Dynamical modeling of the network controlling meiotic divisions

Mitosis and meiosis are both controlled by oscillations in the activities of cyclin- dependent kinase 1 (Cdk1) and the anaphase-promoting complex/cyclosome (APC/C). Nevertheless, these types of cell division differ in fundamental aspects. In mitosis, Cdk1 and APC/C-Cdc20 form a cyclical system whereby each cycle recreates the starting conditions for the next one. As a result, chromosomes duplication during S-phase alternates with chromosome segregation during M-phase. By contrast, meiosis is a linear pathway of precisely two waves of Cdk1 and APC/C-Cdc20 activity that govern the progression through one S-phase followed by two M-phases and a differentiation program dedicated to the formation of gametes or spores. Despite recent advances in our understanding of meiosis, it is unclear how the mitotic cell cycle engine is modified to regulate the two meiotic divisions. Therefore, we combined mathematical modeling with experimental studies on budding yeast to describe the general mechanism of progression through meiotic divisions with special emphasis on the regulation of the exit from meiosis II. We showed that progression through meiotic divisions is driven by a well conserved Cdk1-APC/C-Cdc20 oscillator complemented by a set of meiotic regulators in order to perform two, and only two, meiotic divisions. The machinery that terminates the oscillations after completion of meiosis II consists of a meiosis I-specific mechanism that unleashes the irreversible inactivation of M-phase regulators after the second wave of APC/C-Cdc20 activity, thereby preventing cells from undergoing an additional third division. Here, we describe the roles of the two main APC/C co- activators, Ama1 and Cdc20, in triggering the exit from meiosis and in terminating the oscillations. We show that Ama1 acts as a terminator of the meiotic oscillations, while Cdc20 is important for the proper timing of the exit from meiosis II. We propose that in the absence of Ama1, the properties of the system change, allowing Cdc20 to adopt the function of the terminator precisely after meiosis II. In addition, we evaluate an APC/C-independent mechanisms, which might be important for preventing a third meiotic division

Gonadotropin and kisspeptin gene expression, but not GnRH, are impaired in cFOS deficient mice.

cFOS is a pleiotropic transcription factor, which binds to the AP1 site in the promoter of target genes. In the pituitary gonadotropes, cFOS mediates induction of FSHβ and GnRH receptor genes. Herein, we analyzed reproductive function in the cFOS-deficient mice to determine its role in vivo. In the pituitary cFOS is necessary for gonadotropin subunit expression, while TSHβ is unaffected. Additionally, cFOS null animals have the same sex-steroid levels, although gametogenesis is impeded. In the brain, cFOS is not necessary for GnRH neuronal migration, axon targeting, cell number, or mRNA levels. Conversely, cFOS nulls, particularly females, have decreased Kiss1 neuron numbers and lower Kiss1 mRNA levels. Collectively, our novel findings suggest that cFOS plays a cell-specific role at multiple levels of the hypothalamic-pituitary-gonadal axis, affecting gonadotropes but not thyrotropes in the pituitary, and kisspeptin neurons but not GnRH neurons in the hypothalamus, thereby contributing to the overall control of reproduction

GnRH Receptor Expression and Reproductive Function Depend on JUN in GnRH Receptor‒Expressing Cells.

Gonadotropin-releasing hormone (GnRH) from the hypothalamus regulates synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gonadotropes. LH and FSH are heterodimers composed of a common α-subunit and unique β-subunits, which provide biological specificity and are limiting components of mature hormone synthesis. Gonadotrope cells respond to GnRH via specific expression of the GnRH receptor (Gnrhr). GnRH induces the expression of gonadotropin genes and of the Gnrhr by activation of specific transcription factors. The JUN (c-Jun) transcription factor binds to AP-1 sites in the promoters of target genes and mediates induction of the FSHβ gene and of the Gnrhr in gonadotrope-derived cell lines. To analyze the role of JUN in reproductive function in vivo, we generated a mouse model that lacks JUN specifically in GnRH receptor‒expressing cells (conditional JUN knockout; JUN-cKO). JUN-cKO mice displayed profound reproductive anomalies such as reduced LH levels resulting in lower gonadal steroid levels, longer estrous cycles in females, and diminished sperm numbers in males. Unexpectedly, FSH levels were unchanged in these animals, whereas Gnrhr expression in the pituitary was reduced. Steroidogenic enzyme expression was reduced in the gonads of JUN-cKO mice, likely as a consequence of reduced LH levels. GnRH receptor‒driven Cre activity was detected in the hypothalamus but not in the GnRH neuron. Female, but not male, JUN-cKO mice exhibited reduced GnRH expression. Taken together, our results demonstrate that GnRH receptor‒expression levels depend on JUN and are critical for reproductive function

Drugs In the Workplace: A Manager\u27s Guide

Drugs in the workplace is a growing problem that threatens a valuable human resource - the employee. Managers in the hospitality industry can take a proactive stance in meeting the problem head on. The authors discuss what managers can do

Enhanced near infrared optical access to the brain with a transparent cranial implant and scalp optical clearing.

We report on the enhanced optical transmittance in the NIR wavelength range (900 to 2400 nm) offered by a transparent Yttria-stabilized zirconia (YSZ) implant coupled with optical clearing agents (OCAs). The enhancement in optical access to the brain is evaluated upon comparing ex-vivo transmittance measurements of mice native skull and the YSZ cranial implant with scalp and OCAs. An increase in transmittance of up to 50% and attenuation lengths of up to 2.4 mm (i.e., a five-fold increase in light penetration) are obtained with the YSZ implant and the OCAs. The use of this ceramic implant and the biocompatible optical clearing agents offer attractive features for NIR optical techniques for brain theranostics

NUMERICAL PREDICTION OF THE COMPONENT-RATIO-DEPENDENT COMPRESSIVE STRENGTH OF BONE CEMENT

Changes in the compression strength of the PMMA bone cement with a variable powder/liquid component mix ratio were investigated. The strength test data served to develop basic mathematical models and an artificial neural network was employed for strength predictions. The empirical and numerical results were compared to determine modelling errors and assess the effectiveness of the proposed methods and models. The advantages and disadvantages of mathematical modelling are discussed

Nonlinear analysis of the ripping head power time series

We investigate the power of a ripping head in the process of concrete cutting. Using nonlinear embedding methods we study the corresponding time series obtained during the cutting process. The calculated maximal Lyapunov exponent indicates the exponential divergence typical for chaotic or stochastic systems. The recurrence plots technique has been used to get nonlinear process statistics for identification and description of nonlinear dynamics, lying behind the cutting process