LiSyM: Liver Systems Medicine

In chronic diseases, at some point the liver can suddenly stop functioning. This is called acute-on-chronic liver failure, or ACLF. This is the leading cause of death in liver patients and is often provoked by the use of transcription or freely available drugs or alcohol abuse. For this condition we need an effective treatment quickly. LiSyM-Pillar III researches the factors that contribute significantly to ACLF. What exactly happens then? Are there any early signs that would enable ACLF to be ...

Disorders of the liver show up through changes in blood tests. These blood tests indicate markers for events taking place in the liver. Usually studies of liver tissue cannot be performed: as liver samples would need to be obtained through a liver biopsy, and this procedure is not without risk, therefore these samples are usually unavailable. Complex metabolism models based on existing and new scientific data can simulate changes in the liver caused by disease. They often reveal unknown relationships ...

This comprises the whole LiSyM network

One of the tasks of the healthy liver is to store fat. Yet, at some stage, too much fat makes the liver sick. One critical time point occurs when a healthy fatty liver becomes inflamed and progresses to steatohepatitis, or NASH. LiSyM-Pillar I will identify what events lead to this transition. Does it occur in all parts of the liver? Which molecules indicate that it is taking place? Can the degeneration be stopped or undone - and if so, how?

In one in five people with NAFLD, the functioning liver cells, the hepatocytes, are replaced by connective tissue. Eventually this fibrosis becomes irreversible. In this state the liver is like a ‘scar that never heals’. Through it, the liver loses many of its vital functions. LiSyM-Pillar II wants to know more about which factors promote fibrosis and the conditions under which fibrosis becomes irreversible How can fibrosis be diagnosed as early as possible? Researchers in the pillar are also ...

Dr. Nachiket Vartak (TU University, Dortmund) investigates the role of a particular protein - the GTPase Rab18 - in initiating NAFLD. He tries to influence Rab18 pharmacologically so that NAFLD is not initiated. Vartak also analyzes how bile acids leave the liver. He hopes to find ways to improve the flow of bile in a liver with dysfunctional bile flow.

Dr. Madlen Matz-Soja (University of Leipzig) investigates the importance of a control mechanism - the hedgehog signaling pathway - for fatty liver disease. She has shown that the signaling pathway directs how liver cells in NAFLD accumulate fat. Hedgehog also affects sex hormones in the liver. Therefore, Matz-Soya hopes to clarify why women and men suffer from cirrhosis and liver cancer with varying degrees of frequency.

Major infrastructure backbone of the whole LiSyM network. It comprises the core management tasks of the program directorate and the scientific project management, as well as the central data management. The data management concept relies on FAIRDOM (http://fair-dom.org) and uses the LiSyM SEEK platform as a major hub for exchanging data, models, SOPs and other information, as well as yellow pages for the projects with its corresponding members, institutions, events, presentations and publications. ...

Dr. Ahmed Ghallab (TU University, Dortmund) deals with chronic liver damage caused by toxins. In addition, he investigates processes associated with cholestasis - when bile accumulates in the bile ducts. Ghallab has been able to explain basic mechanisms of acute cholestasis, using a method for intravital two-photon microscopy, which he developed.

This is a generic project that comprises all LiSyM data management PALs and associated FAIRDOM PALs, as well as the LiSyM data management team. Olga Maja Alain

We apply multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially-resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD).

Upon stimulation of cells with transforming growth factorb(TGF-b),Smad proteins form trimeric complexes and activate a broad spectrum of target genes. It remains unresolved which of the possible Smad complexes are formed in cellular contexts and how these contribute to gene expression. Combining quantitative mass spectrometry with a computational selection strategy, we investigate Smad complexes in the mouse hepatoma cell line Hepa1-6.

To investigate the underlying molecular principles of metabolic and morphogenic zonation of the human liver lobule, we generated an integrated epigenetic map across three zones (pericentral, intermediate and periportal) by methylation and transcriptomic analysis of hepatocytes captured by laser micro-dissection. We observe a deep link between epigenetic zonation of human liver and a zonated expression of metabolic and morphogenic pathways: Key transcriptionally zonated enzymes in xenobiotic and ...

