viability loss
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Author(s):  
Cory Haluska ◽  
Fengzhi Jin ◽  
Yanchang Wang

DNA replication stress activates the S-phase checkpoint that arrests the cell cycle, but it is poorly understood how cells recover from this arrest. Cyclin-dependent kinase (CDK) and Protein Phosphatase 2A (PP2A) are key cell cycle regulators, and Cdc55 is a regulatory subunit of PP2A in budding yeast. We found that yeast cells lacking functional PP2ACdc55 showed slow growth in the presence of hydroxyurea (HU), a DNA synthesis inhibitor, without obvious viability loss. Moreover, PP2A mutants exhibited delayed anaphase entry and sustained levels of anaphase inhibitor Pds1 after HU treatment. A DNA damage checkpoint Chk1 phosphorylates and stabilizes Pds1. We showed that chk1Δ and mutation of the Chk1 phosphorylation sites in Pds1 largely restored efficient anaphase entry in PP2A mutants after HU treatment. In addition, deletion of SWE1 that encodes the inhibitory kinase for CDK or mutation of the Swe1 phosphorylation site in CDK ( cdc28F19) also suppressed the anaphase entry delay in PP2A mutants after HU treatment. Our genetic data suggest that Swe1/CDK acts upstream of Pds1. Surprisingly, cdc55Δ showed significant suppression to the viability loss of S-phase checkpoint mutants during DNA synthesis block. Together, our results uncover a PP2A-Swe1-CDK-Chk1-Pds1 axis that promotes recovery from DNA replication stress.


2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Viktorija Juric ◽  
Lance Hudson ◽  
Joanna Fay ◽  
Cathy E. Richards ◽  
Hanne Jahns ◽  
...  

AbstractActivation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options. Since CDKs 2, 7 and 9 were found to be overexpressed in GBM, we tested the therapeutic efficacy of two CDK inhibitors (CKIs) (CYC065 and THZ1) in a heterogeneous panel of GBM patient-derived cell lines (PDCLs) cultured as gliomaspheres, as preclinically relevant models. CYC065 and THZ1 treatments suppressed invasion and induced viability loss in the majority of gliomaspheres, irrespective of the mutational background of the GBM cases, but spared primary cortical neurons. Viability loss arose from G2/M cell cycle arrest following treatment and subsequent induction of apoptotic cell death. Treatment efficacies and treatment durations required to induce cell death were associated with proliferation velocities, and apoptosis induction correlated with complete abolishment of Mcl-1 expression, a cell cycle-regulated antiapoptotic Bcl-2 family member. GBM models generally appeared highly dependent on Mcl-1 expression for cell survival, as demonstrated by pharmacological Mcl-1 inhibition or depletion of Mcl-1 expression. Further analyses identified CKI-induced Mcl-1 loss as a prerequisite to establish conditions at which the BH3-only protein Bim can efficiently induce apoptosis, with cellular Bim amounts strongly correlating with treatment efficacy. CKIs reduced proliferation and promoted apoptosis also in chick embryo xenograft models of primary and recurrent GBM. Collectively, these studies highlight the potential of these novel CKIs to suppress growth and induce cell death of patient-derived GBM cultures in vitro and in vivo, warranting further clinical investigation.


Author(s):  
Maria Tereza Cratiú Moreira ◽  
Evandro Martins ◽  
Ítalo Tuler Perrone ◽  
Rosângela Freitas ◽  
Lucas Sales Queiroz ◽  
...  

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Maud Weiss ◽  
Jiahui Fan ◽  
Mickaël Claudel ◽  
Thomas Sonntag ◽  
Pascal Didier ◽  
...  

