Modular analysis of signal transduction networks

Modularity, signaling networks, sytems biologyMagdeburg, Univ., Fak. für Verfahrens- und Systemtechnik, Diss., 2007von Julio Sáez RodríguezZsfassung in dt. Sprach

Reverse engineering of logic-based differential equation models using a mixed-integer dynamic optimization approach

9 páginas, 6 figuras.-- This is an Open Access article distributed under the terms of the Creative Commons Attribution LicenseMotivation: Systems biology models can be used to test new hypotheses formulated on the basis of previous knowledge or new experimental data, contradictory with a previously existing model. New hypotheses often come in the shape of a set of possible regulatory mechanisms. This search is usually not limited to finding a single regulation link, but rather a combination of links subject to great uncertainty or no information about the kinetic parameters. Results: In this work, we combine a logic-based formalism, to describe all the possible regulatory structures for a given dynamic model of a pathway, with mixed-integer dynamic optimization (MIDO). This framework aims to simultaneously identify the regulatory structure (represented by binary parameters) and the real-valued parameters that are consistent with the available experimental data, resulting in a logic-based differential equation model. The alternative to this would be to perform real-valued parameter estimation for each possible model structure, which is not tractable for models of the size presented in this work. The performance of the method presented here is illustrated with several case studies: a synthetic pathway problem of signaling regulation, a two-component signal transduction pathway in bacterial homeostasis, and a signaling network in liver cancer cellsD.H., J.R.B. and J.S.R. acknowledge funding from the EU FP7 projects ‘NICHE’ (ITN Grant number 289384) and ‘BioPreDyn’ (KBBE grant number 289434). J.R.B. also acknowledges funding from the Spanish Ministerio de Economía y Competitividad (and the FEDER) through the project MultiScales (DPI2011-28112-C04-03).Peer reviewe

Hybrid parallel multimethod hyperheuristic for mixed-integer dynamic optimization problems in computational systems biology

[Abstract] This paper describes and assesses a parallel multimethod hyperheuristic for the solution of complex global optimization problems. In a multimethod hyperheuristic, different metaheuristics cooperate to outperform the results obtained by any of them isolated. The results obtained show that the cooperation of individual parallel searches modifies the systemic properties of the hyperheuristic, achieving significant performance improvements versus the sequential and the non-cooperative parallel solutions. Here we present and evaluate a hybrid parallel scheme of the multimethod, using both message-passing (MPI) and shared memory (OpenMP) models. The hybrid parallelization allows to achieve a better trade-off between performance and computational resources, through a compromise between diversity (number of islands) and intensity (number of threads per island). For the performance evaluation, we considered the general problem of reverse engineering nonlinear dynamic models in systems biology, which yields very large mixed-integer dynamic optimization problems. In particular, three very challenging problems from the domain of dynamic modeling of cell signaling were used as case studies. In addition, experiments have been carried out in a local cluster, a large supercomputer and a public cloud, to show the suitability of the proposed solution in different execution platforms.Gobierno de España; DPI2017-82896-C2-2-RGobierno de España; TIN2016-75845-PXunta de Galicia; R2016/045Xunta de Galicia; ED431C 2017/0

From Non-Alcoholic Fatty Liver Disease to Liver Cancer: Microbiota and Inflammation as Key Players

It is estimated that 25% of the world’s population has non-alcoholic fatty liver disease. This disease can advance to a more severe form, non-alcoholic steatohepatitis (NASH), a disease with a greater probability of progression to cirrhosis and hepatocellular carcinoma (HCC). NASH could be characterized as a necro-inflammatory complication of chronic hepatic steatosis. The combination of factors that lead to NASH and its progression to HCC in the setting of inflammation is not clearly understood. The portal vein is the main route of communication between the intestine and the liver. This allows the transfer of products derived from the intestine to the liver and the hepatic response pathway of bile and antibody secretion to the intestine. The intestinal microbiota performs a fundamental role in the regulation of immune function, but it can undergo changes that alter its functionality. These changes can also contribute to cancer by disrupting the immune system and causing chronic inflammation and immune dysfunction, both of which are implicated in cancer development. In this article, we address the link between inflammation, microbiota and HCC.We also review the different in vitro models, as well as recent clinical trials addressing liver cancer and microbiota

