Delay In Exit Research Articles

Does unionization reduce wage inequality? New evidence from business dynamism

Incorporating the business-dynamism effect, this paper examines distribution and welfare effects of labor unions. An increase in unionization can raise the unskilled wage rate and lower the skilled wage rate in the economy, and wage inequality can be further reduced by the business-dynamism effect of firm exit. Nonetheless, the inequality-reducing role might be mitigated by the delay of firm exit caused by labor unions. In addition, the rise in unionization can solve the problem of excessive entry in the oligopolistic market, thereby improving welfare of the economy. Using multiple-country panel data, we find a negative relationship between unionization and wage inequality. This finding confirms the theoretical prediction of the inequality-reducing effect of labor unions.

The signalling lipid PI3,5P2 is essential for timely mitotic exit.

Coordination of mitotic exit with chromosome segregation is key for successful mitosis. Mitotic exit in budding yeast is executed by the mitotic exit network (MEN), which is negatively regulated by the spindle position checkpoint (SPOC). SPOC kinase Kin4 is crucial for SPOC activation in response to spindle positioning defects. Here, we report that the lysosomal signalling lipid phosphatidylinositol-3,5-bisphosphate (PI3,5P2) has an unanticipated role in the timely execution of mitotic exit. We show that the lack of PI3,5P2 causes a delay in mitotic exit, whereas elevated levels of PI3,5P2 accelerates mitotic exit in mitotic exit defective cells. Our data indicate that PI3,5P2 promotes mitotic exit in part through impairment of Kin4. This process is largely dependent on the known PI3,5P2 effector protein Atg18. Our work thus uncovers a novel link between PI3,5P2 and mitotic exit.

N6-methyladenosine (m6A) depletion regulates pluripotency exit by activating signaling pathways in embryonic stem cells

N6-methyladenosine (m6A) deposition on messenger RNA (mRNA) controls embryonic stem cell (ESC) fate by regulating the mRNA stabilities of pluripotency and lineage transcription factors (TFs) [P. J. Batista etal., Cell Stem Cell 15, 707-719 (2014); Y. Wang etal., Nat. Cell Biol. 16, 191-198 (2014); and S. Geula etal., Science 347, 1002-1006 (2015)]. If the mRNAs of these two TF groups become stabilized, it remains unclear how the pluripotency or lineage commitment decision is implemented. We performed noninvasive quantification of Nanog and Oct4 TF protein levels in reporter ESCs to define cell-state dynamics at single-cell resolution. Long-term single-cell tracking shows that immediate m6A depletion by Mettl3 knock-down in serum/leukemia inhibitory factor supports both pluripotency maintenance and its departure. This is mediated by differential and opposing signaling pathways. Increased FGF5 mRNA stability activates pErk, leading to Nanog down-regulation. FGF5-mediated coactivation of pAkt reenforces Nanog expression. In formative stem cells poised toward differentiation, m6A depletion activates both pErk and pAkt, increasing the propensity for mesendodermal lineage induction. Stable m6A depletion by Mettl3 knock-out also promotes pErk activation. Higher pErk counteracts the pluripotency exit delay exhibited by stably m6A-depleted cells upon differentiation. At single-cell resolution, we illustrate that decreasing m6A abundances activates pErk and pAkt-signaling, regulating pluripotency departure.

Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein

TRAPPC11 was identified as a component of the TRAPP III complex that functions in membrane trafficking and autophagy. Variants in TRAPPC11 have been reported to be associated with a broad spectrum of phenotypes but all affected individuals display muscular pathology. Identifying additional variants will further our understanding of the clinical spectrum of phenotypes and will reveal regions of the protein critical for its functions. Here we report three individuals from unrelated families that have bi-allellic TRAPPC11 variants. Subject 1 harbors a compound heterozygous variant (c.1287 + 5G > A and c.3379_3380insT). The former variant results in a partial deletion of the foie gras domain (p.Ala372_Ser429del), while the latter variant results in a frame-shift and extension at the carboxy terminus (p.Asp1127Valfs*47). Subjects 2 and 3 both harbour a homozygous missense variant (c.2938G > A; p.Gly980Arg). Fibroblasts from all three subjects displayed membrane trafficking defects manifested as delayed endoplasmic reticulum (ER)-to-Golgi transport and/or a delay in protein exit from the Golgi. All three individuals also show a defect in glycosylation of an ER-resident glycoprotein. However, only the compound heterozygous subject displayed an autophagic flux defect. Collectively, our characterization of these individuals with bi-allelic TRAPPC11 variants highlights the functional importance of the carboxy-terminal portion of the protein.

Chronic low dose arsenic exposure preferentially perturbs mitotic phase of the cell cycle

Environmental pollution is a big challenge for human survival. Arsenic compounds are well-known biohazard, the exposure of which is closely linked to onsets of various human diseases, particularly cancers. Upon chronically exposing to arsenic compounds, genomic integrity is often disrupted, leading to tumor development. However, the underlying mechanisms by which chronic, low dose arsenic exposure targets genetic stability to initiate carcinogenesis still remain not fully understood. In this study, human lung epithelial BEAS-2B cells and keratinocytes were treated with 0.5 μM of sodium arsenite for one month (designated as BEAS-2B-SA cells or keratinocytes-SA), and its effect on cell cycle responses was analyzed. After being arrested in mitotic phase of the cell cycle by nocodazole treatment, BEAS-2B-SA cells or keratinocytes-SA were delayed to enter next cytokinesis. The lagging exit of the cells from mitosis was accompanied by a sustained Plk1 phosphorylation, which led to a persistent activation of the mitotic regulators BubR1 and Cdc27. As the result, cyclin B1 (clnB1) degradation was attenuated. BEAS-2B-SA cells or keratinocytes-SA also expressed a constitutively active Akt. The cytogenetic analysis showed an increased numbers of aneuploidy in these cells. The suppression of Akt reversed the aberrant expressions of the mitotic regulators, delay of mitotic exit as well as chromosomal aberrations. Our findings suggest that a long-term exposure to low dose sodium arsenite aberrantly retains the catenation of mitosis, which facilitates establishing genetic instability and predisposes the cells to tumorigenesis.

NQO1 regulates mitotic progression and response to mitotic stress through modulating SIRT2 activity

Previous studies have shown that SIRT2 plays a role in mitosis through deacetylating specific downstream targets. However, the upstream regulation of SIRT2 activity has been relatively unexplored. In this study, we provide evidence that NAD(P)H:quinone oxidoreductase 1 (NQO1) interacts with and activates SIRT2 in an NAD-dependent manner. Strong protein-protein interaction and co-localization of the two proteins during mitosis is required to maintain an active NQO1-SIRT2 axis which is critical for successful completion of mitosis. This is evident by the observed delay in mitotic exit in cells upon NQO1 inhibition. Mechanistically, this phenotype can be explained by the decrease in APC/C complex activity resulting from decreased SIRT2 deacetylation activity. Furthermore, we show that this newly established role of NQO1 has an impact on how cancer cells may respond to mitotic stress. In this regard, both pharmacologic and genetic NQO1 inhibition increases sensitivity to anti-mitotic drugs functioning as microtubule poisons by inducing mitotic arrest and allowing cells to accumulate cell death signals. Therefore, the significant prognostic value of NQO1 in predicting outcome of cancer patients might be explained in part due to the functional contribution of NQO1-SIRT2 axis to mitotic stress. Altogether, this novel mechanism of action further supports the pleiotropic biological effects exerted by NQO1 in addition to its antioxidant function and it might provide the basis for expanding the therapeutic potential of NQO1 inhibition towards increasing sensitivity to standard treatments.

Diagnostic Perturbations.

Diagnostic Perturbations.

Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells.

Chromosomal instability (CIN) is a hallmark of many cancers and a major contributor to tumorigenesis. Centromere and kinetochore associated proteins such as the evolutionarily conserved centromeric histone H3 variant CENP-A, associate with centromeric DNA for centromere function and chromosomal stability. Stringent regulation of cellular CENP-A levels prevents its mislocalization in yeast and flies to maintain genome stability. CENP-A overexpression and mislocalization are observed in several cancers and reported to be associated with increased invasiveness and poor prognosis. We examined whether there is a direct relationship between mislocalization of overexpressed CENP-A and CIN using HeLa and chromosomally stable diploid RPE1 cell lines as model systems. Our results show that mislocalization of overexpressed CENP-A to chromosome arms leads to chromosome congression defects, lagging chromosomes, micronuclei formation and a delay in mitotic exit. CENP-A overexpressing cells showed altered localization of centromere and kinetochore associated proteins such as CENP-C, CENP-T and Nuf2 leading to weakened native kinetochores as shown by reduced interkinetochore distance and CIN. Importantly, our results show that mislocalization of CENP-A to chromosome arms is one of the major contributors for CIN as depletion of histone chaperone DAXX prevents CENP-A mislocalization and rescues the reduced interkinetochore distance and CIN phenotype in CENP-A overexpressing cells. In summary, our results establish that CENP-A overexpression and mislocalization result in a CIN phenotype in human cells. This study provides insights into how overexpression of CENP-A may contribute to CIN in cancers and underscore the importance of understanding the pathways that prevent CENP-A mislocalization for genome stability.

Protein Phosphatase 2A (PP2A) Regulates EG5 to Control Mitotic Progression

EG5 (KIF11) is a member of the kinesin-like protein family involved in centrosome separation and bipolar spindle formation. When a cell enters mitosis, CDK1 phosphorylates EG5 at Thr926 and promotes EG5 localization on the mitotic spindle which drives bipolar spindle formation. EG5 provides power for spindle movement and thus controls the dynamics of spindle assembly. However, little is known about EG5 regulation or how EG5 detaches from the spindle upon mitotic exit. In this study we identify EG5 as a novel substrate of PP2A phosphatase, and we show that the PP2A/B55α complex plays an important role in mitotic exit by a mechanism involving EG5. The PP2A/B55α complex physically associates with the EG5 C-terminal tail domain and dephosphorylates EG5 at Thr926 that enables mitotic exit. Conversely PP2A knockdown cells show a high level of phospho-EG5 in late metaphase, which is associated with a delay in mitotic exit. These phenotypic features are similar to those induced by EG5/T926D transfection that mimics phosphorylated EG5 status. Our results argue that PP2A controls mitotic exit through EG5 dephosphorylation. Lack of PP2A leads to abnormal EG5 activation, resulting in delay of mitotic exit.

Npa3/ScGpn1 carboxy-terminal tail is dispensable for cell viability and RNA polymerase II nuclear targeting but critical for microtubule stability and function

Genetic deletion of the essential GTPase Gpn1 or replacement of the endogenous gene by partial loss of function mutants in yeast is associated with multiple cellular phenotypes, including in all cases a marked cytoplasmic retention of RNA polymerase II (RNAPII). Global inhibition of RNAPII-mediated transcription due to malfunction of Gpn1 precludes the identification and study of other cellular function(s) for this GTPase. In contrast to the single Gpn protein present in Archaea, eukaryotic Gpn1 possesses an extension of approximately 100 amino acids at the C-terminal end of the GTPase domain. To determine the importance of this C-terminal extension in Saccharomyces cerevisiae Gpn1, we generated yeast strains expressing either C-terminal truncated (gpn1ΔC) or full-length ScGpn1. We found that ScGpn1ΔC was retained in the cell nucleus, an event physiologically relevant as gpn1ΔC cells contained a higher nuclear fraction of the RNAPII CTD phosphatase Rtr1. gpn1ΔC cells displayed an increased size, a delay in mitosis exit, and an increased sensitivity to the microtubule polymerization inhibitor benomyl at the cell proliferation level and two cellular events that depend on microtubule function: RNAPII nuclear targeting and vacuole integrity. These phenotypes were not caused by inhibition of RNAPII, as in gpn1ΔC cells RNAPII nuclear targeting and transcriptional activity were unaffected. These data, combined with our description here of a genetic interaction between GPN1 and BIK1, a microtubule plus-end tracking protein with a mitotic function, strongly suggest that the ScGpn1 C-terminal tail plays a critical role in microtubule dynamics and mitotic progression in an RNAPII-independent manner.

Equity stakes and exit: An experimental approach to decomposing exit delay

Research summary: Exit delay is an important problem for entrepreneurs and managers alike, yet relatively little is known about its causes. We conduct a laboratory experiment in which optimal exit is well defined, and in which a treatment group with equity stakes—the actual cash flows of a firm and decision rights over its continuation—is compared to a control group whose compensation is based solely on its assessment of the firm's profitability. While treatment group participants make exit decisions that are nearly optimal given their beliefs, their beliefs are significantly distorted relative to the control group. The pattern of distortion is consistent with confirmatory bias and motivated reasoning. A fundamental finding of our study is that incentives may not only affect behavior, but belief formation as well.Managerial summary: Managers and entrepreneurs frequently destroy significant value by failing to shut down underperforming businesses in a timely manner. To address this problem, we must understand the mechanisms causing exit delay. We examine behavioral mechanisms causing delay through a laboratory experiment in which subjects make decisions about when to exit a failing venture. We find that “equity stakes”—receiving the firm's cash flows and having decision rights over exit—cause participants to discount negative performance information, retain overly optimistic beliefs, and delay exit. By contrast, participants without these high‐powered incentives exit nearly optimally. Our findings suggest ways to reduce exit delay in managerial settings, including implementing automated decision rules, removing equity‐based compensation, and recruiting managers less susceptible to knowledge overconfidence, a trait associated with exit delay. Copyright © 2015 John Wiley & Sons, Ltd.

EFS Centre-Atlantique donor's biobank: Ten years of samples usage

IntroductionThe French Establishment of Blood Centre Atlantique (EFSCA) is one of the French regional blood transfusion centers. Donor's biobank is a mandatory activity leading to the storage of biological samples taken from the blood donor. Samples of each blood donation are preserved for a 5-year period at Châteauroux in the form of two straws of 500microliters stored in liquid nitrogen. The aim of this study was to analyze the samples usage by studying quantitative, qualitative and economic criteria. Material and methodWe analyzed all the requests of stored blood samples from 2005 to 2014. They were coming either from the blood donor qualification laboratory (BDQL), in order to perform complementary tests, or from hemovigilance inquiry. ResultsAmong the blood donation samples, 2,144,636 (whole blood, plasma or platelets apheresis) were preserved during these ten years. During this period, 548 (0.025%) requests for samples were received; 78% were in relation with a request of the BDQL and 22% in relation with a request of hemovigilance. For the straws, the mean exit delay with regard to the blood donation date was 11.5 months (2–55). The cost of samples exit includes only working hours of a laboratory technician. On average, the annual working time dedicated to this activity was 23h. Also, the average price for one-year issuing activity was 620.31 euros. ConclusionIn our study, the donor's biobank was little used. The part of hemovigilance was weak but essential for the blood safety.

American Pikas' (Ochotona princeps) Foraging Response to Hikers and Sensitivity to Heat in an Alpine Environment

Optimal foraging theory predicts tradeoffs in animals balancing net energy intake and predator avoidance. In particular, overall foraging activity could be low if (1) perception of predation risk is high or (2) abiotic conditions are suboptimal. American pikas (Ochotona princeps) are small, food-hoarding mammals whose foraging opportunities are restricted by heat and risk of predation. If hiking disturbance is perceived by pikas as predation risk, it could reduce the amount of food stored overwinter, possibly affecting survival. We simulated hiker disturbance events for 48 pikas in Mount Revelstoke and Glacier National Parks, British Columbia, to estimate foraging time lost due to hikers. We tested risk avoidance hypotheses using four indicators of risk behavior: alert distance (DA), flight initiation distance (DF), exit delay (TE), and delay in return to forage (TR). All hiker disturbance events elicited antipredator behaviors in foraging pikas and reduced foraging time; however, when compared to increasing temperatures over 4–6 hour observation periods, the latter best predicted a reduction in pikas' foraging activity. For every 1 °C increase in temperature, pika foraging activity decreased by 3%. Pikas near trails (<50 m) lost an average of 4.1 (SE = 0.6) minutes of foraging time per disturbance event compared to 13.2 (SE = 1.7) minutes lost by pikas with territories >100 m away from trails. Such differences might reflect habituation in pikas undergoing frequent disturbance. Monitoring pika populations for declines would be sensible given projected trends in warming climate and potential increases in hiking traffic.

Estimating a War of Attrition: The Case of the US Movie Theater Industry

This paper empirically studies firm's strategic exit decisions in an environment where demand is declining. Specifically, I quantify the extent to which the exit process generated by firms' strategic interactions deviates from the outcome that maximizes industry profits. I develop and estimate a dynamic exit game using data from the US movie theater industry in the 1950s, when the industry faced demand declines. Using the estimated model, I quantify the magnitude of strategic delays and find that strategic interactions cause an average delay of exit of 2.7 years. I calculate the relative importance of several components of these strategic delays. (JEL D92, L11, L82, N72)

Sumoylation of Kif18A plays a role in regulating mitotic progression.

BackgroundKif18A, the kinesin-8 motor protein, plays an essential role in regulating alignment of bi-oriented chromosomes at the midzone during mitosis. Kinesin proteins, including Kif18A, are often deregulated in many types of cancers and are thought to play a critical role in cancer progression. However, little is known about the post-translational modifications of Kif18A and their effects on its biological activity.MethodsKif18A was identified to be a SUMO2 acceptor by using Ni-IDA resin to precipitate proteins from cells stably expressing His6-SUMO2. To identify the potential lysine residues, multi-site directed mutagenesis together with transient transfection and Ni-IDA pull-down assay were carried out. The confocal time-lapse imaging and immunofluorescent staining were used to study the roles of SUMO2 modification on Kif18A’s activity during the cell cycle.ResultsKif18A is covalently modified by SUMO2 during the cell cycle, and its sumoylation peaks at metaphase and then rapidly decreases upon anaphase onset. Mutational analysis identifies multiple lysine residues (K148, K442, K533, K660 and K683) as potential SUMO acceptors. The functional studies reveal that sumoylation of Kif18A has little effect on protein stability and subcellular localization. However, compared with the wild-type control, ectopic expression of SUMO-resistant mutants of Kif18A results in a significant delay of mitotic exit. Confocal microscopy shows that cells expressing SUMO-resistant Kif18A display a compromised dissociation of BubR1 from kinetochores after anaphase onset.ConclusionsOur studies reveal that sumoylation functions as an unidentified form of post-translational modification that regulates Kif18A activity during mitotic progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1226-9) contains supplementary material, which is available to authorized users.

