385 research outputs found
The N-terminal domain of the prion protein is required and sufficient for liquid-liquid phase separation: A crucial role of the Aβ-binding domain
No full textFormation of biomolecular condensates through liquid-liquid phase separation (LLPS) has been described for several pathogenic proteins linked to neurodegenerative diseases and is discussed as an early step in the formation of protein aggregates with neurotoxic properties. In prion diseases, neurodegeneration and formation of infectious prions is caused by aberrant folding of the cellular prion protein (PrPC). PrPC is characterized by a large intrinsically disordered N-terminal domain and a structured C-terminal globular domain. A significant fraction of mature PrPC is proteolytically processed in vivo into an entirely unstructured fragment, designated N1, and the corresponding C-terminal fragment C1 harboring the globular domain. Notably, N1 contains a polybasic motif that serves as a binding site for neurotoxic Aβ oligomers. PrP can undergo LLPS; however, nothing is known how phase separation of PrP is triggered on a molecular scale. Here, we show that the intrinsically disordered N1 domain is necessary and sufficient for LLPS of PrP. Similar to full-length PrP, the N1 fragment formed highly dynamic liquid-like droplets. Remarkably, a slightly shorter unstructured fragment, designated N2, which lacks the Aβ-binding domain and is generated under stress conditions, failed to form liquid-like droplets and instead formed amorphous assemblies of irregular structures. Through a mutational analysis, we identified three positively charged lysines in the postoctarepeat region as essential drivers of condensate formation, presumably largely via cation-π interactions. These findings provide insights into the molecular basis of LLPS of the mammalian prion protein and reveal a crucial role of the Aβ-binding domain in this process
Brevican, Neurocan, Tenascin-C and Tenascin-R Act as Important Regulators of the Interplay between Perineuronal Nets, Synaptic Integrity, Inhibitory Interneurons and Otx2
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The legacy of Ruth Bader Ginsburg
No full textL’Autrice approfondisce il personaggio ed il ruolo di Justice Ruth Bader Ginsburg secondo la prospettiva del diritto costituzionale nazionale.
Il saggio ripercorre la storia di Justice Ginsburg, occupandosi prima del suo contributo come avvocata e successivamente come giudice presso la Corte Suprema statunitense.
Attraverso l’analisi di alcune tra le sue opinions più importanti, sia di maggioranza che dissenzienti, il saggio offre un affresco del pensiero di Justice Ginsburg su alcune tematiche fondamentali sotto il profilo dei diritti e dei rapporti tra Giudice costituzionale e legislatore.
In particolare, l’A. si sofferma sulla concezione di eguaglianza promossa da Justice Ginsburg soprattutto, ma non solo, in relazione ai diritti delle donne e con riferimento al concetto di azione positiva; segue, poi, un approfondimento delle funzioni del dissent nel sistema istituzionale statunitense e un’analisi della nozione di giustizia come interpretata da Justice Ginsburg.
Il saggio si propone, quindi, di evidenziare l’eredità che Justice Ginsburg ha lasciato dietro di sè a livello globale.The Author investigates the figure and role of Justice Ruth Bader Ginsburg from a constitutional law perspective.
The paper deals with contribution of Justice Ruth Bader Ginsburg as a lawyer first and later as justice appointed to the United States Supreme Court.
By way of analysis touching upon some her most prominent majority and dissenting opinions, the A. hinges on several issues pertaining to the safeguard of fundamental rights and to the relationships between the legislator and the Constitutional Judge.
The Author then goes on by examining Justice Ginsburg’s concept of equality with respect to women’s rights and affirmative actions to then move on to an in depth focus on the role of the dissent in the US legal system and on Justice Ginsburg’s concept of justice.
