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Hepatic ChREBP orchestrates intrahepatic carbohydrate metabolism to limit hepatic glucose 6-phosphate and glycogen accumulation in a mouse model for acute Glycogen Storage Disease type Ib

Abstract (Expand)

Carbohydrate Response Element Binding Protein (ChREBP) is a glucose 6-phosphate (G6P)-sensitive transcription factor that acts as a metabolic switch to maintain intracellular glucose and phosphate … homeostasis. Hepatic ChREBP is well-known for its regulatory role in glycolysis, the pentose phosphate pathway, and de novo lipogenesis. The physiological role of ChREBP in hepatic glycogen metabolism and blood glucose regulation has not been assessed in detail, and ChREBP's contribution to carbohydrate flux adaptations in hepatic Glycogen Storage Disease type 1 (GSD I) requires further investigation.

Authors: K.A. Krishnamurthy, M.G.S. Rutten, J.A. Hoogerland, T.H. van Dijk, T. Bos, M. Koehorst, M.P. de Vries, N.J. Kloosterhuis, H. Havinga, B.V. Schomakers, M. van Weeghel, J.C. Wolters, B.M. Bakker, M.H. Oosterveer

Date Published: 2024

Publication Type: Journal

Systematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation

Abstract (Expand)

Abstract Cell lines are valuable resources as model for human biology and translational medicine. It is thus important to explore the concordance between the expression in various cell lines vis-à-vis …ous cell lines vis-à-vis human native and disease tissues. In this study, we investigate the expression of all human protein-coding genes in more than 1,000 human cell lines representing 27 cancer types by a genome-wide transcriptomics analysis. The cell line gene expression is compared with the corresponding profiles in various tissues, organs, single-cell types and cancers. Here, we present the expression for each cell line and give guidance for the most appropriate cell line for a given experimental study. In addition, we explore the cancer-related pathway and cytokine activity of the cell lines to aid human biology studies and drug development projects. All data are presented in an open access cell line section of the Human Protein Atlas to facilitate the exploration of all human protein-coding genes across these cell lines.

Authors: Han Jin, Cheng Zhang, Martin Zwahlen, Kalle von Feilitzen, Max Karlsson, Mengnan Shi, Meng Yuan, Xiya Song, Xiangyu Li, Hong Yang, Hasan Turkez, Linn Fagerberg, Mathias Uhlén, Adil Mardinoglu

Date Published: 1st Dec 2023

Publication Type: Journal

The complex biology of aryl hydrocarbon receptor activation in cancer and beyond

Abstract

Not specified

Authors: Christiane A. Opitz, Pauline Holfelder, Mirja Tamara Prentzell, Saskia Trump

Date Published: 1st Oct 2023

Publication Type: Journal

Development of HILIC-MS/MS method for acyl-CoAs covering short- to long-chain species in a single analytical run

Abstract (Expand)

Acyl-CoAs play a significant role in numerous physiological and metabolic processes making it important to assess their concentration levels for evaluating metabolic health. Considering the important …he important role of acyl-CoAs, it is crucial to develop an analytical method that can analyze these compounds. Due to the structural variations of acyl-CoAs, multiple analytical methods are often required for comprehensive analysis of these compounds, which increases complexity and the analysis time. In this study, we have developed a method using a zwitterionic HILIC column that enables the coverage of free CoA and short- to long-chain acyl-CoA species in one analytical run. Initially, we developed the method on a QTOF instrument for the identification of acyl-CoA species, optimizing their chromatography and retention times. Later, a targeted HILIC-MS/MS method was created in scheduled multiple reaction monitoring mode on a QTRAP instrument. The performance of the method was evaluated based on various parameters such as linearity, precision, recovery and matrix effect. This method was applied to identify the difference in acyl-CoA profiles in HepG2 cells cultured in different conditions. Our findings revealed an increase in levels of acetyl-CoA, medium- and long-chain acyl-CoA while a decrease in the profiles of free CoA in the starved state, indicating a clear alteration in the fatty acid oxidation process.

Authors: Madhulika Singh, Ligia Akemi Kiyuna, Christoff Odendaal, Barbara M. Bakker, Amy C Harms, Thomas Hankemeier

Date Published: 11th Sep 2023

Publication Type: Journal

Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients.

Abstract (Expand)

BACKGROUND: Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of … metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients-if untreated-are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. RESULTS: We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. CONCLUSIONS: We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.

Authors: C. Odendaal, E. A. Jager, A. M. F. Martines, M. A. Vieira-Lara, N. C. A. Huijkman, L. A. Kiyuna, A. Gerding, J. C. Wolters, R. Heiner-Fokkema, K. van Eunen, T. G. J. Derks, B. M. Bakker

Date Published: 4th Sep 2023

Publication Type: Journal

Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids

Abstract (Expand)

A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The … compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 μM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite’s plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.

Authors: Marina Roussaki, George E. Magoulas, Theano Fotopoulou, Nuno Santarem, Emile Barrias, Ina Pöhner, Sara Luelmo, Pantelis Afroudakis, Kalliopi Georgikopoulou, Paloma Tejera Nevado, Julia Eick, Eugenia Bifeld, María J. Corral, María Dolores Jiménez-Antón, Bernhard Ellinger, Maria Kuzikov, Irini Fragiadaki, Effie Scoulica, Sheraz Gul, Joachim Clos, Kyriakos C. Prousis, Juan J. Torrado, José María Alunda, Rebecca C. Wade, Wanderley de Souza, Anabela Cordeiro da Silva, Theodora Calogeropoulou

Date Published: 1st Sep 2023

Publication Type: Journal

Inhibitor titrations reveal low control of glyceraldehyde 3-phosphate dehydrogenase and high control of hexokinase on glycolytic flux in an aggressive triple-negative breast cancer cell line

Abstract

Not specified

Authors: Theresa Kouril, Craig October, Stephanie Hollocks, Christoff Odendaal, David D. van Niekerk, Jacky L. Snoep

Date Published: 1st Sep 2023

Publication Type: Journal

Development of a targeted hydrophilic interaction liquid chromatography-tandem mass spectrometry based lipidomics platform applied to a coronavirus disease severity study.

Abstract (Expand)

The importance of lipids seen in studies of metabolism, cancer, the recent COVID-19 pandemic and other diseases has brought the field of lipidomics to the forefront of clinical research. Quantitative … and comprehensive analysis is required to understand biological interactions among lipid species. However, lipidomic analysis is often challenging due to the various compositional structures, diverse physicochemical properties, and wide dynamic range of concentrations of lipids in biological systems. To study the comprehensive lipidome, a hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS)-based screening method with 1200 lipid features across 19 (sub)classes, including both nonpolar and polar lipids, has been developed. HILIC-MS/MS was selected due to its class separation property and fatty acyl chain level information. 3D models of class chromatographic retention behavior were established and evaluations of cross-class and within-class interferences were performed to avoid over-reporting these features. This targeted HILIC-MS/MS method was fully validated, with acceptable analytical parameters in terms of linearity, precision, reproducibility, and recovery. The accurate quantitation of 608 lipid species in the SRM 1950 NIST plasma was achieved using multi-internal standards per class and post-hoc correction, extending current databases by providing lipid concentrations resolved at fatty acyl chain level. The overall correlation coefficients (R(2)) of measured concentrations with values from literature range from 0.64 to 0.84. The applicability of the developed targeted lipidomics method was demonstrated by discovering 520 differential lipid features related to COVID-19 severity. This high coverage and targeted approach will aid in future investigations of the lipidome in various disease contexts.

Authors: Z. Zhang, M. Singh, A. Kindt, A. B. Wegrzyn, M. J. Pearson, A. Ali, A. C. Harms, P. Baker, T. Hankemeier

Date Published: 31st Aug 2023

Publication Type: Journal

Hepatocytes reprogram liver macrophages involving control of TGF-beta activation, influencing liver regeneration and injury.

Abstract (Expand)

BACKGROUND: Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in … terms of their activation state and which other liver cell populations may play a role in regulating the same. METHODS: Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy. RESULTS: We show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)-dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow-derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell-specific deletion of the TGF-beta type II receptor, suggest that the availability of activated TGF-beta and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-betaRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration. CONCLUSIONS: The availability of activated TGF-beta determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-beta may represent an important regulatory mechanism in the early phase of liver regeneration in this context.

Authors: S. D. Wolf, C. Ehlting, S. Muller-Dott, G. Poschmann, P. Petzsch, T. Lautwein, S. Wang, B. Helm, M. Schilling, J. Saez-Rodriguez, M. Vucur, K. Stuhler, K. Kohrer, F. Tacke, S. Dooley, U. Klingmuller, T. Luedde, J. G. Bode

Date Published: 1st Aug 2023

Publication Type: Journal

Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes

Abstract (Expand)

Abstract Background Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-dioxygenase (TDO) are enzymes catabolizing the essential amino acid tryptophan into kynurenine. Expression of these enzymes is … frequently observed in advanced-stage cancers and is associated with poor disease prognosis and immune suppression. Mechanistically, the respective roles of tryptophan shortage and kynurenine production in suppressing immunity remain unclear. Kynurenine was proposed as an endogenous ligand for the aryl hydrocarbon receptor (AHR), which can regulate inflammation and immunity. However, controversy remains regarding the role of AHR in IDO1/TDO-mediated immune suppression, as well as the involvement of kynurenine. In this study, we aimed to clarify the link between IDO1/TDO expression, AHR pathway activation and immune suppression. Methods AHR expression and activation was analyzed by RT-qPCR and western blot analysis in cells engineered to express IDO1/TDO, or cultured in medium mimicking tryptophan catabolism by IDO1/TDO. In vitro differentiation of naïve CD4+ T cells into regulatory T cells (Tregs) was compared in T cells isolated from mice bearing different Ahr alleles or a knockout of Ahr, and cultured in medium with or without tryptophan and kynurenine. Results We confirmed that IDO1/TDO expression activated AHR in HEK-293-E cells, as measured by the induction of AHR target genes. Unexpectedly, AHR was also overexpressed on IDO1/TDO expression. AHR overexpression did not depend on kynurenine but was triggered by tryptophan deprivation. Multiple human tumor cell lines overexpressed AHR on tryptophan deprivation. AHR overexpression was not dependent on general control non-derepressible 2 (GCN2), and strongly sensitized the AHR pathway. As a result, kynurenine and other tryptophan catabolites, which are weak AHR agonists in normal conditions, strongly induced AHR target genes in tryptophan-depleted conditions. Tryptophan depletion also increased kynurenine uptake by increasing SLC7A5 (LAT1) expression in a GCN2-dependent manner. Tryptophan deprivation potentiated Treg differentiation from naïve CD4+ T cells isolated from mice bearing an AHR allele of weak affinity similar to the human AHR. Conclusions Tryptophan deprivation sensitizes the AHR pathway by inducing AHR overexpression and increasing cellular kynurenine uptake. As a result, tryptophan catabolites such as kynurenine more potently activate AHR, and Treg differentiation is promoted. Our results propose a molecular explanation for the combined roles of tryptophan deprivation and kynurenine production in mediating IDO1/TDO-induced immune suppression.

Authors: Marie Solvay, Pauline Holfelder, Simon Klaessens, Luc Pilotte, Vincent Stroobant, Juliette Lamy, Stefan Naulaerts, Quentin Spillier, Raphaël Frédérick, Etienne De Plaen, Christine Sers, Christiane A Opitz, Benoit J Van den Eynde, Jingjing Zhu

Date Published: 21st Jun 2023

Publication Type: Journal

ReStoRunT: Simple Recording, Storing, Running and Tracing changes in Spreadsheets

Abstract (Expand)

In addition to the ubiquitous big data, one key challenge indata processing and management in the life sciences is the diversity ofsmall data. Diverse pieces of small data have to be transformed … intostandards-compliant data. Here, the challenge lies not in the difficulty ofsingle steps that need to be performed, but rather in the fact that manytransformation tasks are to be performed once or only a few times. Thislimits the time that can be put into automated approaches, which inturn severely limits the verifiability of such transformations.As much of the data to be processed is stored in spreadsheets, withinthis paper we justify and propose a lightweight recording-based solutionthat works on a wide variety of spreadsheet programs, from MicrosoftExcel to Google Docs.

Authors: Wolfgang Müller, Lukrécia Mertová

Date Published: 23rd Mar 2023

Publication Type: Journal

Proteome Coverage after Simultaneous Proteo-Metabolome Liquid–Liquid Extraction

Abstract (Expand)

Proteomics and metabolomics are essential in systems biology, and simultaneous proteo-metabolome liquid–liquid extraction (SPM-LLE) allows isolation of the metabolome and proteome from the same sample. … Since the proteome is present as a pellet in SPM-LLE, it must be solubilized for quantitative proteomics. Solubilization and proteome extraction are critical factors in the information obtained at the proteome level. In this study, we investigated the performance of two surfactants (sodium deoxycholate (SDC), sodium dodecyl sulfate (SDS)) and urea in terms of proteome coverage and extraction efficiency of an interphase proteome pellet generated by methanol–chloroform based SPM-LLE. We also investigated how the performance differs when the proteome is extracted from the interphase pellet or by direct cell lysis. We quantified 12 lipids covering triglycerides and various phospholipid classes, and 25 polar metabolites covering central energy metabolism in chloroform and methanol extracts. Our study reveals that the proteome coverages between the two surfactants and urea for the SPM-LLE interphase pellet were similar, but the extraction efficiencies differed significantly. While SDS led to enrichment of basic proteins, which were mainly ribosomal and ribonuclear proteins, urea was the most efficient extraction agent for simultaneous proteo-metabolome analysis. The results of our study also show that the performance of surfactants for quantitative proteomics is better when the proteome is extracted through direct cell lysis rather than an interphase pellet. In contrast, the performance of urea for quantitative proteomics was significantly better when the proteome was extracted from an interphase pellet than by direct cell lysis. We demonstrated that urea is superior to surfactants for proteome extraction from SPM-LLE interphase pellets, with a particularly good performance for the extraction of proteins associated with metabolic pathways. Data are available via ProteomeXchange with identifier PXD027338 (https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD027338)