Liver macrophages (LMs) play a central role in acute and chronic liver pathologies. In our study, we sought to gain further insight into the role of LMs in different liver pathologies and into their characteristics after isolation from liver tissue. Here we will characterize LMs in human liver tissue sections using immunohistochemistry and bioinformatic image analysis. We investigate liver tissues characterized by antiinflammatory LMs which show a homogeneous distribution and increased cell numbers ...

We face a crisis in reproducibility, where it is impossible to believe most of the computational results shown in conferences and papers. Recent replication efforts and theoretical considerations indicate that most published research findings in biomedical research are wrong. This is especially problematic for the translation of computational models into the clinics. Modelling standards, software, and community initiatives are fundamental for reproducibility in systems biology and systems medicine. ...

Test for SEEK API upload.

Introduction: The field of pharmacokinetics describe the kinetics of substances administered to the body, consisting of absorption, distribution, metabolization and elimination (ADME) of the substance. An important use case is the testing of liver function via test substances like caffeine, methacetin or galactose in dynamical liver function tests. Understanding the kinetics of test substances and drugs is crucial to evaluate therapeutic outcome and diagnostic value.

Results: Physiologically based ...

Histopathological analysis of human biopsies. To quantitatively characterize the transition from simple STEA to eNASH, we stained, imaged and digitally reconstructed human liver tissue in 2D and 3D from biopsies of 25 patients classified into four groups: normal control (NC, n = 6), healthy obese (HO, n = 4), steatosis (STEA, n = 8) and eNASH (n = 7).

In this study we identify most relevant Smad complexes in liver-derived cells, the contribution of the Smad complexes on target gene expression, and the role of Smad abundance and Smad2 phosphorylation in hepatocellular carcinoma

The study comprises 19 human liver biopsy donors divided into the groups normal control (NC = 7012, 7173, 7194, 7279), healthy obese (HO = 6758, 6922, 7213, 7230, 7252), bland steatosis (STEA = 6967, 7137, 7172, 7181, 7251) and early NASH (EARLY = 6610, 7041, 7157, 7188, 7344).

Hepatocytes captured by laser microdissection were obtained from three hepatic zones (pericentral, intermediate and periportal) and subjected to reduced representation bisulfite sequencing and RNA-seq resulting in 114 ...

In this study, we investigated human LMs in tissue sections as well as isolated from human liver tissues which were characterized both in suspension and in adherent cultures to find out whether the inflammatory state of primary human LMs corresponds to patients and disease characteristics and whather it is possible to maintain the macrophage pattern in suspension as well as in adherent cultures with just a few limitations. (CCA: cholangiocarcinoma, CRLM: colorectal liver metastasis, FNH: focal ...

A multitude of pharmacokinetics studies have been published. However, due to the lack of an open database, pharmacokinetics data, as well as the corresponding meta-information, have been difficult to access. We present PK-DB (https://develop.pk-db.com), an open database for pharmacokinetics information from clinical trials including pre-clinical research. PK-DB provides curated information on (i) characteristics of studied patient cohorts and subjects (e.g. age, bodyweight, smoking status); (ii) ...

Pharmacokinetics data set for caffeine

Data digitized from publication.

Hetzler1990 Description

Data digitized from publication.

Spigset1999a Description

Data digitized from publication.

Akinyinka2000 Description

Data digitized from publication.

Perera2011 Description

Data digitized from publication.

Amchin1999 Description

Data digitized from publication.

Oh2012 Description

Data digitized from publication.

Kakuda2014 Description

Data digitized from publication.

Haller2002 Description

Data digitized from publication.

Healy1991 Description

Raw data of proteomic analysis of primary murine hepatocytes treated with Hedgehog-modulating compounds

Manuscript: "Impact of Hedgehog Modulators on Signaling Pathways in Primary Murine and Human Hepatocytes in vitro: Insights into Liver Metabolism" Journal Name: Archives of Toxicology Author Names: Fritzi Ott, Christiane Körner, Knut Krohn, Janett Fischer, Georg Damm, Daniel Seehofer, Thomas Berg, Madlen Matz-Soja Corresponding author: Madlen Matz-Soja (madlen.matz-soja@medizin.uni-leipzig.de) ...

