17 research outputs found
Three is the magic number -- distance measurement of NGC 3147 using SN 2021hpr and its siblings
The nearby spiral galaxy NGC 3147 hosted three Type Ia supernovae (SNe Ia) in
the past decades, which have been subjects of intense follow-up observations.
Simultaneous analysis of their data provides a unique opportunity for testing
the different light curve fitting methods and distance estimations. The
detailed optical follow-up of SN 2021hpr allows us to revise the previous
distance estimations to NGC 3147, and compare the widely used light curve
fitting algorithms to each other. After the combination of the available and
newly published data of SN 2021hpr, its physical properties can be also
estimated with higher accuracy. We present and analyse new BVgriz and Swift
photometry of SN 2021hpr to constrain its general physical properties. Together
with its siblings, SNe 1997bq and 2008fv, we cross-compare the individual
distance estimates of these three SNe given by the SALT code, and also check
their consistency with the results from the MLCS2k2 method. The early spectral
series of SN 2021hpr are also fit with the radiative spectral code TARDIS in
order to verify the explosion properties and constrain the chemical
distribution of the outer ejecta. After combining the distance estimates for
the three SNe, the mean distance to their host galaxy, NGC 3127, is 42.5
1.0 Mpc, which matches with the distance inferred by the most up-to-date LC
fitters, SALT3 and BayeSN. We confirm that SN~2021hpr is a Branch-normal Type
Ia SN that ejected M from its progenitor white
dwarf, and synthesized M of radioactive Ni.Comment: 16 pages, 17 figures, 11 tables; accepted for publication in A&
Epigenetic modulation of radiation-induced diacylglycerol kinase alpha expression prevents pro-fibrotic fibroblast response
Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After irradiation, the transcription factor EGR1 is induced and binds to the hypomethylated enhancer, leading to increased DGKA and pro-fibrotic marker expression. We now modulated this DGKA induction by targeted epigenomic and genomic editing of the DGKA enhancer and administering epigenetic drugs. Targeted DNA demethylation of the DGKA enhancer in HEK293T cells resulted in enrichment of enhancer-related histone activation marks and radiation-induced DGKA expression. Mutations of the EGR1-binding motifs decreased radiation-induced DGKA expression in BJ fibroblasts and caused dysregulation of multiple fibrosis-related pathways. EZH2 inhibitors (GSK126, EPZ6438) did not change radiation-induced DGKA increase. Bromodomain inhibitors (CBP30, JQ1) suppressed radiation-induced DGKA and pro-fibrotic marker expression. Similar drug effects were observed in donor-derived fibroblasts with low DNA methylation. Overall, epigenomic manipulation of DGKA expression may offer novel options for a personalized treatment to prevent or attenuate radiotherapy-induced fibrosis
Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer
Genome-wide association studies (GWAS) have identified many genetic susceptibility loci
for colorectal cancer (CRC). However, variants in these loci explain only a small proportion
of familial aggregation, and there are likely additional variants that are associated with CRC
susceptibility. Genome-wide studies of gene-environment interactions may identify variants
that are not detected in GWAS of marginal gene effects. To study this, we conducted a
genome-wide analysis for interaction between genetic variants and alcohol consumption
and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the
Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were
tested using logistic regression. We identified interaction between CRC risk and alcohol
consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76Ć10ā8; permuted pvalue
3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol
consumption was associated with a lower risk of colorectal cancer among individuals with
rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74Ā±0.91]; P = 2.1Ć10ā4) and TT genotypes
(OR,0.62 [95% CI, 0.51Ā±0.75]; P = 1.3Ć10ā6) but not associated among those with the CC
genotype (p = 0.059). No genome-wide statistically significant interactions were observed
for smoking. If replicated our suggestive finding of a genome-wide significant interaction
between genetic variants and alcohol consumption might contribute to understanding colorectal
cancer etiology and identifying subpopulations with differential susceptibility to the
effect of alcohol on CRC risk
Cellular pathogenic mechanisms linked to TBK-1 and optineurin in amyotrophic lateral sclerosis
