8,484 research outputs found

    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    CANCER TREATMENT BY TARGETING HDAC4 TRANSLOCATION INDUCED BY MICROSECOND PULSED ELECTRIC FIELD EXPOSURE: MECHANISTIC INSIGHTS THROUGH KINASES AND PHOSPHATASES

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    Epigenetic modifications, arising from sub-cellular shifts in histone deacetylase (HDAC) activity and localization, present promising strategies for diverse cancer treatments. HDACs, enzymes responsible for post-translational histone modifications, induce these epigenetic changes by removing acetyl groups from ε-N-acetyl-lysine residues on histones, thereby suppressing gene transcription. Within the HDAC group, class IIa HDACs are notable for their responsiveness to extracellular signals, bridging the gap between external stimuli, plasma membrane, and genome through nuclear-cytoplasmic translocation. This localization offers two significant mechanisms for cancer treatment: nuclear accumulation of HDACs represses oncogenic transcription factors, such as myocyte-specific enhancer factor 2C (MEF2C), triggering various cell death pathways. Conversely, cytoplasmic HDAC accumulation acts similarly to HDAC inhibitors by silencing genes. My dissertation introduces an innovative approach for glioblastoma and breast cancer treatment by investigating the application of microsecond pulsed electric fields. It particularly focuses on HDAC4, a class IIa HDAC overexpressed in these cancers. Beyond demonstrating HDAC4 translocation, my research delves into the intricate roles of kinases and phosphatases, shedding light on the underlying factors governing HDAC4 translocation

    Monotheism and the Suffering of Animals in Nature

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    This is the Submitted Manuscript Under Review. The final version is available from Cambridge University Press via the DOI in this recordThis Element concerns itself with a particular aspect of the problem posed to monotheistic religious thought by suffering, namely the suffering of non-human creatures in nature. It makes some comparisons between Judaism, Christianity, and Islam, and then explores the problem in depth within Christian thought. After clarification of the nature of the problem, the Element considers a range of possible responses, including those based on a fall-event, those based on freedom of process, and those hypothesising a constraint on the possibilities for God as creator. Proposals based on the motif of self-emptying are evaluated. Two other aspects of the question concern God's providential relationship to the evolving creation, and the possibility of resurrection lives for animals. After consideration of the possibility of combining different explanations, the Element ends its discussion by looking at two innovative proposals at the cutting-edge of the debate

    The detection of polymorphism of RecKoRV Loci within the Victorian koala population

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    Koala Retrovirus (KoRV) is known to be the most recently acquired endogenous retrovirus and is still settling to its genomic parasitic lifestyle. KoRV has both infectious and endogenous (integrated into the host genome) forms. One hundred percent of the Koalas in northern Australia are positive for the virus. A higher proviral copy number per cell has been observed in Northern koalas due to endogenized KoRV compared to that in the south. The Koalas in southern Australia show a variability in the prevalence rate of the exogenous virus and a lower rate of KoRV induced disease. Southern Australian koalas earlier considered to be disease free or only having the exogenous counterparts of the virus, demonstrate a defective variant of KoRV known as Recombinant KoRV(RecKoRV). RecKoRV is formed due to the recombination between Phascolarctid Endogenous Retroelement (PhER) and KoRV. The presence of RecKoRV variants particularly in the founder population on the French island calls into question the existence of KoRV free animals. The difference in the KoRV profiles between the northern and the southern animals raises the possibility that these replication defective transcripts may be interfering with full length transcripts of the replication competent KoRV. The presence of RecKoRV variants particularly in the founder population and in the Victorian animals indicate that all southern animals have these variants. The aim of this study is to look at the polymorphism of the RecKoRV loci using integration site-specific PCRs to explore whether these are fixed or variable in the Victorian koala population. RT-PCRs were performed on koala samples collected from the Cape Otway region in Victoria, Australia to check for the prevalence of KoRV. RecKoRV Insertion site-specific PCRs were optimized and performed on a second set of samples which were collected from different regions in Victoria Australia and were negative for KoRV to detect the polymorphism of different RecKoRV loci. The design of these PCRs proved problematic with non-specific amplification, possibly due to the repetitive nature of the LTRs of retroviruses. Techniques such as inverse PCR may be necessary to analyze the insertion site variation of these RecKoRV loci

    Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides

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    peer reviewedA series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 µM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 µM was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 µM. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an ‘averaged’ selection-driven interaction pattern was produced based in namely ‘pseudo–consensus’ 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds

    Systematic Analysis of SUMO Paralogue-specific Functions and a Novel SUMO1-Dependent Pathway for Cytosolic Protein Quality Control

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    The small ubiquitin-related modifiers (SUMOs) are essential protein regulators that modulate nearly every aspect of cellular functions. Five SUMO paralogues have been identified in humans, with sequence homologies ranging from 45% to 97%. Among them, SUMO1 and SUMO2 are the least similar and also the best studied. However, to what extent SUMO1 and SUMO2 impart distinct and non-redundant cellular functions, has not been systematically examined and is therefore not well understood. To systematically identify and characterize paralogue-specific functions of SUMO proteins, we used CRISPR-Cas9 to individually knock out SUMO1 and SUMO2 expression in human osteosarcoma (U2OS) cells. Analysis of these knockout cell lines revealed non-redundant roles for SUMO1 and SUMO2 in regulating essential cellular functions, including cellular morphology, PML nuclear body integrity, response to cellular stresses, and control of gene expression. Using SUMO knockout cell lines and yeast strains expressing SUMO mutant proteins, we also identified a conserved SUMO-dependent pathway for degradation of protein quality control (PQC) model proteins containing the CL1 degron (GFP-Ura3-CL1 in yeast and GFP-CL1 in humans) that operates only in the cytosol but not the nucleus. Furthermore, we found that in humans, turnover of GFP-CL1 in the cytosol was uniquely dependent on SUMO1 but not SUMO2, revealing a previously unrecognized role for SUMO1 in regulating cytosolic PQC. PQC is essential for maintaining proteostasis and normal cellular functions, and therefore PQC perturbation proceeds numerous human diseases. Compared to the well-characterized PQC pathways within the endoplasmic reticulum and the nucleus, much less is known about the mechanisms that modulate cytosolic misfolded protein degradation. Findings reported in this thesis reveal a novel regulatory mechanism of cytosolic PQC, which contributes to a comprehensive view of the complicated cellular PQC network and provides novel insights into PQC-associated diseases
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