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- Eisele-Bürger, Anna Maria, et al.
(författare)
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Calmodulin regulates protease versus co-chaperone activity of a metacaspase
- 2023
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Ingår i: Cell Reports. - 2211-1247. ; 42:11
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Tidskriftsartikel (refereegranskat)abstract
- Metacaspases are ancestral homologs of caspases that can either promote cell death or confer cytoprotection. Furthermore, yeast (Saccharomyces cerevisiae) metacaspase Mca1 possesses dual biochemical activity: proteolytic activity causing cell death and cytoprotective, co-chaperone-like activity retarding replicative aging. The molecular mechanism favoring one activity of Mca1 over another remains elusive. Here, we show that this mechanism involves calmodulin binding to the N-terminal pro-domain of Mca1, which prevents its proteolytic activation and promotes co-chaperone-like activity, thus switching from pro-cell death to anti-aging function. The longevity-promoting effect of Mca1 requires the Hsp40 co-chaperone Sis1, which is necessary for Mca1 recruitment to protein aggregates and their clearance. In contrast, proteolytically active Mca1 cleaves Sis1 both in vitro and in vivo, further clarifying molecular mechanism behind a dual role of Mca1 as a cell-death protease versus gerontogene.
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| 3. |
- Kanjala, Chifundo, et al.
(författare)
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Spatial and temporal clustering of mortality in Digkale HDSS in rural northern South Africa
- 2010
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Ingår i: Global Health Action. - : CoAction Publishing. - 1654-9716 .- 1654-9880. ; 3, s. 59-63
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Tidskriftsartikel (refereegranskat)abstract
- Although cause-specific mortality data were not available, the rise in mortality in the 15-49-year age group over time and in areas closer to conurbations strongly suggests that the clustering observed was due to the development of HIV/AIDS-related mortality, as seen similarly elsewhere in South Africa. The HIV/AIDS services offered by the local health centre may have contributed to lower relative mortality around that location.
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- Oprea-Lager, Daniela Elena, et al.
(författare)
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European Association of Nuclear Medicine Focus 5 : Consensus on Molecular Imaging and Theranostics in Prostate Cancer
- 2024
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Ingår i: European Urology. - 0302-2838. ; 85:1, s. 49-60
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Tidskriftsartikel (refereegranskat)abstract
- Background: In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. Objective: We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. Design, setting, and participants: The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. Outcome measurements and statistical analysis: Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. Results and limitations: After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy. Conclusions: There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. Patient summary: There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.
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| 5. |
- Ruiz-Solani, N., et al.
(författare)
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Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates, and delays senescence
- 2023
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Ingår i: Plant Cell. - 1040-4651. ; 35:9, s. 3325-3344
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Tidskriftsartikel (refereegranskat)abstract
- The Arabidopsis metacaspase MC1 is recruited to stress granules upon proteotoxic stress, participates in clearance of pathological protein aggregates, and delays senescence. Stress granules (SGs) are highly conserved cytoplasmic condensates that assemble in response to stress and contribute to maintaining protein homeostasis. These membraneless organelles are dynamic, disassembling once the stress is no longer present. Persistence of SGs due to mutations or chronic stress has been often related to age-dependent protein-misfolding diseases in animals. Here, we find that the metacaspase MC1 is dynamically recruited into SGs upon proteotoxic stress in Arabidopsis (Arabidopsis thaliana). Two predicted disordered regions, the prodomain and the 360 loop, mediate MC1 recruitment to and release from SGs. Importantly, we show that MC1 has the capacity to clear toxic protein aggregates in vivo and in vitro, acting as a disaggregase. Finally, we demonstrate that overexpressing MC1 delays senescence and this phenotype is dependent on the presence of the 360 loop and an intact catalytic domain. Together, our data indicate that MC1 regulates senescence through its recruitment into SGs and this function could potentially be linked to its remarkable protein aggregate-clearing activity.
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