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Article ; Online: Systems biology reveals how altered TGFβ signalling with age reduces protection against pro-inflammatory stimuli.

David Hodgson / Andrew D Rowan / Francesco Falciani / Carole J Proctor

PLoS Computational Biology, Vol 15, Iss 1, p e

2019 Volume 1006685

Abstract: Osteoarthritis (OA) is a degenerative condition caused by dysregulation of multiple molecular signalling pathways. Such dysregulation results in damage to cartilage, a smooth and protective tissue that enables low friction articulation of synovial joints. ...

Abstract	Osteoarthritis (OA) is a degenerative condition caused by dysregulation of multiple molecular signalling pathways. Such dysregulation results in damage to cartilage, a smooth and protective tissue that enables low friction articulation of synovial joints. Matrix metalloproteinases (MMPs), especially MMP-13, are key enzymes in the cleavage of type II collagen which is a vital component for cartilage integrity. Transforming growth factor beta (TGFβ) can protect against pro-inflammatory cytokine-mediated MMP expression. With age there is a change in the ratio of two TGFβ type I receptors (Alk1/Alk5), a shift that results in TGFβ losing its protective role in cartilage homeostasis. Instead, TGFβ promotes cartilage degradation which correlates with the spontaneous development of OA in murine models. However, the mechanism by which TGFβ protects against pro-inflammatory responses and how this changes with age has not been extensively studied. As TGFβ signalling is complex, we used systems biology to combine experimental and computational outputs to examine how the system changes with age. Experiments showed that the repressive effect of TGFβ on chondrocytes treated with a pro-inflammatory stimulus required Alk5. Computational modelling revealed two independent mechanisms were needed to explain the crosstalk between TGFβ and pro-inflammatory signalling pathways. A novel meta-analysis of microarray data from OA patient tissue was used to create a Cytoscape network representative of human OA and revealed the importance of inflammation. Combining the modelled genes with the microarray network provided a global overview into the crosstalk between the different signalling pathways involved in OA development. Our results provide further insights into the mechanisms that cause TGFβ signalling to change from a protective to a detrimental pathway in cartilage with ageing. Moreover, such a systems biology approach may enable restoration of the protective role of TGFβ as a potential therapy to prevent age-related loss of cartilage and the development of OA.
Keywords	Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Sodium Channel B4-Subunits are Dysregulated in Temporal Lobe Epilepsy Drug-Resistant Patients

Mariam A. Sheilabi / Louise Y. Takeshita / Edward J. Sims / Francesco Falciani / Alessandra P. Princivalle

International Journal of Molecular Sciences, Vol 21, Iss 2955, p

2020 Volume 2955

Abstract: Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of ... ...

Abstract	Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of four domains of pore-forming α-subunits and two auxiliary β-subunits, several of which have been well studied in epileptic conditions. However, despite the β4-subunits’ role having been reported in some neurological conditions, there is little research investigating its potential significance in epilepsy. Therefore, the purpose of this work was to assess the role of SCN4β in epilepsy by using a combination of molecular and bioinformatics approaches. We first demonstrated that there was a reduction in the relative expression of SCN4B in the drug-resistant TLE patients compared to non-epileptic control specimens, both at the mRNA and protein levels. By analyzing a co-expression network in the neighborhood of SCN4B we then discovered a linkage between the expression of this gene and K + channels activated by Ca 2+ , or K + two-pore domain channels. Our approach also inferred several potential effector functions linked to variation in the expression of SCN4B . These observations support the hypothesis that SCN4B is a key factor in AED-resistant TLE, which could help direct both the drug selection of TLE treatments and the development of future AEDs.
Keywords	temporal lobe epilepsy ; hippocampal sclerosis ; antiepileptic drug resistance ; SCN4B ; voltage-gated sodium channels ; Nav β4 subunit ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modeling the metabolic profile of Mytilus edulis reveals molecular signatures linked to gonadal development, sex and environmental site

Jaanika Kronberg / Jonathan J. Byrne / Jeroen Jansen / Philipp Antczak / Adam Hines / John Bignell / Ioanna Katsiadaki / Mark R. Viant / Francesco Falciani

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 12

Abstract: Abstract The monitoring of anthropogenic chemicals in the aquatic environment including their potential effects on aquatic organisms, is important for protecting life under water, a key sustainable development goal. In parallel with monitoring the ... ...

