Minimum Action Path theory reveals the details of stochastic biochemical transitions out of oscillatory cellular states

Cell state determination is the outcome of intrinsically stochastic biochemical reactions. Tran- sitions between such states are studied as noise-driven escape problems in the chemical species space. Escape can occur via multiple possible multidimensional paths, with probabilities depending non-locally on the noise. Here we characterize the escape from an oscillatory biochemical state by minimizing the Freidlin-Wentzell action, deriving from it the stochastic spiral exit path from the limit cycle. We also use the minimized action to infer the escape time probability density function

Native \u3cem\u3eV. californicum\u3c/em\u3e Alkaloid Combinations Induce Differential Inhibition of Sonic Hedgehog Signaling

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine whether additional alkaloids in the extracts contribute to Hh signaling inhibition, the concentrations of these four alkaloids present in extracts were replicated using commercially available standards, followed by comparison of extracts to alkaloid standard mixtures for inhibition of Hh signaling using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts are capable of inhibiting Hh signaling

The acute asymmetric effects of hemiovariectomy on testosterone secretion vary along the estrous cycle. The participation of the cholinergic system

The presence of asymmetry in the capacity of the left and right ovaries to secrete testosterone was analyzed by studying the effects of hemiovariectomy along the estrus cycle one hour after surgery. The effects of ether anesthesia on hormone serum levels were also analyzed. Bilateral ovariectomy and the extirpation of the left ovary performed on the day of proestrus resulted in significantly lower testosterone levels. Compared to the anesthetized group, the effects of perforating the peritoneum unilaterally varied according to the day of the estrous cycle and the side of the peritoneum surgery was performed on. Injecting atropine sulfate (ATR) to control or anesthetized rats on D1 resulted in a significant increase of testosterone serum levels. The effects of perforating the peritoneum on testosterone levels depended on the cholinergic innervation and varied along the estrous cycle. Blocking the cholinergic system before performing unilateral or bilateral ovariectomy had different effects depending on the day of the estrous cycle. Testosterone plasma levels increased significantly when surgery was performed on the day of diestrus and dropped when surgery was performed on proestrus. Similar effects were observed when the left adrenal was extirpated from animals with the cholinergic system blocked. The results presented herein support the hypothesis of asymmetry in the ovaries' abilities to secrete steroid hormones, and that the capacity to secrete testosterone varies along the estrous cycle

The effects of intrinsic noise on the behaviour of bistable cell regulatory systems under quasi-steady state conditions

We analyse the effect of intrinsic fluctuations on the properties of bistable stochastic systems with time scale separation operating under1 quasi-steady state conditions. We first formulate a stochastic generalisation of the quasi-steady state approximation based on the semi-classical approximation of the partial differential equation for the generating function associated with the Chemical Master Equation. Such approximation proceeds by optimising an action functional whose associated set of Euler-Lagrange (Hamilton) equations provide the most likely fluctuation path. We show that, under appropriate conditions granting time scale separation, the Hamiltonian can be re-scaled so that the set of Hamilton equations splits up into slow and fast variables, whereby the quasi-steady state approximation can be applied. We analyse two particular examples of systems whose mean-field limit has been shown to exhibit bi-stability: an enzyme-catalysed system of two mutually-inhibitory proteins and a gene regulatory circuit with self-activation. Our theory establishes that the number of molecules of the conserved species are order parameters whose variation regulates bistable behaviour in the associated systems beyond the predictions of the mean-field theory. This prediction is fully confirmed by direct numerical simulations using the stochastic simulation algorithm. This result allows us to propose strategies whereby, by varying the number of molecules of the three conserved chemical species, cell properties associated to bistable behaviour (phenotype, cell-cycle status, etc.) can be controlled.Comment: 33 pages, 9 figures, accepted for publication in the Journal of Chemical Physic

Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and in the anxiogenic response to ethanol withdrawal. Previously, we found that both ethanol and corticotropin releasing factor (CRF) increase GABAergic transmission in mouse and rat CeA neurons, in part by enhancing the release of GABA via activation of presynaptic CRF1 receptors. CRF1 receptors are coupled to the enzyme adenylyl cyclase (AC), which produces the second messenger cyclic AMP. There are nine isoforms of AC, but we recently found that CRF1 receptors in the pituitary were coupled to the Type 7 AC (AC7). Therefore, using an in vitro electrophysiological approach in brain slices, here we have investigated a possible role of the AC7 signaling pathway in ethanol and CRF effects on CeA GABAergic synapses of genetically modified mice with diminished brain Adcy7 activity (HET) compared to their littermate male wild-type (WT) mice. We found no significant differences in basal membrane properties, mean baseline amplitude of evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs), or paired-pulse facilitation (PPF) of GABAA-IPSPs between HET and WT mice. In CeA neurons of WT mice, ethanol superfusion significantly augmented (by 39%) GABAA-IPSPs and decreased PPF (by 25%), suggesting increased presynaptic GABA release. However, these effects were absent in HET mice. CRF superfusion also significantly augmented IPSPs (by 38%) and decreased PPF (by 23%) in WT CeA neurons, and still elicited a significant but smaller (by 13%) increase of IPSP amplitude, but no effect on PPF, in HET mice. These electrophysiological data suggest that AC7 plays an important role in ethanol and CRF modulation of presynaptic GABA release in CeA and thus may underlie ethanol-related behaviors such as anxiety and dependence

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Altres ajuts: CERCA Programme/Generalitat de Cataluny

Should gender be a determinant factor for granting crowdfunded microloans?

Crowdfunded microloans are a suitable tool for financing basic economic activities in developing as well as developed countries, favouring female empowerment. Despite the loans being relatively small, the widespread use of this instrument merits analyzing the factors affecting the microloan. One of these factors is gender because microloans are an important tool to finance projects promoted by women in many developing countries where microfinance is widely diffused. This research aims to determine if the gender of crowdfunded micro-borrowers is related to the main features which define the conditions of a microloan: amount, term, number of lenders, length of time to contact with borrowers and repayment system. The methodology used is the multinomial logit regression. The sample used in this study has been obtained by applying sampling techniques to a extensive public database from Kiva. This provided information on microloans from 56 countries around the world. The results based on amount, term, repayment method and recruitment period indicate that women are the best borrowers. All these variables, except the term, are significant at a 5% level. These findings may be useful to improve financial inclusion and outreach, consistently with the Sustainable Development Goals. Future research is needed to assess how “green and pink” microfinance (with environmental strategies particularly favored by women) can attract more ESG-compliant crowdfunding resources