Abstract Background A positive surface charge has been largely associated with nanoparticle (NP) toxicity. However, by screening a carbon NP library in macrophages, we found that a cationic charge does not systematically translate into toxicity. To get deeper insight into this, we carried out a comprehensive study on 5 cationic carbon NPs (NP2 to NP6) exhibiting a similar zeta (ζ) potential value (from + 20.6 to + 26.9 mV) but displaying an increasing surface charge density (electrokinetic charge, Qek from 0.23 to 4.39 µmol/g). An anionic and non-cytotoxic NP (NP1, ζ-potential = − 38.5 mV) was used as control. Results The 5 cationic NPs induced high (NP6 and NP5, Qek of 2.95 and 4.39 µmol/g, respectively), little (NP3 and NP4, Qek of 0.78 and 1.35 µmol/g, respectively) or no (NP2, Qek of 0.23 µmol/g) viability loss in THP-1-derived macrophages exposed for 24 h to escalating NP dose (3 to 200 µg/mL). A similar toxicity trend was observed in airway epithelial cells (A549 and Calu-3), with less viability loss than in THP-1 cells. NP3, NP5 and NP6 were taken up by THP-1 cells at 4 h, whereas NP1, NP2 and NP4 were not. Among the 6 NPs, only NP5 and NP6 with the highest surface charge density induced significant oxidative stress, IL-8 release, mitochondrial dysfunction and loss in lysosomal integrity in THP-1 cells. As well, in mice, NP5 and NP6 only induced airway inflammation. NP5 also increased allergen-induced immune response, airway inflammation and mucus production. Conclusions Thus, this study clearly reveals that the surface charge density of a cationic carbon NP rather than the absolute value of its ζ-potential is a relevant descriptor of its in vitro and in vivo toxicity.


Cryobiology ◽  
2020 ◽  
Vol 97 ◽  
pp. 285
Author(s):  
Daniela Impe ◽  
Daniel Ballesteros ◽  
Till Ischebeck ◽  
Claudia Koepnick ◽  
Hardy Rolletschek ◽  
...  

2020 ◽  
Vol 87 (3) ◽  
pp. 382-385
Author(s):  
Débora C. Cnossen ◽  
Ramila Cristiane Rodrigues ◽  
Evandro Martins ◽  
José de Castro Cezarino Junior ◽  
Antônio Fernandes de Carvalho

AbstractThe research described in this technical research communication examines the hypothesis that sublethal stress conditions can improve the survival of Lactococcus lactis subsp. lactis during drying and subsequent storage. After drying, the L. lactis that had adapted to acid or osmotic stresses did not differ statistically in terms of cell viability loss compared to the control samples tested (~0.38 log cycles). However, the cells that had adapted to oxidative conditions demonstrated a cell viability loss of only 0.01 log cycles. After 45 d of storage at temperatures of 4 and 25 °C, the final L. lactis sample populations were shown to be higher (112.5%) when they had been submitted to sublethal conditions of oxidative stress. When the cell samples were exposed to acid stress conditions, they exhibited a viability loss (0.82 log cycles) that was statistically different from the control sample (0.58 log cycles) after 45 d. Osmotic stress conditions did not demonstrate any influence over cell survival rates. Thus, submitting cells to oxidative stress conditions prior to storage has been shown to be a potential strategy for producing dehydrated cultures of L. lactis strains that are less sensitive to oxygen exposure.


2020 ◽  
Vol 30 (2) ◽  
pp. 161-172
Author(s):  
Christina Walters ◽  
Margaret B. Fleming ◽  
Lisa M. Hill ◽  
Emma J. Dorr ◽  
Christopher M. Richards

AbstractCharacterizing non-lethal damage within dry seeds may allow us to detect early signs of ageing and accurately predict longevity. We compared RNA degradation and viability loss in seeds exposed to stressful conditions to quantify relationships between degradation rates and stress intensity or duration. We subjected recently harvested (‘fresh’) ‘Williams 82’ soya bean seeds to moisture, temperature and oxidative stresses, and measured time to 50% viability (P50) and rate of RNA degradation, the former using standard germination assays and the latter using RNA Integrity Number (RIN). RIN values from fresh seeds were also compared with those from accessions of the same cultivar harvested in the 1980s and 1990s and stored in the refrigerator (5°C), freezer (−18°C) or in vapour above liquid nitrogen (−176°C). Rates of viability loss (P50−1) and RNA degradation (RIN⋅d−1) were highly correlated in soya bean seeds that were exposed to a broad range of temperatures [holding relative humidity (RH) constant at about 30%]. However, the correlation weakened when fresh seeds were maintained at high RH (holding temperature constant at 35°C) or exposed to oxidizing agents. Both P50−1 and RIN⋅d−1 parameters exhibited breaks in Arrhenius behaviour near 50°C, suggesting that constrained molecular mobility regulates degradation kinetics of dry systems. We conclude that the kinetics of ageing reactions at RH near 30% can be simulated by temperatures up to 50°C and that RNA degradation can indicate ageing prior to and independent of seed death.


