95 research outputs found
Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch
Cellular transformations which involve a significant phenotypical change of
the cell's state use bistable biochemical switches as underlying decision
systems. In this work, we aim at linking cellular decisions taking place on a
time scale of years to decades with the biochemical dynamics in signal
transduction and gene regulation, occuring on a time scale of minutes to hours.
We show that a stochastic bistable switch forms a viable biochemical mechanism
to implement decision processes on long time scales. As a case study, the
mechanism is applied to model the initiation of follicle growth in mammalian
ovaries, where the physiological time scale of follicle pool depletion is on
the order of the organism's lifespan. We construct a simple mathematical model
for this process based on experimental evidence for the involved genetic
mechanisms. Despite the underlying stochasticity, the proposed mechanism turns
out to yield reliable behavior in large populations of cells subject to the
considered decision process. Our model explains how the physiological time
constant may emerge from the intrinsic stochasticity of the underlying gene
regulatory network. Apart from ovarian follicles, the proposed mechanism may
also be of relevance for other physiological systems where cells take binary
decisions over a long time scale.Comment: 14 pages, 4 figure
Inhibin removes the inhibitory effects of activin on steroid enzyme expression and androgen production by normal ovarian thecal cells
Activin and inhibin are important local modulators of theca cell steroidogenesis in the ovary. Using a serum-free primary theca cell culture system, this study investigated the effects of inhibin on theca cell androgen production and expression of steroidogenic enzymes. Androstenedione secretion from theca cells cultured in media containing activin, inhibin and follistatin was assessed by RIA over 144âh. Activin (1â100âng/ml) suppressed androstenedione production. Inhibin (1â100âng/ml) blocked the suppressive effects of added activin, but increased androstenedione production when added alone, suggesting it was blocking endogenous activin produced by theca cells. Addition of SB-431542 (activin receptor inhibitor) and follistatin (500âng/ml) increased androstenedione production, supporting this concept. Infection of theca cells with adenoviruses expressing inhibitory Smad6 or 7 increased androstenedione secretion, confirming that the suppressive effects of activin required activation of the Smad2/3 pathway. Activin decreased the expression levels of steroidogenic acute regulatory protein (STAR), whereas STAR expression was increased by inhibin and SB-431542, alone and in combination. CYP11A was unaffected. The expression of CYP17 encoding 17α-hydroxylase was unaffected by activin but increased by inhibin and SB-431542, and when added in combination the effect was further enhanced. The expression of 3ÎČ-hydroxysteroid dehydrogenase (3ÎČ-HSD) was significantly decreased by activin, while inhibin alone and in combination with SB-431542 both potently increased the expression of 3ÎČ-HSD. In conclusion, activin suppressed theca cell androstenedione production by decreasing the expression of STAR and 3ÎČ-HSD. Inhibin and other blockers of activin action reversed this effect, supporting the concept that endogenous thecal activin modulates androgen production in theca cells
Modeling mitochondrial dysfunctions in the brain: from mice to men
The biologist Lewis Thomas once wrote: âmy mitochondria comprise a very large proportion of me. I cannot do the calculation, but I suppose there is almost as much of them in sheer dry bulk as there is the rest of meâ. As humans, or indeed as any mammal, bird, or insect, we contain a specific molecular makeup that is driven by vast numbers of these miniscule powerhouses residing in most of our cells (mature red blood cells notwithstanding), quietly replicating, living independent lives and containing their own DNA. Everything we do, from running a marathon to breathing, is driven by these small batteries, and yet there is evidence that these molecular energy sources were originally bacteria, possibly parasitic, incorporated into our cells through symbiosis. Dysfunctions in these organelles can lead to debilitating, and sometimes fatal, diseases of almost all the bodiesâ major organs. Mitochondrial dysfunction has been implicated in a wide variety of human disorders either as a primary cause or as a secondary consequence. To better understand the role of mitochondrial dysfunction in human disease, a multitude of pharmacologically induced and genetically manipulated animal models have been developed showing to a greater or lesser extent the clinical symptoms observed in patients with known and unknown causes of the disease. This review will focus on diseases of the brain and spinal cord in which mitochondrial dysfunction has been proven or is suspected and on animal models that are currently used to study the etiology, pathogenesis and treatment of these diseases
Menstrual function among women exposed to polybrominated biphenyls: A follow-up prevalence study
BACKGROUND: Alteration in menstrual cycle function is suggested among rhesus monkeys and humans exposed to polybrominated biphenyls (PBBs) and structurally similar polychlorinated biphenyls (PCBs). The feedback system for menstrual cycle function potentially allows multiple pathways for disruption directly through the hypothalamic-pituitary-ovarian axis and indirectly through alternative neuroendocrine axes. METHODS: The Michigan Female Health Study was conducted during 1997â1998 among women in a cohort exposed to PBBs in 1973. This study included 337 women with self-reported menstrual cycles of 20â35 days (age range: 24â56 years). Current PBB levels were estimated by exponential decay modeling of serum PBB levels collected from 1976â1987 during enrollment in the Michigan PBB cohort. Linear regression models for menstrual cycle length and the logarithm of bleed length used estimated current PBB exposure or enrollment PBB exposure categorized in tertiles, and for the upper decile. All models were adjusted for serum PCB levels, age, body mass index, history of at least 10% weight loss in the past year, physical activity, smoking, education, and household income. RESULTS: Higher levels of physical activity were associated with shorter bleed length, and increasing age was associated with shorter cycle length. Although no overall association was found between PBB exposure and menstrual cycle characteristics, a significant interaction between PBB exposures with past year weight loss was found. Longer bleed length and shorter cycle length were associated with higher PBB exposure among women with past year weight loss. CONCLUSION: This study suggests that PBB exposure may impact ovarian function as indicated by menstrual cycle length and bleed length. However, these associations were found among the small number of women with recent weight loss suggesting either a chance finding or that mobilization of PBBs from lipid stores may be important. These results should be replicated with larger numbers of women exposed to similar lipophilic compounds
Does âsoft conditionalityâ increase the impact of cash transfers on desired outcomes? Evidence from a randomized control trial in Lesotho
Cash transfers programs have been shown to have positive effects on a variety of outcomes. While much of the literature focuses on the role of conditionality in achieving desired impact, this paper focuses on the role of âsoft conditionalityâ implemented through both âlabelingâ and âmessagingâ in evaluating the impact of the Child Grants Program in Lesotho, an unconditional cash transfer targeting poor households with orphans and vulnerable children. Beneficiary households received a clear message that the transfer should be spent on the interest and needs of children. Our findings are based on a randomized experiment and suggest that âsoft conditionalityâ does play a strong role in increasing expenditure for children, especially on education, clothing and footwear. Results indicate in fact that transfer income is spent differently from general income as it exerts both an income and a substitution effect. This behavioral change is confirmed by comparing the ex-ante expected behaviors with the ex-post actual response to the program. We find that for expenditure categories linked to the wellbeing of children the ex-post response was much higher than the ex-ante expected behavior
Schizophrenia-spectrum patients treated with long-acting injectable risperidone in real-life clinical settings: functional recovery in remitted versus stable, non-remitted patients (the EVeREST prospective observational cohort study)
FecX Bar a Novel BMP15 mutation responsible for prolificacy and female sterility in Tunisian Barbarine Sheep
Quantification of relevance of quality of life assessment for patients with cognitive impairment: the suitability indices
Influence of Insulin-like Growth Factor I (IGF-I) on the survival and the in vitro development of caprine preantral follicles
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