, and the intensity of transpiration appeared to be the main factors within the framework of the experiment. Obtained values documented that the results of tree core analyses can be used to indicate the presence of CE in the subsurface. The results may also be helpful to identify the best sampling period for tree coring and to learn about the time it takes until tree core concentrations react to changes in groundwater conditions. Interval sampling of tree cores revealed possible preservation of the contaminant in the wood of trees.
- MeSH
- Hydrocarbons, Chlorinated analysis MeSH
- Environmental Pollutants analysis MeSH
- Environmental Monitoring methods MeSH
- Groundwater analysis MeSH
- Trees chemistry MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.
- MeSH
- Child MeSH
- Adult MeSH
- Phenotype MeSH
- Immunoenzyme Techniques MeSH
- Intracellular Signaling Peptides and Proteins genetics MeSH
- Cohort Studies MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Lymphoproliferative Disorders diagnosis genetics therapy MeSH
- Survival Rate MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mutation genetics MeSH
- Child, Preschool MeSH
- Retrospective Studies MeSH
- Aged MeSH
- X-Linked Inhibitor of Apoptosis Protein genetics MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. OBJECTIVE: To examine the role of PSAP mutations in iRBD. METHODS: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). RESULTS: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. CONCLUSION: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.
