Synucleinopathies are a group of clinically and neuropathologically distinct protein misfolding diseases caused by unique α-synuclein conformations, or strains. While multiple atomic resolution ...cryo-electron microscopy structures of α-synuclein fibrils are now deposited in Protein Data Bank, significant gaps in the biological consequences arising from each conformation have yet to be unraveled. Mutations in the α-synuclein gene (
SNCA
), cofactors, and the solvation environment contribute to the formation and maintenance of each disease-causing strain. This review highlights the impact of each of these factors on α-synuclein misfolding and discusses the implications of the resulting structural variability on therapeutic development.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Toxoplasmosis, caused by an intracellular protozoan parasite, Toxoplasma gondii, is widespread throughout the world. The disease is of major medical and veterinary importance, being a cause of ...congenital disease and abortion in humans and domestic animals. In addition, recently it has gained importance owing to toxoplasma encephalitis in AIDS patients. In the last few years, there has been considerable progress towards the development of a vaccine for toxoplasmosis, and a vaccine based on the live-attenuated S48 strain was developed for veterinary uses. However, this vaccine is expensive, causes side effects and has a short shelf life. Furthermore, this vaccine may revert to a pathogenic strain and, therefore, is not suitable for human use. Various experimental studies have shown that it may be possible to develop a vaccine against human toxoplasmosis. Recent progress in knowledge of the protective immune response generated by T. gondii and the current status of development of a vaccine for toxoplasmosis are highlighted.
Prince Christian Kraft von Hohenlohe bought his first properties in the High Tatras area in 1879 and gradually bought more (about 19,000 ha in total). Several of his buying activities caused great ...emotions of nationalism in the Kingdom of Hungary. As a German from the Reich, he came into conflict with the opinion that the High Tatras should remain in domestic hands. Even here, however, no one was clear whether it wasmeant to be Hungarians, Zips Germans, Slovaks or Poles. In addition, the Hungarian state entered the nationalist discourse, which had ambitions to buy property into state hands, which was supposed to be an expression of a positive attitude towards the country and opposition to the most beautiful areas falling into the hands of foreigners. Hohenlohe programmatically demonstrated a positive relationship to the state and its politics. On the other hand, he came into conflict with domestic tourists on his properties, and with his contradictory conservation activities, he justified closing the properties to tourists, which again caused only resistance and resentment from the public. In the Hungarian-Polish border dispute at the beginning of the 20th century, he took the Hungarian side and after 1918 pragmatically defended Czechoslovak interests against Polish territorial claims, because it both suited him and enabled him to avoid the intentions of the later Czechoslovak land reform. The state was also accommodating to the heirs of the estates and dealt with them very generously, as it did not desire a conflict with the Reich Germans in the 1930s. The fates of the Hohenlohe properties thus remained rather exceptional in the Hungarian and Czechoslovak state context.
