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In Vivo Characterization of CLR01, an Aggregation and Toxicity Inhibitor, with an Alzheimer's Disease Focus
No full textAberrant protein self-assembly underlies over 30 human diseases called amyloidoses, for which there are no cures. In these diseases, particular proteins misfold and self-assemble into toxic oligomers that disrupt cellular function, and proceed to form insoluble amyloid fibrils that deposit in specific tissues. A promising strategy for preventing and treating amyloidoses is inhibition or modulation of the self-assembly process to disrupt the formation of the toxic oligomers. In practice, this has proven immensely difficult because the oligomer structures are unknown, are metastable, and do not have distinct binding sites. In this dissertation, three primary studies are presented that evaluate and characterize a small molecule, CLR01, which utilizes a novel strategy circumventing these challenges and has been found to be efficacious as an aggregation and toxicity inhibitor in vitro and in vivo. In the first study, CLR01 was evaluated for its ability to rescue synaptic toxicity in cell culture and brain slices. Additionally, it was tested in a transgenic mouse model of AD for its ability to reduce the pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles. This study found positive results in all domains tested; a rescue from amyloid β-protein (Aβ)-induced depletion of synaptic spine density, a rescue of Aβ-induced disruption of basal synaptic transmission and long-term potentiation, and reduction of brain Aβ, hyperphosphorylated tau, and microglia burden. CLR01 also showed low propensity for causing metabolic toxicity or drug-drug interaction, indicating favorable drug-like characteristics. In the second study, CLR01's safety and pharmacological profile were characterized in mice. CLR01 was found not to disrupt normal protein assembly, to have a high safety margin in mice, and to penetrate the blood-brain barrier (BBB) at 1-3%. Interestingly, brain levels of CLR01 remained stable for 72 hours following administration despite rapid clearance from the plasma. These results suggest a large safety margin for CLR01 and a pharmacokinetic profile that allows reaching high levels in the brain by administering relatively low doses. The third study delineates a detailed optimization of behavioral testing of mice for detection of memory deficits using the Barnes maze, and validates for the first time memory deficits in a triple-transgenic mouse model of AD at the youngest age described in the literature. The study provides a framework for analysis of CLR01's influence on learning and memory deficits in this triple transgenic model. Additionally, the study provides specific and detailed guidelines for optimizing both the performance and the analysis of the Barnes maze in a manner that increases the likelihood of detecting subtle changes in future studies using mouse models of AD. The work described in this dissertation provides a strong foundation supporting formal pre-clinical development of CLR01 as a promising disease-modifying therapeutic drug for AD
Chapter Fifteen Disease-modifying therapy for proteinopathies: Can the exception become the rule?
No full textDisease-modifying therapies for proteinopathies are urgently needed yet clinical trials for the major neurodegenerative diseases, Alzheimer's and Parkinson's, have been failing at an alarming rate leaving patients and caregivers scrambling for any sign of hope. At the same time, for one family of proteinopathies, the rare TTR amyloidoses, disease-modifying therapy has existed for almost 3 decades and two new types of disease-modifying therapy have become available more recently. In this chapter, I discuss those therapies, examine to what extent they can be generalized for other diseases, and consider what we may learn from their relative success
Structural Studies of Prion Proteins and Prions
No full textPrion diseases are a group of fatal and incurable neurodegenerative disorders of mammals. They uniquely manifest as sporadic, genetic, and infectious maladies. The agent responsible for prion diseases is the prion. A prion is defined as a proteinaceous infectious particle, which is solely constituted by an alternately folded form of the prion protein (PrP) (Prusiner 1982).
In diseased animals and humans, PrP exists in two forms, the physiological, cel- lular form of PrP, PrPC, and the pathological prion form denoted as PrPSc. The mech- anism whereby nascent PrPSc is generated is currently unknown. Structural studies of either isoform are of great importance for understanding the biology of prion diseases since they may clarify the molecular mechanisms responsible for these pathologies. In this chapter, we present an overview of the studies into PrPC as well as structures of prions
The recent failure of the PROMESA clinical trial for multiple system atrophy raises the question—are polyphenols a viable therapeutic option against proteinopathies?