Leucistic plumage as a result of progressive greying in a cryptic nocturnal bird

Leucism, broadly defined as the lack of melanin pigmentation, occurs in many animal species. Most studies on leucism and other colour aberrations are based on opportunistic observations or small cross-sectional samples, thus limiting our ability to produce reliable results and test theoretical predictions. This study combines cross-sectional and longitudinal data collected in 2016–2020 from a population of red-necked nightjars (Caprimulgus ruficollis). The goals of the study are (i) to investigate sex and age effects on partial leucism, (ii) to separate within-subject effects (progressive greying) from between-subject effects (selective disappearance), and (iii) to examine differences in body mass, structural size, and life span between leucistic and non-leucistic individuals. The probability of leucism in nightjars increased from juveniles to adults at similar rates in males and females. Our longitudinal analysis and life-span comparisons indicated a minor contribution of selective disappearance to age-related changes in leucism, but rather suggested that the loss of melanin from feathers can be attributed to progressive greying in ageing adults. Body mass and size were consistently smaller (5% and 1.5%, respectively) in leucistic than in non-leucistic nightjars, although the reason for this difference remains unclear. Our study sheds light on the sources and mechanisms of variation in leucism in natural populations and its relationship with important life-history traits, such as life span.Open access funding provided by Lund University. C.C. received financial support from Fundación Ramón Areces (BEVP-31A6148) and the Spanish Ministry of Science, Innovation and Universities (FJC2018-038412-I). PH-R received financial support from the University Pablo de Olavide (Seville) through the contract of reference ‘Plan Propio de Investigación’ No. 1903

La fragilidad en candidatos a trasplante renal

Candidat; Fragilitat; Trasplantament renalCandidato; Fragilidad; Trasplante renalCandidate; Frailty; Kidney transplantEl concepto de fragilidad ha sido desarrollado principalmente en el campo de la geriatría y surgió para identificar a aquellos pacientes que presentaban vulnerabilidad al enfrentarse a un evento clínico estresante. Los pacientes frágiles tienen mayor riesgo de mortalidad, complicaciones y discapacidad, independientemente de su edad o comorbilidades. Se ha descrito una alta prevalencia de fragilidad entre sujetos con enfermedad renal crónica, sobre todo en terapia renal sustitutiva. El porcentaje de pacientes frágiles o prefrágiles en lista de espera de trasplante renal se sitúa en torno a un 20-30% y se ha demostrado que estos pacientes tienen peores resultados tras el trasplante renal, que constituye un evento estresante. Las herramientas para evaluar la fragilidad, escalas e índices, pueden ser útiles para identificar qué pacientes están en riesgo de padecer más complicaciones postrasplante, lo que resulta necesario para adaptar nuestra práctica clínica y evitar morbilidad. La más utilizada en pacientes renales es la escala de Fried, que se basa en la detección de cinco dimensiones fenotípicas. Además, conocer la fragilidad de nuestros pacientes permite plantear intervenciones prehabilitadoras durante el tiempo que estén en lista de espera, con el objetivo de mejorar esta vulnerabilidad pretrasplante, y así optimizar los resultados postrasplante. Se necesitan estudios en población renal para mejorar y prevenir la fragilidad.Frailty is a concept that has been mainly developed in geriatrics and it came from the need of identifying subjects at risk to develop complications when they faced a stressful event. Frail patients have higher risk of mortality, poor outcomes and disability, and this is independent from their age or comorbidities. Chronic kidney disease patients present with high prevalence of frailty, especially those who are in renal replacement therapy. Frail or pre-frail patients on the kidney transplant waiting list represent 20-30%, and these patients are proven to have poorer results after the transplant, which is a stressful event itself. Tools for frailty assessment, both scales or indexes, may be usefulto identify which subjects might be at risk for complications after transplant, and this is necessary to adapt our clinical practice and minimize morbidity. The most used frailty scale in kidney patients is Fried scale, which is based in five phenotypic items. Besides that, knowing frail population allows potential interventions such as prehabilitation while the patient is waiting for the kidney transplant, which the aim of improving their vulnerability prior to transplant and, therefore, optimizing results after transplant. More studies are needed amongst kidney patients to improve and prevent frailtyMJPS y JP están financiados con el proyecto FIS-FEDER PI19/00037 del ISCII