In multiple system atrophy (MSA), the α-synuclein protein misfolds into a self-templating prion conformation that spreads throughout the brain, leading to progressive neurodegeneration. While the ...E46K mutation in α-synuclein causes familial Parkinson's disease (PD), we previously discovered that this mutation blocks in vitro propagation of MSA prions. Recent studies by others indicate that α-synuclein adopts a misfolded conformation in MSA in which a Greek key motif is stabilized by an intramolecular salt bridge between residues E46 and K80. Hypothesizing that the E46K mutation impedes salt bridge formation and, therefore, exerts a selective pressure that can modulate α-synuclein strain propagation, we asked whether three distinct α-synuclein prion strains could propagate in TgM47+/- mice, which express human α-synuclein with the E46K mutation. Following intracranial injection of these strains, TgM47+/- mice were resistant to MSA prion transmission, whereas recombinant E46K preformed fibrils (PFFs) transmitted neurological disease to mice and induced the formation of phosphorylated α-synuclein neuropathology. In contrast, heterotypic seeding following wild-type (WT) PFF-inoculation resulted in preclinical α-synuclein prion propagation. Moreover, when we inoculated TgM20+/- mice, which express WT human α-synuclein, with E46K PFFs, we observed delayed transmission kinetics with an incomplete attack rate. These findings suggest that the E46K mutation constrains the number of α-synuclein prion conformations that can propagate in TgM47+/- mice, expanding our understanding of the selective pressures that impact α-synuclein prion replication.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In multiple system atrophy (MSA), the protein α-synuclein misfolds into a prion conformation that self-templates and causes progressive neurodegeneration. While many point mutations in the ...α-synuclein gene,
SNCA
, have been identified as the cause of heritable Parkinson’s disease (PD), none have been identified as causing MSA. To examine whether MSA prions can transmit disease to mice expressing wild-type (WT) human α-synuclein, we inoculated transgenic (Tg) mice denoted TgM20
+/−
with brain homogenates prepared from six different deceased MSA patients. All six samples transmitted CNS disease to the mice, with an average incubation period of ~ 280 days. Interestingly, TgM20
+/−
female mice developed disease > 60 days earlier than their male counterparts. Brains from terminal mice contained phosphorylated α-synuclein throughout the hindbrain, consistent with the distribution of α-synuclein inclusions in MSA patients. In addition, using our α-syn–YFP cell lines, we detected α-synuclein prions in brain homogenates prepared from terminal mice that retained MSA strain properties. To our knowledge, the studies described here are the first to show that MSA prions transmit neurological disease to mice expressing WT
SNCA
and that the rate of transmission is sex dependent. By comparison, TgM20
+/−
mice inoculated with WT preformed fibrils (PFFs) developed severe neurological disease in ~ 210 days and exhibited robust α-synuclein neuropathology in both limbic regions and the hindbrain. Brain homogenates from these animals exhibited biological activities that are distinct from those found in MSA-inoculated mice when tested in the α-syn–YFP cell lines. Differences between brains from MSA-inoculated and WT PFF-inoculated mice potentially argue that α-synuclein prions from MSA patients are distinct from the PFF inocula and that PFFs do not replicate MSA strain biology.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Text se věnuje historii pobytu v přírodě v českých zemích – zejména okamžikům, které zásadně ovlivnily dnešní pojetí výchovy v přírodě (reprezentované zejména Prázdninovou školou Lipnice) a využití ...jeho programů, postupů a metod ve výchově holistické, reflektované zážitkovou pedagogikou.
Discovering new binding function via a combinatorial library in small protein scaffolds requires balance between appropriate mutations to introduce favorable intermolecular interactions while ...maintaining intramolecular integrity. Sitewise constraints exist in a non-spatial gradient from diverse to conserved in evolved antibody repertoires; yet non-antibody scaffolds generally do not implement this strategy in combinatorial libraries. Despite the fact that biased amino acid distributions, typically elevated in tyrosine, serine, and glycine, have gained wider use in synthetic scaffolds, these distributions are still predominantly applied uniformly to diversified sites. While select sites in fibronectin domains and DARPins have shown benefit from sitewise designs, they have not been deeply evaluated. Inspired by this disparity between diversity distributions in natural libraries and synthetic scaffold libraries, we hypothesized that binders resulting from discovery and evolution would exhibit a non-spatial, sitewise gradient of amino acid diversity. To identify sitewise diversities consistent with efficient evolution in the context of a hydrophilic fibronectin domain, >105 binders to six targets were evolved and sequenced. Evolutionarily favorable amino acid distributions at 25 sites reveal Shannon entropies (range: 0.3-3.9; median: 2.1; standard deviation: 1.1) supporting the diversity gradient hypothesis. Sitewise constraints in evolved sequences are consistent with complementarity, stability, and consensus biases. Implementation of sitewise constrained diversity enables direct selection of nanomolar affinity binders validating an efficient strategy to balance inter- and intra-molecular interaction demands at each site.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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