Distinct Type of Transmission Barrier Revealed by Study of Multiple Prion Determinants of Rnq1

Prions are self-propagating protein conformations. Transmission of the prion state between non-identical proteins, e.g. between homologous proteins from different species, is frequently inefficient. Transmission barriers are attributed to sequence differences in prion proteins, but their underlying mechanisms are not clear. Here we use a yeast Rnq1/[PIN+]-based experimental system to explore the nature of transmission barriers. [PIN+], the prion form of Rnq1, is common in wild and laboratory yeast strains, where it facilitates the appearance of other prions. Rnq1's prion domain carries four discrete QN-rich regions. We start by showing that Rnq1 encompasses multiple prion determinants that can independently drive amyloid formation in vitro and transmit the [PIN+] prion state in vivo. Subsequent analysis of [PIN+] transmission between Rnq1 fragments with different sets of prion determinants established that (i) one common QN-rich region is required and usually sufficient for the transmission; (ii) despite identical sequences of the common QNs, such transmissions are impeded by barriers of different strength. Existence of transmission barriers in the absence of amino acid mismatches in transmitting regions indicates that in complex prion domains multiple prion determinants act cooperatively to attain the final prion conformation, and reveals transmission barriers determined by this cooperative fold

Prion Formation and Polyglutamine Aggregation Are Controlled by Two Classes of Genes

Prions are self-perpetuating aggregated proteins that are not limited to mammalian systems but also exist in lower eukaryotes including yeast. While much work has focused around chaperones involved in prion maintenance, including Hsp104, little is known about factors involved in the appearance of prions. De novo appearance of the [PSI+] prion, which is the aggregated form of the Sup35 protein, is dramatically enhanced by transient overexpression of SUP35 in the presence of the prion form of the Rnq1 protein, [PIN+]. When fused to GFP and overexpressed in [ps−] [PIN+] cells, Sup35 forms fluorescent rings, and cells with these rings bud off [PSI+] daughters. We investigated the effects of over 400 gene deletions on this de novo induction of [PSI+]. Two classes of gene deletions were identified. Class I deletions (bug1Δ, bem1Δ, arf1Δ, and hog1Δ) reduced the efficiency of [PSI+] induction, but formed rings normally. Class II deletions (las17Δ, vps5Δ, and sac6Δ) inhibited both [PSI+] induction and ring formation. Furthermore, class II deletions reduced, while class I deletions enhanced, toxicity associated with the expanded glutamine repeats of the huntingtin protein exon 1 that causes Huntington's disease. This suggests that prion formation and polyglutamine aggregation involve a multi-phase process that can be inhibited at different steps.National Institutes of Health (U.S.) (grant GM56350)National Institutes of Health (U.S.) (NSRA F32 postdoctoral fellowship GM072340)National Institutes of Health (U.S.) (grant GM25874)Howard Hughes Medical Institut

Національна доповідь про стан і перспективи розвитку освіти в Україні: монографія (До 30-річчя незалежності України)

The publication provides a comprehensive analysis of the state and development of national education over the 30 years of Ukraine’s independence, identifies current problems in education, ascertains the causes of their emergence, offers scientifically reasoned ways to modernise domestic education in the context of globalisation, European integration, innovative development, and national self-identification. Designed for legislators, state officials, education institutions leaders, teaching and academic staff, the general public, all those who seek to increase the competitiveness of Ukrainian education in the context of civilisation changes.У виданні здійснено всебічний аналіз стану і розвитку національної освіти за 30-річний період незалежності України, визначено актуальні проблеми освітньої сфери, виявлено причини їх виникнення, запропоновано науково обґрунтовані шляхи модернізації вітчизняної освіти в умовах глобалізації, європейської інтеграції, інноваційного розвитку та національної самоідентифікації. Розраховано на законодавців, державних управлінців, керівників закладів освіти, педагогічних і науково-педагогічних працівників, широку громадськість, усіх, хто прагне підвищення конкурентоспроможності української освіти в контексті цивілізаційних змін

Half a century of amyloids: past, present and future

Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-ß architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward. This journal i

Variant-specific [PSI+] Infection Is Transmitted by Sup35 Polymers within [PSI+] Aggregates with Heterogeneous Protein Composition

The [PSI+] prion is the aggregated self-propagating form of the Sup35 protein from the yeast Saccharomyces cerevisiae. Aggregates of Sup35 in [PSI+] cells exist in different heritable conformations, called “variants,” and they are composed of detergent-resistant Sup35 polymers, which may be closely associated with themselves, other proteins, or both. Here, we report that disassembly of the aggregates into individual Sup35 polymers and non-Sup35 components increases their infectivity while retaining their variant specificity, showing that variant-specific [PSI+] infection can be transmitted by Sup35 polymers alone. Morphological analysis revealed that Sup35 isolated from [PSI+] yeast has the appearance of short barrels, and bundles, which seem to be composed of barrels. We show that the major components of two different variants of [PSI+] are interacting infectious Sup35 polymers and Ssa1/2. Using a candidate approach, we detected Hsp104, Ssb1/2, Sis1, Sse1, Ydj1, and Sla2 among minor components of the aggregates. We demonstrate that Ssa1/2 efficiently binds to the prion domain of Sup35 in [PSI+] cells, but that it interacts poorly with the nonaggregated Sup35 found in [psi−] cells. Hsp104, Sis1, and Sse1 interact preferentially with the prion versus nonprion form of Sup35, whereas Sla2 and Ssb1/2 interact with both forms of Sup35 with similar efficiency

National report on the status and prospects of educational development in Ukraine: monograph (On the 30th anniversary of the independence of Ukraine)

Die Publikation enthält eine umfassende Analyse des Standes und der Entwicklung des nationalen Bildungswesens in den 30 Jahren der Unabhängigkeit der Ukraine. Sie zeigt aktuelle Probleme im Bildungswesen auf, identifiziert deren Ursachen und bietet wissenschaftlich fundierte Wege zur Modernisierung des nationalen Bildungswesens im Kontext von Globalisierung, europäischer Integration, innovativer Entwicklung und nationaler Identität. Es richtet sich an Gesetzgeber, Regierungsbeamte, Leiter von Bildungseinrichtungen, pädagogische und wissenschaftlich-pädagogische Fachkräfte, die breite Öffentlichkeit und alle, die sich für die Verbesserung der Wettbewerbsfähigkeit des ukrainischen Bildungswesens im Kontext des zivilisatorischen Wandels einsetzen.Видання містить комплексний аналіз стану та розвитку національної системи освіти за 30 років незалежності України. Показано актуальні проблеми в системі освіти, визначено їх причини та запропоновано науково обґрунтовані шляхи модернізації національної системи освіти в умовах глобалізації, євроінтеграції, інноваційного розвитку та національної ідентичності. Розраховано на законодавців, державних службовців, керівників навчальних закладів, педагогів і науково-освітніх працівників, широку громадськість та всіх, хто працює над підвищенням конкурентоспроможності української системи освіти в контексті цивілізаційних змін.The publication contains a comprehensive analysis of the status and development of the national education system during the 30 years of Ukraine's independence. It shows current problems in the education system, identifies their causes and offers scientifically sound ways to modernize the national education system in the context of globalization, European integration, innovative development and national identity. It is intended for legislators, government officials, heads of educational institutions, pedagogical and scientific-educational professionals, the general public and everyone working to improve the competitiveness of the Ukrainian education system in the context of civilizational change