Screening of contaminants of emerging concern in surface water and wastewater effluents, assisted by the Persistency-Mobility-Toxicity Criteria

Contaminants of emerging concern (CECs) are compounds of diverse origins that have not been deeply studied in the past which are now accruing growing environmental interest. The NOR-Water project aimed to identify the main CECs and their sources in the water environment of Northern Portugal–Galicia (located in northwest Spain) transnational region. To achieve these goals, a suspect screening analytical methodology based on the use of liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) was applied to 29 sampling sites in two campaigns. These sampling sites included river and sea water, as well as treated wastewater. The screening was driven by a library of over 3500 compounds, which included 604 compounds prioritized from different relevant lists on the basis of the persistency, mobility, and toxicity criteria. Thus, a total of 343 chemicals could be tentatively identified in the analyzed samples. This list of 343 identified chemicals was submitted to the classification workflow used for prioritization and resulted in 153 chemicals tentatively classified as persistent, mobile, and toxic (PMT) and 23 as very persistent and very mobile (vMvP), pinpointing the relevance of these types of chemicals in the aqueous environment. Pharmaceuticals, such as the antidepressant venlafaxine or the antipsychotic sulpiride, and industrial chemicals, especially high production volume chemicals (HPVC) such as ε-caprolactam, were the groups of compounds that were detected at the highest frequencies.This research was funded by Xunta de Galicia (ED431C 2021/06) and the European Regional Development Fund through the Interreg V-A Spain-Portugal Programme (POCTEP) 2014-2020 (ref. 0725_NOR_WATER_1_P). R. M. acknowledges Banco Santander and Universidade de Santiago de Compostela for her outstanding researcher contract and N. A. acknowledges the Portuguese Foundation for Science and Technology (FCT) for his Ph.D. grant DFA/BD/6218/2020.S

Outcomes of Frail Patients While Waiting for Kidney Transplantation : Differences between Physical Frailty Phenotype and FRAIL Scale

Frailty is associated with poorer outcomes among patients waiting for kidney transplantation (KT). Several different tools to measure frailty have been used; however, their predictive value is unknown. This is a prospective longitudinal study of 449 KT candidates evaluated for frailty by the Physical Frailty Phenotype (PFP) and the FRAIL scale. During the study period, 296 patients received a KT, while 153 remained listed. Patients who did not get receive a transplant were more frequently frail according to PFP (16.3 vs. 7.4%, p = 0.013). Robust patients had fewer hospital admissions during the 1st year after listing (20.8% if PFP = 0 vs. 43.4% if ≥1, and 27.1% if FRAIL = 0 vs. 48.9% if ≥1) and fewer cardiovascular events (than FRAIL ≥ 1) or major infectious events (than PFP ≥ 1). According to PFP, scoring 1 point had an impact on patient survival and chance of transplantation in the univariate analysis. The multivariable analysis corroborated the result, as candidates with PFP ≥ 3 had less likelihood of transplantation (HR 0.45 [0.26-0.77]). The FRAIL scale did not associate with any of these outcomes. In KT candidates, pre-frailty and frailty according to both the PFP and the FRAIL scale were associated with poorer results while listed. The PFP detected that frail patients were less likely to receive a KT, while the FRAIL scale did not