SET levels contribute to cohesion fatigue.
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ABSTRACT:
SUBMITTER: Yang L
PROVIDER: S-EPMC8351544 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chromosome instability is thought to be a major contributor to cancer malignancy and birth defects. For balanced chromosome segregation in mitosis, kinetochores on sister chromatids bind and pull on microtubules emanating from opposite spindle poles. This tension contributes to the correction of improper kinetochore attachments and is opposed by the cohesin complex that holds the sister chromatids together. Normally, within minutes of alignment at the metaphase plate, chromatid cohesion is released, allowing each cohort of chromatids to move synchronously to opposite poles in anaphase, an event closely coordinated with mitotic exit.Here we show that during experimentally induced metaphase delay, spindle pulling forces can cause asynchronous chromatid separation, a phenomenon we term "cohesion fatigue." Cohesion fatigue is not blocked by inhibition of Plk1, a kinase essential for the "prophase pathway" of cohesin release from chromosomes, or by depletion of separase, the protease that normally drives chromatid separation at anaphase. Cohesion fatigue is inhibited by drug-induced depolymerization of mitotic spindle microtubules and by experimentally increasing the levels of cohesin on mitotic chromosomes. In cells undergoing cohesion fatigue, cohesin proteins remain associated with the separated chromatids.In cells arrested at metaphase, pulling forces originating from kinetochore-microtubule interactions can, with time, rupture normal sister chromatid cohesion. This cohesion fatigue, resulting in unscheduled chromatid separation in cells delayed at metaphase, constitutes a previously overlooked source for chromosome instability in mitosis and meiosis.
| S-EPMC3119564 | biostudies-literature
Project description:Cells delayed in metaphase with intact mitotic spindles undergo cohesion fatigue, where sister chromatids separate asynchronously, while cells remain in mitosis. Cohesion fatigue requires release of sister chromatid cohesion. However, the pathways that breach sister chromatid cohesion during cohesion fatigue remain unknown. Using moderate-salt buffers to remove loosely bound chromatin cohesin, we show that "cohesive" cohesin is not released during chromatid separation during cohesion fatigue. Using a regulated protein heterodimerization system to lock different cohesin ring interfaces at specific times in mitosis, we show that the Wapl-mediated pathway of cohesin release is not required for cohesion fatigue. By manipulating microtubule stability and cohesin complex integrity in cell lines with varying sensitivity to cohesion fatigue, we show that rates of cohesion fatigue reflect a dynamic balance between spindle pulling forces and resistance to separation by interchromatid cohesion. Finally, while massive separation of chromatids in cohesion fatigue likely produces inviable cell progeny, we find that short metaphase delays, leading to partial chromatid separation, predispose cells to chromosome missegregation. Thus, complete separation of one or a few chromosomes and/or partial separation of sister chromatids may be an unrecognized but common source of chromosome instability that perpetuates the evolution of malignant cells in cancer.
| S-EPMC6085821 | biostudies-literature
Project description:PurposeCardiovascular responses of traditional resistance (TS) training have been extensively explored. However, the fatigue mechanisms associated with an intra-set rest configuration (ISR) have not been investigated. This study compares two modalities of set configurations for resistance exercise that equates work to rest ratios and measures the central and peripheral fatigue in combination with cortical, hemodynamic and cardiovascular measures.Methods11 subjects performed two isometric knee extension training sessions using TS and ISR configurations. Voluntary activation (VA), single twitch amplitude, low frequency fatigue (LFF), Mwave, motor evoked potential (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF) and heart rate variability were evaluated before and after each training session. During each session beat to beat heart rate, blood pressure and rate pressure product (RPP) were also evaluated.ResultsAfter exercise VA decreased significantly for TS but not for ISR (P < 0.001), single twitch amplitude and LFF values were lower for TS than ISR (P < 0.004), and SICI was reduced only for the TS configuration (P = 0.049). During exercise RPP values were significantly higher for the TS than for ISR (P = 0.001). RPP correlated with VA for TS (r = -.85 P < 0.001) suggesting a relationship between central fatigue and cardiovascular stress.ConclusionsWe conclude that ISR induced lower central and peripheral fatigue as well as lower cardiovascular stress in comparison with TS configuration. Our study suggests that set configuration is a key factor in the regulation of the neuromuscular and cardiovascular responses of resistance training.
| S-EPMC4794235 | biostudies-literature
Project description:Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1?+?aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.