2020 ◽  
Vol 30 (2) ◽  
pp. 122-132 ◽  
Author(s):  
Nicholas G. Genna ◽  
Christina Walters ◽  
Héctor E. Pérez

AbstractRecent evidence points to relationships between intra-specific seed mass variation and viability loss in response to ageing stress. However, little is known about how seed quality may change temporally in response to such stress. Here we examined seed–water relations of mass-separated Rudbeckia mollis seeds to better understand physiological status among mass classes. We then evaluated seed viability and vigour changes in response to various storage conditions or post-storage vigour tests (a 41°C, 75% RH stress for up to 45 d). We found similar pre-storage physiology among mass classes. However, seeds of lower mass deteriorated up to 1.5-fold faster than heavier seeds under certain conditions. Stressing seeds after storage resulted in distinct vigour differences among mass classes. For example, vigour in lower mass seeds tended to decline more compared to heavier seeds following storage in a climate-controlled room. Alternatively, vigour loss varied among mass classes following storage in a non-climate-controlled shed. Our results highlight the importance of distinguishing between pre-sowing storage and post-storage vigour effects when quantifying relative levels of viability loss among seeds of different mass. Furthermore, differential responses to storage and ageing stress among mass classes may have important implications for post-storage regeneration and subsequent population dynamics.


Food Research ◽  
2020 ◽  
Vol 4 (4) ◽  
pp. 964-975
Author(s):  
A.S.L. Sulabo ◽  
M.E.L. Villasanta ◽  
K.G. Hermo ◽  
R.A. Lascano ◽  
L.S. Collado ◽  
...  

Development of an active starter culture is essential in the production of safe and highquality fermented foods. Freeze-drying is an effective microbial cell immobilization technology intended to produce active and stable starter cultures for long-term storage. To determine the influence of various drying medium formulations with mung bean powder and disaccharides on the viability of L. plantarum S20 during freeze-drying and subsequent storage at 6±2°C and 30±1°C, three treatments of drying medium consisting of mung bean powder without disaccharides (MBP), MBP with 5% (w/v) trehalose (MBP+T), and MBP with 5% (w/v) sucrose (MBP+T) were evaluated. Results showed that L. plantarum S20 viability after freeze-drying ranged from 9.56 to 10.03 log (CFU/g) with viability loss ranging from 0.20 to 0.51 log (CFU/g), with MBP being the least effective (p<0.05) in minimizing viability loss. Supplementing MBP with either 5% sucrose or 5% trehalose improved (p<0.05) survival of freeze-dried L. plantarum S20; and both disaccharides exhibit similar (p>0.05) cryoprotective effects on L. plantarum S20 during freeze-drying and subsequent storage. Storage at 6±2°C for 180 days resulted in significant decreases of 2.15, 2.17, and 3.27 log (CFU/g) in L. plantarum S20 population in MBP+T, MBP+S, and MBP, respectively. A more drastic decline [>6.0 Log (CFU/g)] in L. plantarum S20 population was observed in freeze-dried culture stored at 30±1°C for 60 days. Fermentation characteristics of freeze-dried L. plantarum S20 in mung bean slurry were also determined. Freeze-dried L. plantarum S20 in MBP with 5% (w/v) sucrose was able to acidify mung bean slurry from pH 6.8 to pH 3.8 after 8 hrs with maximum LAB population of 9.2 log (CFU/mL). Acidification of mung bean slurry by fresh culture (non-freeze-dried) on the other hand was relatively slower where pH dropped from 6.8 to pH 3.72 after 24 hrs. Current work suggested that lyophilized L. plantarum S20 could be used as a starter culture for mung bean-based fermentations but further research on this area is needed.


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