Abstract	Abstract The monitoring of anthropogenic chemicals in the aquatic environment including their potential effects on aquatic organisms, is important for protecting life under water, a key sustainable development goal. In parallel with monitoring the concentrations of chemicals of concern, sentinel species are often used to investigate the biological effects of contaminants. Among these, bivalve molluscs such as mussels are filter-feeding and sessile, hence an excellent model system for measuring localized pollution. This study investigates the relationship between the metabolic state of the blue mussel (Mytilus edulis) and its physiology in different environments. We developed a computational model based on a reference site (relatively unpolluted) and integrated seasonal dynamics of metabolite relative concentrations with key physiological indicators and environmental parameters. The analysis of the model revealed that changes in metabolite levels during an annual cycle are influenced by water temperature and are linked to gonadal development. This work supports the importance of data-driven biology and its potential in environmental monitoring.
Keywords	Medicine ; R ; Science ; Q
Subject code	333
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Assessing technical and biological variation in SWATH-MS-based proteomic analysis of chronic lymphocytic leukaemia cells

Gina L. Eagle / John M. J. Herbert / Jianguo Zhuang / Melanie Oates / Umair T. Khan / Neil R. Kitteringham / Kim Clarke / B. Kevin Park / Andrew R. Pettitt / Rosalind E. Jenkins / Francesco Falciani

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 15

Abstract: Abstract Chronic lymphocytic leukaemia (CLL) exhibits variable clinical course and response to therapy, but the molecular basis of this variability remains incompletely understood. Data independent acquisition (DIA)-MS technologies, such as SWATH ( ... ...

Abstract	Abstract Chronic lymphocytic leukaemia (CLL) exhibits variable clinical course and response to therapy, but the molecular basis of this variability remains incompletely understood. Data independent acquisition (DIA)-MS technologies, such as SWATH (Sequential Windowed Acquisition of all THeoretical fragments), provide an opportunity to study the pathophysiology of CLL at the proteome level. Here, a CLL-specific spectral library (7736 proteins) is described alongside an analysis of sample replication and data handling requirements for quantitative SWATH-MS analysis of clinical samples. The analysis was performed on 6 CLL samples, incorporating biological (IGHV mutational status), sample preparation and MS technical replicates. Quantitative information was obtained for 5169 proteins across 54 SWATH-MS acquisitions: the sources of variation and different computational approaches for batch correction were assessed. Functional enrichment analysis of proteins associated with IGHV mutational status showed significant overlap with previous studies based on gene expression profiling. Finally, an approach to perform statistical power analysis in proteomics studies was implemented. This study provides a valuable resource for researchers working on the proteomics of CLL. It also establishes a sound framework for the design of sufficiently powered clinical proteomics studies. Indeed, this study shows that it is possible to derive biologically plausible hypotheses from a relatively small dataset.
Keywords	Medicine ; R ; Science ; Q
Subject code	310
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Comparative toxicity of three phenolic compounds on the embryo of fathead minnow, Pimephales promelas

Li, Erchao / Derek G. Bolser / Erica K. Brockmeier / Francesco Falciani / Kevin J. Kroll / Nancy D. Denslow

Aquatic toxicology. 2018 Aug., v. 201

2018

Abstract: Phenols are classified as polar narcotics, which are thought to cause toxicity by non-specific mechanisms, possibly by disrupting membrane structure and function. Here we test three phenolic chemicals, phenol, 2,4-dichlorphenol and pentachlorophenol on ... ...

Abstract	Phenols are classified as polar narcotics, which are thought to cause toxicity by non-specific mechanisms, possibly by disrupting membrane structure and function. Here we test three phenolic chemicals, phenol, 2,4-dichlorphenol and pentachlorophenol on embryo development, heartbeat rate and mitochondrial respiration in fathead minnow (Pimephales promelas). While these chemicals have been used on isolated mitochondria, they have not yet been used to verify respiration in intact embryos. Mitochondrial respiration in intact embryos was measured after optimizing the Seahorse XFe24 Extracellular Flux Analyzer. Heartbeat rate and mitochondrial respiration patterns of fathead minnow embryos at different developmental stages were also characterized. Exposures of embryos at developmental stage 20 occurred for 24 h with five concentrations of each phenolic compound ranging from 0.85 to 255 μM for phenol, 0.49 to 147 μM for 2,4-dichlorophenol and 0.3 to 90 μM for pentachlorophenol. Exposure to phenol at the concentrations tested had no effects on development, heartbeat or mitochondrial respiration. However, both 2,4-dichlorophenol and pentachlorophenol showed dose-dependent effects on development, heartbeat rate, and mitochondrial respiration, with the effects occurring at lower concentrations of pentachlorophenol, compared to 2,4-dichlorophenol, highlighting the higher toxicity of the more chlorinated phenols. Both 2,4-dichlorophenol and pentachlorophenol decreased basal mitochondrial respiration of embryos and ATP production. These results indicate that higher chlorinated phenolic chemicals cause developmental toxicity in fathead minnow embryos by decreasing mitochondrial respiration and heartbeat rate.
Keywords	2,4-dichlorophenol ; adenosine triphosphate ; developmental stages ; developmental toxicity ; dose response ; embryogenesis ; heart rate ; mitochondria ; narcotics ; pentachlorophenol ; Pimephales promelas
Language	English
Dates of publication	2018-08
Size	p. 66-72.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	782699-0
ISSN	1879-1514 ; 0166-445X
ISSN (online)	1879-1514
ISSN	0166-445X
DOI	10.1016/j.aquatox.2018.05.024
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Genomics and transcriptomics landscapes associated to changes in insulin sensitivity in response to endurance exercise training