Bibliography: pages 102-110.1. Introduction -- 2. Thesis topic -- 3. Materials and methods -- 4. Results -- 5. Discussion.Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with the loss of both upper and lower motor neurons in the motor cortex, brain stem and spinal cord. The pathogenic mechanisms underlying ALS remaln largely unknown. The pathological hallmark of ALS is the presence of cytoplasmic inclusions containing misfolded proteins in degenerating motor neurons. These inclusions are present regardless of the site of symptom onset. age or gender of the patient. Moreover, these inclusions are present in both sporadic and familial forms of ALS. Misfolded protein accumulation triggers stress in the endoplasmic reticulum (ER), inducing the unfolded protein response (UPR), and ER stress is now a well described feature of ALS. The UPR aims to restore proteostasis, but if unresolved triggers apoptosis. The UPR is also linked to autophagy, a self- degradative process that could clear protein aggregates. However. the presence of protein Inclusions suggests that both UPR and autophagy could be dysfunctional in ALS. One of the genes most recently identified In ALS encoded, TBK-1, a kinase involved in different forms of selective autophagy including mitophagy and xenophagy. Interestingly, TBK-1 phosphorylates optienurin an autophagy adaptor protein that is also linked genetically to ALS. In this project the effect of ALS-causing mutations in TBK1 on ER-stress, autophagy and the association between optienurin and TBK-1 autophagy were examined. Using site directed mutagenesis kinase and substrate binding deficient ALSĀ·mutant TBKĀ·1 overexpresslng constructs were generated and the effect of expression of the mutants was examined. Preliminary results showed that expresslon of kinase deficient mutants decreased expression of CHOP, a pro-apoptotic transcription factor, normally induced during ER-stress. This suggests that the kinase activity ofTBK-1 is associated with CHOP independent of ALS. Furthermore. a slight but significantly decrease In LC3-11 levels was detected upon ALSĀ·mutant TBK-1 overexpresslon, suggesting AlS-mutants inhibit autophagy. Additionally, ALS-mutant optineurin failed to recruit endogenous TBK-1 to autophagosomes In NSC-34 cells. This thesis therefore provides novel insight into cellular pathways perturbed in ALSĀ· associated mutants of TBKĀ·1.Mode of access: World wide web1 online resource (xx, 110 pages) illustration
Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma
Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and glaucoma, affect millions of people worldwide. ALS is caused by the loss of motor neurons in the spinal cord, brainstem, and brain, and genetic mutations are responsible for 10% of all ALS cases. Glaucoma is characterized by the loss of retinal ganglion cells and is the most common cause of irreversible blindness. Interestingly, mutations in OPTN, encoding optineurin, are associated with both ALS and glaucoma. Optineurin is a highly abundant protein involved in a wide range of cellular processes, including the inflammatory response, autophagy, Golgi maintenance, and vesicular transport. In this review, we summarize the role of optineurin in cellular mechanisms implicated in neurodegenerative disorders, including neuroinflammation, autophagy, and vesicular trafficking, focusing in particular on the consequences of expression of mutations associated with ALS and glaucoma. This review, therefore showcases the impact of optineurin dysfunction in ALS and glaucoma
Rab1-dependent ER-Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS
Several diverse proteins are linked genetically/pathologically to neurodegeneration in amyotrophic lateral sclerosis (ALS) including SOD1, TDP-43 and FUS. Using a variety of cellular and biochemical techniques, we demonstrate that ALS-associated mutant TDP-43, FUS and SOD1 inhibit protein transport between the endoplasmic reticulum (ER) and Golgi apparatus in neuronal cells. ERāGolgi transport was also inhibited in embryonic cortical and motor neurons obtained from a widely used animal model (SOD1G93A mice), validating this mechanism as an early event in disease. Each protein inhibited transport by distinct mechanisms, but each process was dependent on Rab1. Mutant TDP-43 and mutant FUS both inhibited the incorporation of secretory protein cargo into COPII vesicles as they bud from the ER, and inhibited transport from ER to the ERāGolgi intermediate (ERGIC) compartment. TDP-43 was detected on the cytoplasmic face of the ER membrane, whereas FUS was present within the ER, suggesting that transport is inhibited from the cytoplasm by mutant TDP-43, and from the ER by mutant FUS. In contrast, mutant SOD1 destabilised microtubules and inhibited transport from the ERGIC compartment to Golgi, but not from ER to ERGIC. Rab1 performs multiple roles in ERāGolgi transport, and over-expression of Rab1 restored ERāGolgi transport, and prevented ER stress, mSOD1 inclusion formation and induction of apoptosis, in cells expressing mutant TDP-43, FUS or SOD1. Rab1 also co-localised extensively with mutant TDP-43, FUS and SOD1 in neuronal cells, and Rab1 formed inclusions in motor neurons of spinal cords from sporadic ALS patients, which were positive for ubiquitinated TDP-43, implying that Rab1 is misfolded and dysfunctional in sporadic disease. These results demonstrate that ALS-mutant forms of TDP-43, FUS, and SOD1 all perturb protein transport in the early secretory pathway, between ER and Golgi compartments. These data also imply that restoring Rab1-mediated ERāGolgi transport is a novel therapeutic target in ALS.19 page(s
Protein quality control and the amyotrophic lateral sclerosis/frontotemporal dementia continuum
Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials