1,720,984 research outputs found
Chromosomal, metabolic, environmental, and hormonal origins of aneuploidy in mammalian oocytes
No full textAneuploidy is a leading cause of early embryo loss, miscarriage and birth defects in humans. It is predominantly brought about by the mis-segregation of homologous chromosomes (bivalents) in the first meiotic division (MI) of the oocyte, with advanced maternal age being a risk factor. Although its etiology is likely to be multifactorial the predominating factors remain amenable for study in models such as mice. Homologous chromosome separation in MI is achieved by the mono-orientation of functionally paired sister kinetochores but despite this unique division the Spindle Assembly Checkpoint (SAC), which prevents sister chromatid mis-segregation in mitosis, is functional in mouse oocytes. However, it remains to be fully established what types of error the SAC respond to, for example the presence of univalents, and how sensitive it is to attachment or tension defects in bivalent alignment. Such errors may increase with advanced maternal age as chromosomes lose their cohesive ties and the oocyte has less capacity to service the metabolic needs associated with meiotic division. Environmental insults and hormonal changes could also affect the fidelity of this process. Here we review how all these factors converge on the meiotic spindle during MI to cause mis-segregation errors.<br/
Non-canonical function of spindle assembly checkpoint proteins after APC activation reduces aneuploidy in mouse oocytes
No full textThe spindle assembly checkpoint (SAC) prevents aneuploidy by coupling anaphase onset, through anaphase-promoting complex (APC) activation, with chromosome attachment to spindle microtubules. Here, we examine APC activity in oocytes, noted for their susceptibility to chromosome mis-segregation during the first meiotic division (MI). We find that MI oocytes only contain sub-maximal APC activity, measured through cyclin B1–GFP degradation, because inhibition of SAC proteins when the APC is normally fully active increases cyclin B1 degradation twofold and reduces the length of this division by 2?h. In addition, inhibiting the SAC component Mps1 only when the APC is already active increases aneuploidy rates in the resulting egg by up to 30%. We therefore establish that the activities of SAC proteins and the APC co-exist in oocytes, and such concurrence has a vital role in reducing aneuploidy rates by extending MI, probably by allowing time for numerous erroneous microtubule attachments to be correcte
Chapter Seven - The control of meiotic maturation in mammalian oocytes
No full textMammalian oocytes spend the majority of their lives in a dormant state, residing in primordial follicles. This arrest, most analogous to the G2 stage of the mitotic cell cycle division, is only broken in the hours preceding ovulation, when a hormonal rise induces meiotic resumption and entry into the first meiotic division. At a molecular level, this event is triggered by CDK1 activity, and here, we examine how CDK1 is suppressed during meiotic arrest and raised for oocyte maturation. We focus on signaling: intercellular signaling between the oocyte and the somatic cells of the follicle, and spatial signaling involving the anaphase-promoting complex (APC) within the oocyte. Meiotic arrest is achieved through APCFZR1-mediated cyclin B1 degradation. Once meiotic resumption resumes, CDK1 levels rise, but its activity eventually needs to be suppressed for completion of the first meiotic division. This is achieved by APCCDC20, whose activity is critically regulated by the spindle assembly checkpoint, and which induces both a loss in CDK1 activity as well as the cohesive ties holding chromosomes together
Premature dyad separation in meiosis II is the major segregation error with maternal age in mouse oocytes
Full text linkAs women get older their oocytes become susceptible to chromosome mis-segregation. This generates aneuploid embryos, leading to increased infertility and birth defects. Here we examined the provenance of aneuploidy by tracking chromosomes and their kinetochores in oocytes from young and aged mice. Changes consistent with chromosome cohesion deterioration were found with age, including increased interkinetochore distance and loss of the centromeric protector of cohesion SGO2 in metaphase II arrested (metII) eggs, as well as a rise in the number of weakly attached bivalents in meiosis I (MI) and lagging chromosomes at anaphase I. However, there were no MI errors in congression or biorientation. Instead, premature separation of dyads in meiosis II was the major segregation defect in aged eggs and these were associated with very low levels of SGO2. These data show that although considerable cohesion loss occurs during MI, its consequences are observed during meiosis II, when centromeric cohesion is needed to maintain dyad integrit
Timing of anaphase-promoting complex activation in mouse oocytes is predicted by microtubule-kinetochore attachment but not by bivalent alignment or tension
No full textHomologous chromosome segregation errors during meiosis I are common and generate aneuploid embryos. Here, we provide a reason for this susceptibility to mis-segregation by live cell imaging of mouse oocytes. Our results show that stable kinetochore-microtubule attachments form in mid-prometaphase, 3-4 hours before anaphase. This coincided with the loss of Mad2 from kinetochores and with the start of anaphase-promoting complex/cyclosome (APC/C)-mediated cyclin B1 destruction. Therefore, the spindle assembly checkpoint (SAC) ceased to inhibit the APC/C from mid-prometaphase. This timing did not coincide with bivalent congression in one-third of all oocytes examined. Non-aligned bivalents were weakly positive for Mad2, under less tension than congressed bivalents and, by live-cell imaging, appeared to be in the process of establishing correct bi-orientation. The time from when the APC/C became active until anaphase onset was affected by the rate of loss of CDK1 activity, rather than by these non-aligned bivalents, which occasionally persisted until anaphase, resulting in homolog non-disjunction. We conclude that, in oocytes, a few erroneous attachments of bivalent kinetochores to microtubules do not generate a sufficient SAC 'wait anaphase' signal to inhibit the APC/C. <br/
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The Aurora kinase inhibitor ZM447439 accelerates first meiosis in mouse oocytes by overriding the spindle assembly checkpoint
No full textPrevious studies have established that when maturing mouse oocytes are continuously incubated with the Aurora inhibitor ZM447439, meiotic maturation is blocked. In this study, we observe that by altering the time of addition of the inhibitor, oocyte maturation can actually be accelerated by 1 h as measured by the timing of polar body extrusion. ZM447439 also had the ability to overcome a spindle assembly checkpoint (SAC) arrest caused by nocodazole and so rescue polar body extrusion. Consistent with the ability of the SAC to inhibit cyclin B1 degradation by blocking activation of the anaphase-promoting complex, we could also observe a rescue in cyclin B1 degradation when ZM447439 was added to nocodazole-treated oocytes. The acceleration of the first meiotic division by ZM447439, which has not been achieved previously, and its effects on the SAC are all consistent with the proposed mitotic role of Aurora B in activating the SAC. We hypothesize that Aurora kinase activity controls the SAC in meiosis I, despite differences to the mitotic cell cycle division in spindle architecture brought about by the meiotic mono-orientation of sister kinetochores
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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