No full textThe Role of Anisakis sp. in α-Gal Sensitization: Implications for Parasitic-Induced Meat Allergy
No full textAuthor Contributions:
Conceptualization, M.R., A.S.O., F.V., A.D. and C.C.; methodology, M.R., S.R., Á.V. and J.G.-F.; validation, M.R., J.G.-F., A.D. and C.C.; formal analysis, M.R., J.G.-F., A.D. and C.C.; investigation, M.R., S.R., Á.V., J.G.-F., A.S.O., F.V., A.D. and C.C.; resources, A.S.O., F.V. and C.C.; data curation, M.R., J.G.-F., A.D. and C.C.; writing—original draft preparation, M.R. and C.C.; writing—review and editing, M.R., J.G.-F., A.D. and C.C.; funding acquisition, A.S.O., F.V. and C.C. All authors have read and agreed to the published version of the manuscriptBackground/Objectives:
This study investigates the potential of Anisakis sp. as a novel source of α-Gal (Galα1-3Galβ1-4GlcNAc-R) epitopes capable of inducing allergic sensitization in humans. While α-Gal is classically associated with delayed IgE-mediated hypersensitivity following tick bites, emerging evidence suggests that parasitic helminths such as Anisakis sp. may also express α-Gal-containing glycoconjugates, offering an alternative sensitization pathway.
Methods:
Protein extracts from Anisakis sp. third-stage larvae and mammalian tissues (beef, pork) were analyzed by SDS-PAGE and Western blot using a monoclonal anti-α-Gal antibody (clone M86), and α-Gal epitopes were detected by ELISA. Sera from urticaria patients, stratified by Anisakis sp. sensitization status, were evaluated for anti-α-Gal IgG, IgE, and IgG4 antibodies. Inhibition assays assessed cross-reactivity
Results:
Results confirmed the presence of α-Gal epitopes on Anisakis sp. proteins, with prominent bands at ~250 kDa and 65 kDa. Urticaria patients sensitized to Anisakis sp. exhibited significantly elevated anti-α-Gal antibody levels compared to controls. Inhibition ELISA demonstrated substantial reduction in antibody binding with Anisakis sp. extracts, indicating shared antigenic determinants with mammalian α-Gal.
Conclusions:
These findings establish Anisakis sp. as a source of α-Gal-containing glycoproteins capable of eliciting specific antibody responses in humans, highlighting a potential parasitic route for α-Gal sensitizationDepto. de Microbiología y ParasitologíaDepto. de Sanidad AnimalFac. de FarmaciaFac. de VeterinariaTRUEpu
The Gal family
No full textKnjiga "Porodica Gal" Magde Simin predstavlja dirljivu i dokumentaristički utemeljenu pripovest o jevrejskoj porodici iz Vojvodine, čija sudbina osvetljava širi kontekst stradanja, opstanka i identiteta tokom burnih istorijskih previranja 20. veka. Kroz priču o članovima porodice Gal, autorka pažljivo rekonstruiše svakodnevni život, porodične veze, kulturne običaje i tragediju Holokausta, oslanjajući se na arhivsku građu, fotografije, svedočanstva i lična sećanja. Ovo delo je i omaž izgubljenim životima, ali i čin sećanja koji doprinosi kulturi pamćenja i očuvanju jevrejskog nasleđa u Srbiji. "Porodica Gal" je važan doprinos lokalnoj istoriji, ali i univerzalna priča o ljubavi, gubitku i ljudskoj istrajnosti."The Gal Family" by Magda Simin is a touching, documentary-style narrative about a Jewish family from Vojvodina, reflecting the broader themes of suffering, survival, and identity amid the turbulent events of the 20th century. Through the story of the Gal family members, the author carefully reconstructs their daily lives, family bonds, cultural customs, and the tragedy of the Holocaust, drawing on archival materials, photographs, testimonies, and personal memories. This work serves as both a tribute to those who were lost and an act of remembrance that contributes to the culture of memory and the preservation of Jewish heritage in Serbia. "The Gal Family" makes a significant contribution to local history and remains a universal story of love, loss, and human resilience.Biblioteka Dokument
Comparative analysis of geographical names in the slovenian translations of j. r. r. tolkien`s the lord of the rings
No full textTema magistrske naloge je prevajanje in primerjava prevodov zemljepisnih imen, ki so vključena v fantazijsko delo Gospodar prstanov avtorja J. R. R. Tolkiena, ki je v pomoč prevajalcem izdal tudi navodila o prevajanju imen v Gospodarju prstanov. Roman so leta 1995 prvič prevedli Polona Mertelj, Primož Pečovnik in Zoran Obradović, drugi prevod pa je med letoma 2002 in 2004 opravil Branko Gradišnik. V sklopu analize naloga obravnava še teorijo posodabljanja prevodov. V romanu so prisotna številna edinstvena imena, ki na zanimiv in pretkan način opisujejo značilnosti različnih krajev. Velikokrat vključujejo tudi prvine staroangleškega in nordijskega besedišča ter so ukoreninjena z zgodovinskimi dejstvi iz romana. Zaradi tega so v prevodih uporabljene različne prevajalske strategije. Da bi bralci razumeli pomen in kulturno zasidranost teh imen, so v