On the origins and rarity of locally but not globally identifiable parameters in biological modeling

Structural identifiability determines the possibility of estimating the parameters of a model by observing its output in an ideal experiment. If a parameter is structurally locally identifiable, but not globally (SLING), its true value cannot be uniquely inferred because several equivalent solutions exist. In biological modeling it is sometimes assumed that local identifiability entails global identifiability, which is convenient because local identifiability tests are typically less computationally demanding than global tests. However, this assumption has never been investigated beyond demonstrating the existence of counter-examples. To clarify this matter, in this paper we began by asking how often a structurally locally identifiable parameter is not globally identifiable in systems biology. To answer this question empirically we assembled a collection of 102 mathematical models from the literature, with a total of 763 parameters. We analysed their identifiability, determining that approximately 5% of the parameters are SLING. Next we investigated how the SLING parameters arise, tracing their origin to particular features of the model equations. Finally, we investigated the possibility of obtaining false estimates. Some of the solutions that are mathematically equivalent to the true one involved parameters and/or initial conditions with negative values, which are not biologically meaningful. In other cases the true solution and the equivalent one were in the same range. These results provide insight about a previously unexplored hypothesis, and suggest that in most (albeit not all) systems biology applications it suffices to test for structural local identifiability.MCIN/AEI/ 10.13039/50110001103300004837 | Ref. PID2020-113992RA-I00MCIN/AEI/ 10.13039/50110001103300004837 | Ref. RYC-2019-027537-IXunta de Galicia | Ref. ED431F 2021/00

Benchmarking tools for a priori identifiability analysis

Motivation: The theoretical possibility of determining the state and parameters of a dynamic model by measuring its outputs is given by its structural identifiability and observability. These properties should be analysed before attempting to calibrate a model, but their a priori analysis can be challenging, requiring symbolic calculations that often have a high computational cost. In recent years a number of software tools have been developed for this task, mostly in the systems biology community. These tools have vastly different features and capabilities, and a critical assessment of their performance is still lacking. Results: Here we present a comprehensive study of the computational resources available for analysing structural identifiability. We consider 13 software tools developed in 7 programming languages and evaluate their performance using a set of 25 case studies created from 21 models. Our results reveal their strengths and weaknesses, provide guidelines for choosing the most appropriate tool for a given problem, and highlight opportunities for future developments. Availability: https://github.com/Xabo-RB/Benchmarking_files.Xunta de Galicia | Ref. ED431F 2021/003Agencia Estatal de Investigación | Ref. PID2020-113992RA-I00MCIN/AEI/10.13039/501100011033 | Ref. RYC-2019-027537-IFinanciado para publicación en acceso aberto: Universidade de Vigo/CISU

STRIKE-GOLDD 4.0: user-friendly, efficient analysis of structural identifiability and observability

Structural identifiability and observability are desirable properties of systems biology models. Many software toolboxes have been developed for their analysis in the last decades. STRIKE-GOLDD is a generally applicable tool that can analyse non-linear, non-rational ODE models with unknown inputs. However, this generality comes at the expense of a lower computational efficiency than other tools. Here we present STRIKE-GOLDD 4.0, which includes a new algorithm, ProbObsTest, specifically designed for the analysis of rational models. ProbObsTest is significantly faster than the FISPO algorithm - which was already available in older versions of the toolbox - when applied to computationally expensive models. An important feature of both algorithms is their ability to analyse models with unknown inputs. Thus, their coexistence in the same toolbox provides a combination of general applicability and computational efficiency. STRIKE-GOLDD 4.0 is implemented as a free and open-source Matlab toolbox with a user-friendly graphical interface. It is available under a GPLv3 license and it can be downloaded from GitHub at https://github.com/afvillaverde/strike-goldd.Comment: 14 pages, 1 figur

STRIKE-GOLDD 4.0: user-friendly, efficient analysis of structural identifiability and observability

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGMotivation: STRIKE-GOLDD is a toolbox that analyses the structural identifiability and observability of possibly non-linear, non-rational ODE models that may have known and unknown inputs. Its broad applicability comes at the expense of a lower computational efficiency than other tools. Results: STRIKE-GOLDD 4.0 includes a new algorithm, ProbObsTest, specifically designed for the analysis of rational models. ProbObsTest is significantly faster than the previously available FISPO algorithm when applied to computationally expensive models. Providing both algorithms in the same toolbox allows combining generality and computational efficiency. STRIKE-GOLDD 4.0 is implemented as a Matlab toolbox with a user-friendly graphical interface. Availability and implementation: STRIKE-GOLDD 4.0 is a free and open-source tool available under a GPLv3 license. It can be downloaded from GitHub at https://github.com/afvillaverde/strike-goldd. Supplementary information: Supplementary data are available at Bioinformatics online.MCIN/AEI/10.13039/501100011033 | Ref. PID2020-113992RA-I00MCIN/AEI/10.13039/501100011033 | Ref. RYC-2019-027537-IXunta de Galicia | Ref. ED431F 2021/00

Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas

Activation of an oncogene via its juxtaposition to the IGH locus by a chromosomal translocation or, less frequently, by genomic amplification is considered a major mechanism of B-cell lymphomagenesis. However, amplification of an IGH/oncogene fusion, coined a complicon, is a rare event in human cancers and has been associated with poor outcome and resistance to treatment. In this article are descriptions of two cases of germinal-center-derived B-cell lymphomas with IGH/BCL2 fusion that additionally displayed amplification of an IGH/MYC fusion. As shown by fluorescence in situ hybridization, the first case contained a IGH/MYC complicon in double minutes, whereas the second case showed a BCL2/IGH/MYC complicon on a der(8)t(8;14)t(14;18). Additional molecular cytogenetic and mutation analyses revealed that the first case also contained a chromosomal translocation affecting the BCL6 oncogene and a biallelic inactivation of TP53. The second case harbored a duplication of REL and acquired a translocation affecting IGL and a biallelic inactivation of TP53 during progression. Complicons affecting Igh/Myc have been reported previously in lymphomas of mouse models simultaneously deficient in Tp53 and in genes of the nonhomologous end-joining DNA repair pathway. To the best of our knowledge, this is the first time that IGH/MYC complicons have been reported in human lymphomas. Our findings imply that the two mechanisms resulting in MYC deregulation, that is, translocation and amplification, can occur simultaneously

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Nuevos diseños y materiales para conductores desnudos de aluminio y sus aleaciones en líneas de alta tensión

Ingeniería Técnica IndustrialIndustria Ingeniaritza Tekniko

Alteraciones genéticas en las neoplasias hematológicas de origen linfoide implicaciones en la práctica clínica

La mejora de las técnicas de citogenética convencional, el desarrollo de la citogenética molecular y la aplicación de técnicas de biología molecular al análisis genético ha conducido a una verdadera revolución en el conocimiento de los procesos implicados en el desarrollo y progresión de las neoplasias linfoides. De esta manera, se han caracterizado gran parte de las alteraciones presentes en las células malignas estableciendo cuáles son los genes implicados en el proceso transformativo. Esto tiene importantes consecuencias en el manejo clínico de este tipo de enfermedades y permite un diagnóstico más exacto a través de una sistematización de las distintas entidades basada en sus características biológicas. Por otra parte, la introducción de nuevas técnicas de análisis, como la PCR en tiempo real, posibilitará la monitorización cuantitativa de la enfermedad permitiendo valorar la respuesta a los distintos tratamientos y estableciendo valores predictivos de recaídas. En el futuro, todo este conocimiento permitirá el establecimiento de terapias genotipo-específicas y el desarrollo de nuevos fármacos dirigidos a la alteración causante del proceso maligno y con menores efectos colaterales indeseables.The improvement of the conventional cytogenetic techniques, the development of molecular cytogenetics and the application of techniques of molecular biology to genetic analysis have led to an authentic revolution in the knowledge of the processes implied in the development and progression of lymphoid neoplasias. In this way, a great part of the alterations present in malign cells have been characterised, and the genes involved in the transformative process have been established. This has important consequences for the clinical handling of this type of disease and makes possible a more exact diagnosis through a systematisation of the different entities based on their biological characteristics. On the other hand, the introduction of new techniques of analysis, such as real time PCR, will make it possible to monitor the disease quantitatively, making it possible to evaluate response to the different treatments and to establish predictive values for relapses. In the future, all of this knowledge will make it possible to establish genotype-specific therapies and to develop new medicines aimed at the alteration responsible for the malignant process and with less undesired collateral effects

Alteraciones genéticas en las neoplasias hematológicas de origen linfoide implicaciones en la práctica clínica

La mejora de las técnicas de citogenética convencional, el desarrollo de la citogenética molecular y la aplicación de técnicas de biología molecular al análisis genético ha conducido a una verdadera revolución en el conocimiento de los procesos implicados en el desarrollo y progresión de las neoplasias linfoides. De esta manera, se han caracterizado gran parte de las alteraciones presentes en las células malignas estableciendo cuáles son los genes implicados en el proceso transformativo. Esto tiene importantes consecuencias en el manejo clínico de este tipo de enfermedades y permite un diagnóstico más exacto a través de una sistematización de las distintas entidades basada en sus características biológicas. Por otra parte, la introducción de nuevas técnicas de análisis, como la PCR en tiempo real, posibilitará la monitorización cuantitativa de la enfermedad permitiendo valorar la respuesta a los distintos tratamientos y estableciendo valores predictivos de recaídas. En el futuro, todo este conocimiento permitirá el establecimiento de terapias genotipo-específicas y el desarrollo de nuevos fármacos dirigidos a la alteración causante del proceso maligno y con menores efectos colaterales indeseables.The improvement of the conventional cytogenetic techniques, the development of molecular cytogenetics and the application of techniques of molecular biology to genetic analysis have led to an authentic revolution in the knowledge of the processes implied in the development and progression of lymphoid neoplasias. In this way, a great part of the alterations present in malign cells have been characterised, and the genes involved in the transformative process have been established. This has important consequences for the clinical handling of this type of disease and makes possible a more exact diagnosis through a systematisation of the different entities based on their biological characteristics. On the other hand, the introduction of new techniques of analysis, such as real time PCR, will make it possible to monitor the disease quantitatively, making it possible to evaluate response to the different treatments and to establish predictive values for relapses. In the future, all of this knowledge will make it possible to establish genotype-specific therapies and to develop new medicines aimed at the alteration responsible for the malignant process and with less undesired collateral effects