Raw data of RNA-seq analysis of primary murine hepatocytes treated with Hh modulating compounds

Manuscript: "Impact of Hedgehog Modulators on Signaling Pathways in Primary Murine and Human Hepatocytes in vitro: Insights into Liver Metabolism" Journal Name: Archives of Toxicology Author Names: Fritzi Ott, Christiane Körner, Knut Krohn, Janett Fischer, Georg Damm, Daniel Seehofer, Thomas Berg, Madlen Matz-Soja Corresponding author: Madlen Matz-Soja (madlen.matz-soja@medizin.uni-leipzig.de)

Supplementary Tables 1-7 of the Manuscript: "Multiomics and kinetic modeling reveal dominance of 12-hour rhythms in global liver metabolism"

for table headings please refer to Supplementary Material

Human RNA-Seq data set GSM2819712 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819698 stored in NCBI (GEO)

liver tissue sample : 6922_IZ_RNA

Human RNA-Seq data set GSM2819714 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819713 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819711 stored in NCBI (GEO)

ODE model describes dynamics of IFNalpha-induced signaling in Huh7.5 cells for a time scale up to 32 hours after stimulation with IFNalpha. The model consists of an IFN receptor model, formation/degradation and cytoplasmic/nuclear shuttling of STAT1-homodimers, STAT1-STAT2-heterodimers and STAT1-STAT2-IRF9 (ISGF3) complexes. On top, formation of feedback proteins STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3 and IRF2 and corresponding influences on IFNalpha signaling dynamics was incorporated. The model ...

Taken from https://github.com/Benchmarking-Initiative/Benchmark-Models See the github repository for license Import and execute the model in d2d

Taken from https://github.com/Benchmarking-Initiative/Benchmark-Models License according to the github repository's license Import and execute with d2d

not yet calibrated, not yet reduced

The model is adapted from A.P. Kupinski, I. Raabe, M. Michel, D. Ail, L. Brusch, T. Weidemann, C. Bökel (2013) Phosphorylation of the Smo tail is controlled by membrane localization and is dispensable for clustering, J. Cell Sci., 126, 20, 4684-4697 https://doi.org/10.1242/jcs.128926

The model format is MorpheusML that can readily be loaded and run in Morpheus: https://morpheus.gitlab.io

Model for the interaction of Wnt and Hh as published in Kolbe et al.: Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human, Cell Reports, 29,4553,

https://doi.org/10.1016/j.celrep.2019.11.104

For the spatio-temporal dynamics of bile transport, bile canalicular dilation, mechanical stimulation and transduction of YAP signaling during liver regeneration see the open access publication and its appendix: Meyer et al. (2020) Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration. Molecular Systems Biology 16:e8985. https://doi.org/10.15252/msb.20198985

The model format is MorpheusML that can readily be loaded and run in the free and open source software ...

Morpheus is the modelling and simulation framework for multicellular systems biology developed at Technische Universität Dresden. Manual, examples and binaries for Windows, Linux, MacOS at: https://morpheus.gitlab.io Open source code at: https://gitlab.com/morpheus.lab/morpheus

Code for the bile flow model in Segovia-Miranda et al.: Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression (https://www.nature.com/articles/s41591-019-0660-7)

See the README file in the link for details installing and running the code.

This model describes a core process during endocytosis. Intracellular vesicles called early endosomes contain the endocytosed cargo, e.g. signaling components like growth factors and RTKs, pathogens like viruses and nutrients like iron in transferrin. Early endosomes form an interacting pool of thousands of vesicles and jointly constitute the sorting and transport machinery in the endocytic pathway. Together with the cargo, membrane components travel to other compartments of the pathway which ...

Empty SOP template based on nature protocol format and reqiremeents

SOP : liver tissue microdissection for RNA sequencing

The purpose of this document is to define procedures to follow for exchanging the following items between collaboration partners within the LiSyM network: a) Exchanging samples of human origin obtained from a natural person (i.e. a patient or other human subject). b) Exchanging material derived from samples of human origin as defined in a). c) Exchanging associated data describing samples of human origin and derived material as defined in a) and b). d) Exchanging data derived from samples of human ...

