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

Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis.

Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy

A New Kind of Quinonic-Antibiotic Useful Against Multidrug-Resistant S. aureus and E. faecium Infections

Indexación: Scopus.A rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics and reducing the therapeutic arsenal available for treatment of infectious diseases. In the present study, we developed a new class of compounds with antibacterial activity obtained by a simple, two step synthesis and screened the products for in vitro antibacterial activity against ATCC® strains using the broth microdilution method. The compounds exhibited minimum inhibitory concentrations (MIC) of 1⁻32 μg/mL against Gram-positive ATCC® strains. The structure⁻activity relationship indicated that the thiophenol ring is essential for antibacterial activity and the substituents on the thiophenol ring module, for antibacterial activity. The most promising compounds detected by screening were tested against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. We found remarkable activity against VREF for compounds 7 and 16, were the MIC50/90 were 2/4 µg/mL and 4/4 µg/mL, respectively, while for vancomycin the MIC50/90 was 256/512 µg/mL. Neither compound affected cell viability in any of the mammalian cell lines at any of the concentrations tested. These in vitro data show that compounds 7 and 16 have an interesting potential to be developed as new antibacterial drugs against infections caused by VREF.https://www.mdpi.com/1420-3049/23/7/177

Analog gravity from field theory normal modes?

We demonstrate that the emergence of a curved spacetime ``effective Lorentzian geometry'' is a common and generic result of linearizing a field theory around some non-trivial background. This investigation is motivated by considering the large number of ``analog models'' of general relativity that have recently been developed based on condensed matter physics, and asking whether there is something more fundamental going on. Indeed, linearization of a classical field theory (a field theoretic ``normal mode analysis'') results in fluctuations whose propagation is governed by a Lorentzian-signature curved spacetime ``effective metric''. For a single scalar field, this procedure results in a unique effective metric, which is quite sufficient for simulating kinematic aspects of general relativity (up to and including Hawking radiation). Quantizing the linearized fluctuations, the one-loop effective action contains a term proportional to the Einstein--Hilbert action, suggesting that while classical physics is responsible for generating an ``effective geometry'', quantum physics can be argued to induce an ``effective dynamics''. The situation is strongly reminiscent of Sakharov's ``induced gravity'' scenario, and suggests that Einstein gravity is an emergent low-energy long-distance phenomenon that is insensitive to the details of the high-energy short-distance physics. (We mean this in the same sense that hydrodynamics is a long-distance emergent phenomenon, many of whose predictions are insensitive to the short-distance cutoff implicit in molecular dynamics.)Comment: Revtex 4 (beta 5); 12 pages in single-column forma

Backyard poultry production in Chile: animal health management and contribution to food access in an upper middle-income country

Backyard production systems (BPS) that involve poultry are a good way to improve food security and poverty alleviation. Few studies have been carried out to quantify the contribution of poultry production to these households and the constraints they might face if a priority animal disease enters these systems. This study aims to characterize the poultry-rearing BPS in central Chile and to identify socio-economic factors associated to households’ consumption of poultry. Data was collected from 384 BPS through a face-to-face semi-structured questionnaire. Value chain framework associated with BPS poultry rearing and cash flow analysis of BPS was done to identify the inputs/outputs of the system and to know the profitability of the system. Multiple linear regression was performed to identify the BPS and household factors associated to poultry consumption. The results of this study suggest that BPS in central Chile have biosecurity deficiencies such as: lack of confinement, lack of veterinary assistance and incorrect handling of dead animals. Cash flow analysis indicated that 62% of the BPS had a positive balance from production. Distance to closest market and per capita income were factors associated to poultry value to farmers. Different factors were significant predictors of household poultry consumption. Positive predictors of consumption were identified as: (i) older owners, (ii) higher transportation price to closest market, (iii) larger flock size (iv) birds raised by women and (v) owning a car. On the contrary, (i) higher per capita income and (ii) bigger household size predicted a reduction in consumption. The results indicate the importance of BPS to low-income families and those living in remote areas while also highlighting the vulnerability of these systems to disease risks

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain

More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 hours of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 hours seems to have some neuroprotective efficacy. TH duration longer than 72 hours or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for cooling devices for the transfer of these patients and their centralisationSe cumple ahora más de una década del inicio de la hipotermia terapéutica (HT) en España, la única intervención neuroprotectora que ha venido a ser práctica estándar en el tratamiento de la encefalopatía hipóxico-isquémica perinatal (EHI). El objetivo de este artículo es ofrecer un panorama actual y presentar las controversias surgidas alrededor de la aplicación de esta terapia. En esta década se ha implantado con éxito la HT en la gran mayoría de los hospitales terciarios de España y más del 85% de los recién nacidos con EHI moderada-grave reciben esta terapia. Entre los aspectos que pueden mejorar la eficacia de la HT están su inicio precoz dentro de las primeras 6 horas de vida y el control de factores comórbidos asociados a la asfixia perinatal. En los pacientes con EHI moderada el inicio después de las 6 horas parece mantener cierta eficacia neuroprotectora. Una duración de la HT mayor de 72 horas o un enfriamiento más profundo no ofrecen mayor eficacia neuroprotectora y aumentan el riesgo de efectos adversos. Persiste la controversia acerca de la sedación durante la HT, la aplicación de esta intervención a los neonatos con EHI leve y en otros escenarios. La información pronóstica y su marco temporal es uno de los aspectos más desafiantes. La HT es universal en países con recursos económicos, aunque existen puntos de controversia no resueltos. Si bien es un tratamiento generalizado en nuestro país, falta disponer de dispositivos para el traslado de estos pacientes y su centralizació