prevodih prisotne podomačitve in prilagoditve izvirnika ciljnemu jeziku. Primerjalna analiza izvirnika in obeh prevodov je pokazala, da so imena v prvotnem prevodu bolj podomačena kot v novejšem prevodu. Obenem pa je razvidno, da je prevajalec novejšega prevoda bolj dosledno upošteval Tolkienova navodila, kot pa so to storili prevajalci prvotnega prevoda.The thesis focuses on translations of geographical names in The Lord of the Rings, a fantasy work by J. R. R. Tolkien. The novel includes many unique names which describe the features of different landscapes in an interesting and exuberant manner. The names often include elements from the Old English and Nordic vocabulary and are rooted in the historical events of the novel. It is particularly interesting that to guide future translators the author published an essay Guide to the Names in The Lord of the Rings, in which he gave instructions on how to properly translate the names in his works. The novel was first translated into Slovene in 1995 by Polona Mertelj, Primož Pečovnik in Zoran Obradović. The novel was retranslated by Branko Gradišnik between 2002 and 2004. The thesis is based on the hypothesis of retranslation which claims that the initial translation is more domesticated and source-oriented than the subsequent. As we discovered, the translators often used the strategies of adaptation and substitution to help the readers understand all cultural connotations attached to the original meaning. Comparative analysis of the source text and both translations showed that in the first translation the names were more often translated by adaptation than in the second translation. On the other hand, the results of the research demonstrated that Gradišnik followed Tolkien\u27s rules more precisely than the translators of the first translation
Radical research as research at the roots: Practitioner self-image, public relations and ethics
No full textSemantically, radical derives from ‘radix’, the Latin for root. This paper argues that little public relations research goes back to the roots of actual practice and addresses this neglect through a project focusing on practitioner accounts of their work. When considering public relations ethics, practitioner self-images and cultural values become an essential research component. In addressing this neglected area of research, this paper examines the subjective perceptions of public relations practitioners regarding their role, commitments, and responsibilities within the framework of their specific culture and national history. In considering practitioner testimonials about professional integrity, briefs, and goals, especially as members of the society and nation to which they belong, the paper engages with ethical aspects of the practice from a cultural perspective that assumes different cultures can have different ethical expectations. In revealing the impact of features that are often ‘taken for granted’ in one country, the paper uses the example of four generations of practitioners who served one major institution in Israel to suggest how similar research at the professional roots in other nations might enable knowledge of international similarities and difference in relation to ethics in action
I frutti dello Spirito Santo - il commento di san Tommaso d\u27Aquino ai Gal 5,22ss
No full textIn the presentation of the subject – preceded by an Introduction, where the Aquinas is presented as Bible’s Commentator – the author examines the saint Thomas’ interpretations of saint Paul’s texts regarding the theme of this research, confronted with the contemporary exegesis, and presents three points: 1 – The vices (Gal 5,19-21); 2 – The fruits of the Holy Spirit (Gal 5,22-23a); 3 – Against such there is no Law (Gal 5,23b; whit the interpretation of Gal 5,24-25). All this permits to the author to conclude that the doctrine of the fruits of the Holy Spirit presented by Saint Thomas in this Commentary is very clear, rich and remains valid and topical and permits to remain in the faith, morality and spirituality of the Church.In the presentation of the subject – preceded by an Introduction, where the Aquinas is presented as Bible’s Commentator – the author examines the saint Thomas’ interpretations of saint Paul’s texts regarding the theme of this research, confronted with the contemporary exegesis, and presents three points: 1 – The vices (Gal 5,19-21); 2 – The fruits of the Holy Spirit (Gal 5,22-23a); 3 – Against such there is no Law (Gal 5,23b; whit the interpretation of Gal 5,24-25). All this permits to the author to conclude that the doctrine of the fruits of the Holy Spirit presented by Saint Thomas in this Commentary is very clear, rich and remains valid and topical and permits to remain in the faith, morality and spirituality of the Church
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