At the outset, the Articles aims at highlighting the legacy of Ruth Bader Ginsburg on a global dimension
Biomechanical signals and the C-type natriuretic peptide counteract catabolic activities induced by IL-1? in chondrocyte/agarose constructs
No full textIntroduction: The present study examined the effect of C-type natriuretic peptide (CNP) on the anabolic and catabolic activities in chondrocyte/agarose constructs subjected to dynamic compression. Methods: Constructs were cultured under free-swelling conditions or subjected to dynamic compression with low (0.1 to 100 pM) or high concentrations (1 to 1,000 nM) of CNP, interleukin-1? (IL-1?), and/or KT-5823 (inhibits cyclic GMP-dependent protein kinase II (PKGII)). Anabolic and catabolic activities were assessed as follows: nitric oxide (NO) and prostaglandin E2 (PGE2) release, and [3H]-thymidine and 35SO4 incorporation were quantified by using biochemical assays. Gene expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), aggrecan, and collagen type II were assessed with real-time quantitative PCR (qPCR). Two-way ANOVA and the post hoc Bonferroni-corrected t tests were used to examine data. Results: CNP reduced NO and PGE2 release and partially restored [3H]-thymidine and 35SO4 incorporation in constructs cultured with IL-1?. The response was dependent on the concentration of CNP, such that 100 pM increased [3H]-thymidine incorporation (P < 0.001). This is in contrast to 35SO4 incorporation, which was enhanced with 100 or 1000 nM CNP in the presence and absence of IL-1? (P < 0.001). Stimulation by both dynamic compression and CNP and/or the PKGII inhibitor further reduced NO and PGE2 release and restored [3H]-thymidine and 35SO4 incorporation. In the presence and absence of IL-1?, the magnitude of stimulation for [3H]-thymidine and 35SO4 incorporation by dynamic compression was dependent on the concentration of CNP and the response was inhibited with the PKGII inhibitor. In addition, stimulation by CNP and/or dynamic compression reduced IL-1?-induced iNOS and COX-2 expression and restored aggrecan and collagen type II expression. The catabolic response was not further influenced with the PKGII inhibitor in IL-1?-treated constructs. Conclusions: Treatment with CNP and dynamic compression increased anabolic activities and blocked catabolic effects induced by IL-1?. The anabolic response was PKGII mediated and raises important questions about the molecular mechanisms of CNP with mechanical signals in cartilage. Therapeutic agents like CNP could be administered in conjunction with controlled exercise therapy to slow the OA disease progression and to repair damaged cartilage. The findings from this research provide the potential for developing novel agents to slow the pathophysiologic mechanisms and to treat OA in the young and old. <br/
Sounds Local, 1997 May 10
No full textInterview with author Ellyn Bache on her new novel, The Activist's Daughter, about young people in the 1960s; Ken Bader interviews operatic soprano singer Jayne West on performing opera vs. cabaret music; Romy and Michele's High School Reunion (film) review by WHQR's film commentator, Steve Taylor; Overview of upcoming events on the cultural calendar
LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF‐κB to the nucleus
No full textRemodeling of the Fibrillation Pathway of α-Synuclein by Interaction with Antimicrobial Peptide LL-III
No full textLiquid-liquid phase separation (LLPS) has emerged as a key mechanism for intracellular organization, and many recent studies have provided important insights into the role of LLPS in cell biology. There is also evidence that LLPS is associated with a variety of medical conditions, including neurodegenerative disorders. Pathological aggregation of α-synuclein, which is causally linked to Parkinson's disease, can proceed via droplet condensation, which then gradually transitions to the amyloid state. We show that the antimicrobial peptide LL-III is able to interact with both monomers and condensates of α-synuclein, leading to stabilization of the droplet and preventing conversion to the fibrillar state. The anti-aggregation activity of LL-III was also confirmed in a cellular model. We anticipate that studying the interaction of antimicrobial-type peptides with liquid condensates such as α-synuclein will contribute to the understanding of disease mechanisms (that arise in such condensates) and may also open up exciting new avenues for intervention
Reportages about Russia by Krystyna Kurczab-Redlich and Jacek Hugo-Bader
No full textThe main purpose of this article is to present the image of Russia in the Polish literary reportage. I would like to show how often the contemporary Polish reportage refers to national stereotypes, even if it wants to argue with them. My analysis mainly focus on the books of Krystyna Kurczab-Redlich and Jacek Hugo-Bader, who describe the contemporary russian politics and culture from different perspectives. While the author of "Pandrioszka" mostly concentrates on Moscow, the author of "Dzienniki kołymskie" is particularly interested in Kolyma
Cross-seeding by prion protein inactivates TDP-43
No full textAbstract A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the physiological activity of the aggregating protein and/or a gain of toxic function of the misfolded protein conformers. In transmissible spongiform encephalopathies or prion diseases, neurodegeneration is caused by aberrantly folded isoforms of the prion protein (PrP). However, it is poorly understood how pathogenic PrP conformers interfere with neuronal viability. Employing in vitro approaches, cell culture, animal models, and patients’ brain samples, we show that misfolded PrP can induce aggregation and inactivation of TDP-43. Purified PrP aggregates interact with TDP-43 in vitro and in cells and induce the conversion of soluble TDP-43 into non-dynamic protein assemblies. Similarly, mislocalized PrP conformers in the cytosol bind to and sequester TDP-43 in cytosolic aggregates. As a consequence, TDP-43-dependent splicing activity in the nucleus is significantly decreased, leading to altered protein expression in cells with cytosolic PrP aggregates. Finally, we present evidence for cytosolic TDP-43 aggregates in neurons of transgenic flies expressing mammalian PrP and Creutzfeldt–Jakob disease patients. Our study identified a novel mechanism of how aberrant PrP conformers impair physiological pathways by cross-seeding
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