Non-parenchymal liver cells are isolated and staining for FACS analysis

Macrophage staining in paraffin-embedded tissue

This SOP - Standard Operating Procedure for Sample Collection and Preservation of Blood and Endometrial Tissue were developed at NIH University of California San Francisco Human Endometrial Tissue and DNA Bank by Elizabeth Sheldonand, Ramsey A McIntire

Talk at the Jamboree 2021 about epigenomic map of human liver zonation and loss of zonation in end-stage liver disease

Jamboree presentation

Computational modeling and simulation become increasingly important for Systems Medicine. A number of corresponding software tools have been developed but require scientists to encode their models in an imperative programming language. Morpheus [1,2], on the other hand, is an extensible open-source software framework that is entirely based on declarative modeling. It uses the domain-specific language MorpheusML to define multicellular models through a user-friendly GUI and has since proven ...

ICSB is one of the largest international conferences on systems biology. Since the first conference in Tokyo in 2000, which was organized by Dr. Hiroaki Kitano, it has been held annually in different countries.

SBMC 2020 was postponed to 10th - 12th of May 2021. Further information will follow soon.

The "Computational Modeling in Biology" Network (COMBINE) is an initiative to coordinate the development of the various community standards and formats in systems biology, systems medicine, synthetic biology and related fields. COMBINE 2020 will be a workshop-style event with invited lectures, oral presentations and posters, but also reserving enough time for afternoon breakout sessions to discuss topics around data and model standardization and integration, as well as harmonization and further ...

The Computational Modeling in Biology Network (COMBINE) is an initiative to coordinate the development of the various community standards and formats in systems biology, synthetic biology and related fields. HARMONY is a codefest-type meeting, with a focus on development of the standards, interoperability and infrastructure. There are generally not many general discussions or oral presentations during HARMONY; instead, the time is devoted to allowing hands-on hacking and interaction between people ...

e:Med brings together leading scientists and exceptional young researchers from all over Germany in the emerging field of Systems Medicine. Systems medicine uses interdisciplinary systems-oriented research on diseases to create a basis for understanding complex physiological and pathological processes for development of innovative personalized diagnosis, therapies, and preventive measures. Key to the appropriate analysis and possibly to the modelling of Big Data derived from information levels ...

Registration: https://docs.google.com/document/d/1ZokiSDgj-ekNpzqHnnEl4OMqX57w6LtuB56EEnCMpng/edit

60 Poster boards will be prepared for your poster presentation. Please register your poster in the following link: https://docs.google.com/document/d/1ej2Mf_5Hkz28xDYEQiYA9cqWAztfmxO2KQn7AB1C-Y8/edit

Venue : Evangelische Tagungsstätte Hofgeismar, Kassel-Wilhelmshöhe

This young scientist retreat is being organized by the Junior Group Leaders, Madlen Matz-Soja, Matthias König, Ahmed Ghallab and Nachiket Vartak.

This workshop is a satellite meeting to the LiSyM Young Scientist Retreat. It takes place just before the retreat and is organised by Matthias König (Junior Group), Michael Kücken and Lutz Brusch (Pillar I). The aim of this additional workshop for the modelers is to demonstrate and discuss the wider applicability, but also the limitations of the mathematical and computational methods and software used and even (co-)developed within LiSyM and to exchange them among LiSyM groups. These methods and ...

One of the major themes of ICSB 2019 is “Systems Biology meets AI.” ICSB is one of the largest international conferences on systems biology. Since the first conference in Tokyo in 2000, which was organized by Dr. Hiroaki Kitano, it has been held annually in different countries.

Call for Tutorials & Workshops: February 2019 Call for Papers: April 2019 Registration opens: April 2019

This tutorial workshop is a satellite of the 20th International Conference on Systems Biology (ICSB). Participants will learn how to set up computer models of biological systems (e.g. metabolic or signalling networks) using experimental kinetic data and how to simulate them in different systems biology platforms. Hands-on sessions, lectures and software demonstrations will be included, providing attendees with the necessary skills to access experimental kinetics data from available resources, to ...

Poster for the PhD retreat in Hofgeismar - Svenja Kemmer

Small movie explaining how to associate authors to profiles.

Non-alcoholic fatty liver disease and nonalcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.