Louise Y. Takeshita / Peter K. Davidsen / John M. Herbert / Philipp Antczak / Matthijs K. C. Hesselink / Patrick Schrauwen / S. John Weisnagel / Jeremy M. Robbins / Robert E. Gerszten / Sujoy Ghosh / Mark A. Sarzynski / Claude Bouchard / Francesco Falciani

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 14

Abstract: Abstract Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not ... ...

Abstract	Abstract Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (Si) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on Si. An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline Si and ∆Si, focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆Si further strengthens the relevance of calcium signalling in EET mediated Si response.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alteration of barrier properties, stratum corneum ceramides and microbiome composition in response to lotion application on cosmetic dry skin

Barry Murphy / Sally Grimshaw / Michael Hoptroff / Sarah Paterson / David Arnold / Andrew Cawley / Suzanne E. Adams / Francesco Falciani / Tony Dadd / Richard Eccles / Alex Mitchell / William F. Lathrop / Diana Marrero / Galina Yarova / Ana Villa / John S. Bajor / Lin Feng / Dawn Mihalov / Andrew E. Mayes

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 11

Abstract: Abstract Xerosis, commonly referred to as dry skin, is a common dermatological condition affecting almost a third of the population. Successful treatment of the condition traditionally involves the application of cosmetic products facilitating the ... ...

Abstract	Abstract Xerosis, commonly referred to as dry skin, is a common dermatological condition affecting almost a third of the population. Successful treatment of the condition traditionally involves the application of cosmetic products facilitating the moisturisation of the skin with a range of ingredients including glycerol and fatty acids. While the effectiveness of these treatments is not in question, limited information exists on the impact on the skin microbiome following use of these products and the improvement in skin hydration. Here, we describe improvements in skin barrier properties together with increased levels of cholesterol, ceramides and long-chain fatty acids following application of Body Lotion. Concomitant alterations in the skin microbiome are also seen via 16S rRNA metataxonomics, in combination with both traditional and novel informatics analysis. Following 5 weeks of lotion use, beneficial skin bacteria are increased, with improvements in microbiome functional potential, and increases in pathways associated with biosynthesis of multiple long chain fatty acids.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Transcriptional responses to hyperplastic MRL signalling in Drosophila

Vincent Jonchère / Nada Alqadri / John Herbert / Lauren Dodgson / David Mason / Giovanni Messina / Francesco Falciani / Daimark Bennett

Open Biology, Vol 7, Iss

2017 Volume 2

Abstract: Recent work has implicated the actin cytoskeleton in tissue size control and tumourigenesis, but how changes in actin dynamics contribute to hyperplastic growth is still unclear. Overexpression of Pico, the only Drosophila Mig-10/RIAM/Lamellipodin ... ...

Abstract	Recent work has implicated the actin cytoskeleton in tissue size control and tumourigenesis, but how changes in actin dynamics contribute to hyperplastic growth is still unclear. Overexpression of Pico, the only Drosophila Mig-10/RIAM/Lamellipodin adapter protein family member, has been linked to tissue overgrowth via its effect on the myocardin-related transcription factor (Mrtf), an F-actin sensor capable of activating serum response factor (SRF). Transcriptional changes induced by acute Mrtf/SRF signalling have been largely linked to actin biosynthesis and cytoskeletal regulation. However, by RNA profiling, we find that the common response to chronic mrtf and pico overexpression in wing discs was upregulation of ribosome protein and mitochondrial genes, which are conserved targets for Mrtf/SRF and are known growth drivers. Consistent with their ability to induce a common transcriptional response and activate SRF signalling in vitro, we found that both pico and mrtf stimulate expression of an SRF-responsive reporter gene in wing discs. In a functional genetic screen, we also identified deterin, which encodes Drosophila Survivin, as a putative Mrtf/SRF target that is necessary for pico-mediated tissue overgrowth by suppressing proliferation-associated cell death. Taken together, our findings raise the possibility that distinct targets of Mrtf/SRF may be transcriptionally induced depending on the duration of upstream signalling.
Keywords	drosophila ; hyperplastic growth ; wing development ; serum response factor ; mrl proteins ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	The Royal Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: In Silico Computational Transcriptomics Reveals Novel Endocrine Disruptors in Largemouth Bass (Micropterus salmoides)