Equity Stakes and Exit: An Experimental Approach to Decomposing Exit Delay

Despite evidence that delayed exit is a pervasive and consequential problem, relatively little is known about its causes. Moreover, the study of exit delay is confounded by the fact that behavioral theories arising in the literature on escalation of commitment and economic theories that incorporate option value both yield predictions that delay increases in sunk costs and uncertainty. We construct a laboratory experiment that enables us to compare the timing of participants’ exit decisions with optimal choices that incorporate option value in the absence of sunk costs. We show that receiving equity stakes – the actual cash flows of the enterprise and control rights over continuation – generates delay beyond the optimal exit point for participants allocated to unprofitable firms. While participants with equity stakes make decisions that are nearly optimal given their beliefs, their beliefs are significantly distorted relative to a control group that does not receive equity stakes. The pattern of distortion is consistent with confirmatory bias and motivated reasoning. More generally, we show that incentives affect decision making not only by affecting the payoffs of different outcomes but also by distorting information processing, which in turn affects how decision-makers see the relative likelihood of different outcomes. This suggests that models of behavior that assume incentives affect behavior alone may be incomplete.

Chasing Their Tails: Why Do Firms Subsidize Underperforming Business Units?

Firms repeatedly fail to exit from underperforming lines of business. To explore the managerial motives of exit delay, this paper joins theory on scope economies and real options with a theory of internal capital market efficiency. I show that economies of scope, along with characteristics of the firm’s chief executive officer (CEO), play a significant role in the managerial decision to delay exit from an underperforming line of business. In the final stage of the analysis, I present evidence that managers may be overestimating the scope economies and option values behind their investment decisions, and that these decisions may also be subject to an escalation of commitment.

Time to exit: Rational, behavioral, and organizational delays

Existing studies of exit delay typically focus on rational, behavioral, or organizational explanations in isolation. We integrate these different theoretical explanations, develop testable hypotheses for each, and examine them using the population of US banks between 1984 and 1997. Banks' exit behavior is not consistent with theories emphasizing the option value of avoiding reentry costs. Patterns of exit do, however, support models of rational delay under ability uncertainty. Controlling for this source of rational delay, we find evidence of delay due to behavioral bias—firms discount negative signals of profitability relative to positive signals—and organizational considerations—delay increases with the separation of ownership and control. These results demonstrate that all three sets of theories are necessary to describe exit behavior

Liver X Receptor activation delays chondrocyte hypertrophy during endochondral bone growth

Activation of the Liver X Receptor (LXR) has recently been identified as a therapeutic strategy for osteoarthritis (OA). Human OA articular cartilage explants show decreased LXR expression, and LXRβ-null mice display OA-like symptoms. LXR agonist administration to OA articular cartilage explants suppresses proteoglycan degradation and restores LXR-activated transcription. We aimed to investigate the effect of LXR activation on chondrocyte differentiation to elucidate the molecular mechanisms behind its protection against OA. The specific LXR agonist, GW3965, was used to examine the effect of LXR activation on chondrocyte differentiation. Tibia organ cultures were used to examine the effect of LXR activation on bone growth and growth plate morphology, followed by immunohistochemical analysis. In ATDC5 and micromass cultures, chondrocyte differentiation was examined through cellular staining and proliferation assays. Various chondrogenic markers were analyzed by real-time reverse-transcription polymerase chain reaction (qRT-PCR) in micromass RNA. Chondrocyte hypertrophy was suppressed by GW3965 treatment, as shown by decreased hypertrophic zone length in the tibial growth plate, decreased alkaline phosphatase staining in ATDC5 and micromass cultures, and down regulation of Col10a1, Mmp13 and Runx2 expression. Increased proliferation in treated ATDC5 cells and up-regulation of Col2a1 expression in treated micromass cultures suggest hypertrophy is suppressed secondary to prolonged proliferation. Decreased p57 levels in treated growth plates suggest this to be due to cell-cycle exit delay. Our findings regarding LXR's role in cartilage development provide insight into how LXR activation prevents cartilage breakdown, further solidifying its potential as a therapeutic target of OA.

기술경쟁에서 구기술의 퇴출 지연 현상에 관한 연구: 범선 효과를 중심으로

기술경쟁에서 구기술의 퇴출 지연 현상에 관한 연구: 범선 효과를 중심으로