| S-EPMC5472593 | biostudies-literature
Project description:Sustained spindle tension applied to sister centromeres during mitosis eventually leads to uncoordinated loss of sister chromatid cohesion, a phenomenon known as "cohesion fatigue." We report that Aurora A-dependent phosphorylation of serine 7 of the centromere histone variant CENP-A (p-CENP-AS7) protects bioriented chromosomes against cohesion fatigue. Expression of a non-phosphorylatable version of CENP-A (CENP-AS7A) weakens sister chromatid cohesion only when sister centromeres are under tension, providing the first evidence of a regulated mechanism involved in protection against passive cohesion loss. Consistent with this observation, p-CENP-AS7 is detected at the inner centromere where it forms a discrete domain. The depletion or inhibition of Aurora A phenocopies the expression of CENP-AS7A and we show that Aurora A is recruited to centromeres in a Bub1-dependent manner. We propose that Aurora A-dependent phosphorylation of CENP-A at the inner centromere protects chromosomes against tension-induced cohesion fatigue until the last kinetochore is attached to spindle microtubules.
| S-EPMC5951908 | biostudies-other
Project description:The Spindle Assembly Checkpoint (SAC) delays the onset of anaphase in response to unattached kinetochores by inhibiting the activity of the Anaphase-Promoting Complex/Cyclosome (APC/C), an E3 ubiquitin ligase. Once all the chromosomes have bioriented, SAC signalling is somehow silenced, which allows progression through mitosis. Recent studies suggest that the APC/C itself participates in SAC silencing by targeting an unknown factor for proteolytic degradation. Key evidence in favour of this model comes from the use of proTAME, a small molecule inhibitor of the APC/C. In cells, proTAME causes a mitotic arrest that is SAC-dependent. Even though this observation comes at odds with the current view that the APC/C acts downstream of the SAC, it was nonetheless argued that these results revealed a role for APC/C activity in SAC silencing. However, we show here that the mitotic arrest induced by proTAME is due to the induction of cohesion fatigue, a phenotype that is caused by the loss of sister chromatid cohesion following a prolonged metaphase. Under these conditions, the SAC is re-activated and APC/C inhibition is maintained independently of proTAME. Therefore, these results provide a simpler explanation for why the proTAME-induced mitotic arrest is also dependent on the SAC. While these observations question the notion that the APC/C is required for SAC silencing, we nevertheless show that APC/C activity does partially contribute to its own release from inhibitory complexes, and importantly, this does not depend on proteasome-mediated degradation.
| S-EPMC3492190 | biostudies-literature
Project description:BackgroundThe primary aim of this study was to examine the relationship between maximal oxygen update (V̇O2max) and within-set fatigue and between-set recovery during resistance exercise in men and women.MethodsWe examined the relationship between V̇O2max and various indices of fatigue and recovery during parallel squats (3 sets, 90 s rest, 70% of 1RM to failure) and isokinetic knee extensions (3 × 10 maximal repetitions at 60 deg/s, 45 s rest) in 28 (age 27.0 ± 3.6 years) resistance-trained subjects (14 men and 14 women). We also examined whether there were sex differences in within-set fatigue and between-set recovery.ResultsV̇O2max was weakly related to recovery and fatigue in both men and women (range of P-values for V̇O2max as a covariate; 0.312-0.998, range of R-values, 0.005-0.604). There were no differences between the sexes in fatigue within a set for the squat, but men showed less within-set fatigue than women in the first set of the isokinetic knee extension exercise (~ 8% torque loss difference, main effect of sex P = 0.034). Regarding recovery between sets, men showed greater relative peak power (P = 0.016) and peak torque (P = 0.034) loss between sets in both exercises, respectively, compared to women. Women also tended to complete more repetitions than men (main effect of sex, P = 0.057). Loss of peak torque between sets in knee extension was evident in both absolute and relative (%) values in men but not in women.ConclusionsOur study suggests that aerobic capacity is weakly associated with within-set fatigue and between-set recovery in resistance training in both men and women. Women and men show comparable levels of within-set fatigue in the multi-joint squat, but women show more within-set fatigue during the single-joint isokinetic knee extension compared with men. In contrast, women recover better than men between sets in both exercises.