Basili, Danilo / Christopher J. Martyniuk / Francesco Falciani / Ji-Liang Zhang / John Herbert / Kevin Kroll / Nancy D. Denslow / Philipp Antczak

Environmental science & technology. 2018 June 07, v. 52, no. 13

2018

Abstract: In recent years, decreases in fish populations have been attributed, in part, to the effect of environmental chemicals on ovarian development. To understand the underlying molecular events we developed a dynamic model of ovary development linking gene ... ...

Abstract	In recent years, decreases in fish populations have been attributed, in part, to the effect of environmental chemicals on ovarian development. To understand the underlying molecular events we developed a dynamic model of ovary development linking gene transcription to key physiological end points, such as gonadosomatic index (GSI), plasma levels of estradiol (E2) and vitellogenin (VTG), in largemouth bass (Micropterus salmoides). We were able to identify specific clusters of genes, which are affected at different stages of ovarian development. A subnetwork was identified that closely linked gene expression and physiological end points and by interrogating the Comparative Toxicogenomic Database (CTD), quercetin and tretinoin (ATRA) were identified as two potential candidates that may perturb this system. Predictions were validated by investigation of reproductive associated transcripts using qPCR in ovary and in the liver of both male and female largemouth bass treated after a single injection of quercetin and tretinoin (10 and 100 μg/kg). Both compounds were found to significantly alter the expression of some of these genes. Our findings support the use of omics and online repositories for identification of novel, yet untested, compounds. This is the first study of a dynamic model that links gene expression patterns across stages of ovarian development.
Keywords	animal ovaries ; databases ; dynamic models ; endocrine-disrupting chemicals ; environmental science ; estradiol ; females ; fish communities ; gene expression ; gene expression regulation ; genes ; gonadosomatic index ; liver ; males ; Micropterus salmoides ; ovarian development ; prediction ; quantitative polymerase chain reaction ; quercetin ; transcription (genetics) ; transcriptomics ; vitellogenin
Language	English
Dates of publication	2018-0607
Size	p. 7553-7565.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5851
DOI	10.1021/acs.est.8b02805
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Experimental and computational modeling for signature and biomarker discovery of renal cell carcinoma progression

Molecular Cancer, Vol 20, Iss 1, Pp 1-

2021 Volume 21

Abstract: Abstract Background Renal Cell Carcinoma (RCC) is difficult to treat with 5-year survival rate of 10% in metastatic patients. Main reasons of therapy failure are lack of validated biomarkers and scarce knowledge of the biological processes occurring ... ...

Abstract	Abstract Background Renal Cell Carcinoma (RCC) is difficult to treat with 5-year survival rate of 10% in metastatic patients. Main reasons of therapy failure are lack of validated biomarkers and scarce knowledge of the biological processes occurring during RCC progression. Thus, the investigation of mechanisms regulating RCC progression is fundamental to improve RCC therapy. Methods In order to identify molecular markers and gene processes involved in the steps of RCC progression, we generated several cell lines of higher aggressiveness by serially passaging mouse renal cancer RENCA cells in mice and, concomitantly, performed functional genomics analysis of the cells. Multiple cell lines depicting the major steps of tumor progression (including primary tumor growth, survival in the blood circulation and metastatic spread) were generated and analyzed by large-scale transcriptome, genome and methylome analyses. Furthermore, we performed clinical correlations of our datasets. Finally we conducted a computational analysis for predicting the time to relapse based on our molecular data. Results Through in vivo passaging, RENCA cells showed increased aggressiveness by reducing mice survival, enhancing primary tumor growth and lung metastases formation. In addition, transcriptome and methylome analyses showed distinct clustering of the cell lines without genomic variation. Distinct signatures of tumor aggressiveness were revealed and validated in different patient cohorts. In particular, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. Machine learning and mathematical modeling confirmed the importance of CFB and SAA2 together, which had the highest impact on distant metastasis-free survival. From these data sets, a computational model predicting tumor progression and relapse was developed and validated. These results are of great translational significance. Conclusion A combination of experimental and mathematical modeling was able to generate meaningful data for ...
Keywords	Metastasis ; Prognostic markers renal cell carcinoma ; Systems biology approach ; Tumor model ; SAA2 ; CFB ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	610
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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