Efficacy and safety of trabectedin in metastatic uterine leiomyosarcoma: A retrospective multicenter study of the Spanish ovarian cancer research group (GEICO)

Objective: We assessed trabectedin in patients with advanced uterine leiomyosarcoma (uLMS) in real-life clinical practice given according to the marketing authorization. Methods: Thirty-six women from 11 tertiary hospitals across Spain who received trabectedin after anthracycline-containing regimen/s were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Results: Median PFS and overall survival (OS) since starting trabectedin treatment were 5.4 (95%CI: 3.5–7.3) and 18.5 months (95%CI: 11.5–25.6), respectively. Median OS was significantly higher (P = 0.028) in patients receiving trabectedin in = 2nd line (25.3 months) than in = 3rd (15.1 months) and with ECOG performance status = 1 at trabectedin start (19.8 months) than ECOG 2–3 (6.0 months, P = 0.013). When calculating OS since diagnosis, patients had longer OS with localized disease at diagnosis (87.4 months) vs. locally advanced (30.0 months) or metastatic (44.0 months, P = 0.041); and patients who received adjuvant therapy (87.4 months) compared with those who did not (30.0 months, P = 0.003), especially when receiving radiochemotherapy (106.7 months, P = 0.027). One patient (2.8%) had a complete response (CR) and nine patients (25.0%) achieved a partial response (PR) for an objective response rate of 27.8% with median response duration of 11 months (range: 4–93). Eighteen patients (50.0%) had disease stabilization for a disease control rate (DCR) of 77.8%. More patients receiving trabectedin in 1st-line of advanced disease achieved CR (16.7%) and PR (50.0%) than those in = 2nd line/s (0.0% and 20.0%), whereas the DCR was similar across treatment lines. Reversible neutropenia was the most common grade 3/4 laboratory abnormality (19.4%). Conclusions: Trabectedin confers clinical benefit in patients with recurrent/metastatic uLMS, given after failure to an anthracycline-based regimen being comparable to those reported in clinical trials and with a manageable safety profile

Stochastic Resonance in Nonpotential Systems

We propose a method to analytically show the possibility for the appearance of a maximum in the signal-to-noise ratio in nonpotential systems. We apply our results to the FitzHugh-Nagumo model under a periodic external forcing, showing that the model exhibits stochastic resonance. The procedure that we follow is based on the reduction to a one-dimensional dynamics in the adiabatic limit, and in the topology of the phase space of the systems under study. Its application to other nonpotential systems is also discussed.Comment: Submitted to Phys. Rev.

Efecto de un anticoccidial natural a base de saponinas de Yucca schidigera y Trigonella foenum-graecum sobre el control de coccidiosis en pollos de carne

The aim of this study was to evaluate the effect of a natural anticoccidial based on saponins from Yucca schidigera and Trigonella foenum-graecumen in the control of coccidiosis in broilers. It was used 75 1-day-old chicks from the Cobb 500 line, randomly distributed in three treatments: DBSA (base diet without addition of anticoccidial), DBAN (base diet with addition of natural anticoccidial), DBQI (base diet with addition of chemical anticoccidial - ionophore) with five repetitions and five chicks per experimental unit. The birds were inoculated on day 14 with 15 times the recommended dose of the live vaccine (Coccivac-D) which contains Eimeria acervulina, E. maxima, E. mivati, E. tenella, E. necatrix, E. brunetti, E. hagani and E. praecox to induce the disease. The variables oocyst count per gram of faeces (ROpgh), intestinal lesions and various productive parameters were evaluated. The values ​​of ROpgh were similar for DBAN and DBQI peaking at the seventh week (328.8 and 455.8 Opgh, respectively), and then decreasing. Intestinal lesions on days 10, 20 and 28 post-infection and the productive parameters at the end of the study were similar for both treatments, but significantly better than the DBSA control. It is concluded that the saponins from Y. schidigera and T. foenum-graecum can efficiently replace chemical anticoccidials in bird feeds.  El objetivo del estudio fue evaluar el efecto de un anticoccidial natural a base de saponinas procedentes de Yucca schidigera y Trigonella foenum-graecumen en el control de coccidiosis en pollos de carne. Se utilizaron 75 pollos machos de la línea Cobb 500 de un día de edad, distribuidos al azar en tres tratamientos: DBSA (dieta base sin adición de anticoccidial), DBAN (dieta base con adición de anticoccidial natural), DBQI (dieta base con adición de anticoccidial químico - ionóforo) con cinco repeticiones y cinco aves por unidad experimental. Los pollos fueron inoculados en día 14 con 15 veces la dosis recomendada de la vacuna viva (Coccivac-D), que contiene Eimeria acervulina, E. maxima, E. mivati, E. tenella, E. necatrix, E. brunetti, E. hagani y E. praecox para inducir la enfermedad. Se evaluaron las variables recuento de ooquistes por gramo de heces (ROpgh), lesiones intestinales y diversos parámetros productivos. Los valores de ROpgh fueron similares para DBAN y DBQI llegando a su pico a la séptima semana (328.8 y 455.8 Opgh, respectivamente), para luego disminuir. Las lesiones intestinales los días 10, 20 y 28 pos-infección y los parámetros productivos al final del estudio fueron similares para ambos tratamientos, pero significativamente mejores que el control DBSA. Se concluye que las saponinas procedentes de Y. schidigera y T. foenum-graecum pueden remplazar eficientemente a los anticoccidiales químicos en la alimentación de las aves