| S-EPMC10863198 | biostudies-literature
Project description:BackgroundGeneral practitioners (GPs) make numerous care decisions throughout their workdays. Extended periods of decision making can result in decision fatigue, a gradual shift toward decisions that are less cognitively effortful. This study examines whether observed patterns in GPs' prescribing decisions are consistent with the decision fatigue phenomenon. We hypothesized that the likelihood of prescribing frequently overprescribed medications (antibiotics, benzodiazepines, opioids; less effortful to prescribe) will increase and the likelihood of prescribing frequently underprescribed medications (statins, osteoporosis medications; more effortful to prescribe) will decrease over the workday.MethodsThis study used nationally representative primary care data on GP-patient encounters from the Bettering the Evaluation and Care of Health program from Australia. The association between prescribing decisions and order of patient encounters over a GP's workday was assessed with generalized linear mixed models accounting for clustering and adjusting for patient, provider, and encounter characteristics.ResultsAmong 262,456 encounters recorded by 2,909 GPs, the odds of prescribing antibiotics significantly increased by 8.7% with 15 additional patient encounters (odds ratio [OR] = 1.087; confidence interval [CI] = 1.059-1.116). The odds of prescribing decreased significantly with 15 additional patient encounters by 6.3% for benzodiazepines (OR = 0.937; CI = 0.893-0.983), 21.9% for statins (OR = 0.791; CI = 0.753-0.831), and 25.0% for osteoporosis medications (OR = 0.750; CI = 0.690-0.814). No significant effects were observed for opioids. All findings were replicated in confirmatory analyses except the effect of benzodiazepines.ConclusionsGPs were increasingly likely to prescribe antibiotics and were less likely to prescribe statins and osteoporosis medications as the workday wore on, which was consistent with decision fatigue. There was no convincing evidence of decision fatigue effects in the prescribing of opioids or benzodiazepines. These findings establish decision fatigue as a promising target for optimizing prescribing behavior.HighlightsWe found that as general practitioners progress through their workday, they become more likely to prescribe antibiotics that are reportedly overprescribed and less likely to prescribe statins and osteoporosis medications that are reportedly underprescribed.This change in decision making over time is consistent with the decision fatigue phenomenon. Decision fatigue occurs when we make many decisions without taking a rest break. As we make those decisions, we become gradually more likely to make decisions that are less difficult.The findings of this study show that decision fatigue is a possible target for improving guideline-compliant prescribing of pharmacologic medications.
| S-EPMC11346129 | biostudies-literature
Project description:Splitting sets into clusters has been shown to maintain performance during resistance training. This study compared the acute fatigue produced by a traditional (TSC) versus a cluster (CSC) set configuration in the smith machine half squat exercise. Fifteen males performed a single bout of TSC and CSC separated by 72-96 h. In the TSC, participants performed as many repetitions as possible until reaching a 20% drop in barbell velocity (MPV), while in the CSC, they performed the same number of repetitions with 15 seconds inter-repetition rest. Effects of both protocols in MPV, countermovement jump height (CMJ), and blood lactate (BLa) were measured. Significant differences between protocols were found for MPV of the last repetition (0.4 vs 0.5 m/s TSC and CSC) and BLa (6.8 mmol/L vs 3.2 mmol/L TSC and CSC). Significant drop of velocity from the first to the last repetition of the set (19.9%), decrease in CMJ height (35.4 vs 32.6 cm), and increase in BLa (2.1 vs 6.8 mmol/L) pre-post-exercise was observed just for the TSC protocol. The results of the present study showed that CSC reduces the lactate response and mechanical fatigue produced by a single set on the half squat exercise in comparison with TSC.
| S-EPMC7240581 | biostudies-literature
Project description:BackgroundThe aim of our meta-analysis is to understand the relationship between the pathogenesis of osteoarthritis and the expression levels of vascular endothelial growth factor (VEGF) in multiple disease tissues in osteoarthritis patients.MethodsThe following electronic databases were searched, without language restrictions, to retrieve published studies relevant to VEGF and osteoarthritis: MEDLINE (1966?~?2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980?~?2013), CINAHL (1982?~?2013), Web of Science (1945?~?2013) and the Chinese Biomedical Database (CBM) (1982?~?2013). Meta-analysis of the extracted data was performed using the STATA statistical software. Standardized mean difference (SMD) with its corresponding 95% confidence interval (95% CI) was calculated.ResultsA total of 11 case-control studies, containing 302 osteoarthritis patients and 195 healthy controls, met our selection criteria for this meta-analysis. Our analyses of the data available from multiple disease tissues demonstrate that VEGF expression levels in osteoarthritis patients are significantly higher than healthy controls (SMD?=?1.18, 95% CI: 4.91?~?9.11, P?<?0.001). A subgroup analysis based on ethnicity revealed that both Asian and Caucasian osteoarthritis patients had higher levels of VEGF expression compared to their respective healthy counterparts (Asians: SMD?=?5.49, 95% CI: 3.44?~?7.54, P?<?0.001; Caucasians: SMD?=?15.17, 95% CI: 5.21?~?25.13, P?=?0.003; respectively). We also performed other subgroup analyses based on country, language and sample source, and the results showed that, in all these subgroups, osteoarthritis patients had higher levels of VEGF expression than healthy controls (all P?>?0.05).ConclusionOur meta-analysis provides evidence that higher VEGF expression levels strongly correlate with the pathogenesis of osteoarthritis.
| S-EPMC4391471 | biostudies-literature