Authors: Alienke van Pijkeren, Anna-Sophia Egger, Madlen Hotze, Elisabeth Zimmermann, Tobias Kipura, Julia Grander, André Gollowitzer, Andreas Koeberle, Rainer Bischoff, Kathrin Thedieck, Marcel Kwiatkowski

Date Published: 3rd Mar 2023

Publication Type: Journal

Tryptophan stress activates EGFR-RAS-signaling to MTORC1 and p38/MAPK to sustain translation and AHR-dependent autophagy

Abstract (Expand)

Limited supply and catabolism restrict the essential amino acid tryptophan (Trp) in tumors. How tumors sustain translation under Trp stress remains unclear. Unlike other amino acids, Trp stress activates …s the EGFR, which enhances macropinocytosis and RAS signaling to the MTORC1 and p38/MAPK kinases, sustaining translation. The AHR forms part of the Trp stress proteome and promotes autophagy to sustain Trp levels, and ceramide biosynthesis. Thus, Trp restriction elicits pro-translation signals enabling adaptation to nutrient stress, placing Trp into a unique position in the amino acid-mediated stress response. Our findings challenge the current perception that Trp restriction inhibits MTORC1 and the AHR and explain how both cancer drivers remain active. A glioblastoma patient subgroup with enhanced MTORC1 and AHR displays an autophagy signature, highlighting the clinical relevance of MTORC1-AHR crosstalk. Regions of high Trp or high ceramides are mutually exclusive, supporting that low Trp activates the EGFR-MTORC1-AHR axis in glioblastoma tissue.

Authors: Pauline Pfänder, Lucas Hensen, Patricia Razquin Navas, Marie Solvay, Mirja Tamara Prentzell, Ahmed Sadik, Alexander M. Heberle, Sophie Seifert, Leon Regin, Tobias Bausbacher, Anna-Sophia Egger, Madlen Hotze, Tobias Kipura, Bianca Berdel, Ivana Karabogdan, Luis F. Somarribas Patterson, Michele Reil, Deepak Sayeeram, Vera Peters, Jose Ramos Pittol, Ineke van ’t Land-Kuper, Teresa Börding, Saskia Trump, Alienke van Pijkeren, Yang Zhang, Fabricio Loayza-Puch, Alexander Kowar, Sönke Harder, Lorenz Waltl, André Gollowitzer, Tetsushi Kataura, Viktor I. Korolchuk, Shad A. Mohammed, Phillipp Sievers, Felix Sahm, Hartmut Schlüter, Andreas Koeberle, Carsten Hopf, Marcel Kwiatkowski, Christine Sers, Benoit J. Van den Eynde, Christiane A. Opitz, Kathrin Thedieck

Date Published: 17th Jan 2023

Publication Type: Journal

Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions.

Abstract (Expand)

The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key … ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a-t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH. Interesting structure-activity relationships (SARs), deeply analyzed by molecular docking and molecular dynamic (MD) simulations, were obtained. All the newly developed inhibitors showed an excellent selectivity profile evaluated against monoacylglycerol lipase and cannabinoid receptors. The reversible mechanism of action was determined by a rapid dilution assay. Absence of toxicity was confirmed in mouse fibroblasts NIH3T3 (for compounds 4e, 4g, 4n-o, and 4s) and in human astrocytes cell line 1321N1 (for compounds 4e, 4n, and 4s). The absence of undesired cardiac effects was also confirmed for compound 4n. Selected analogues (compounds 4e, 4g, 4n, and 4s) were able to reduce oxidative stress in 1321N1 astrocytes and exhibited notable neuroprotective effects when tested in an ex vivo model of neuroinflammation.

Authors: A. Papa, S. Pasquini, F. Galvani, M. Cammarota, C. Contri, G. Carullo, S. Gemma, A. Ramunno, S. Lamponi, B. Gorelli, S. Saponara, K. Varani, M. Mor, G. Campiani, F. Boscia, F. Vincenzi, A. Lodola, S. Butini

Date Published: 15th Jan 2023

Publication Type: Journal

Chemical identification and indexing in full-text articles: an overview of the NLM-Chem track at BioCreative VII

Abstract (Expand)

Abstract The BioCreative National Library of Medicine (NLM)-Chem track calls for a community effort to fine-tune automated recognition of chemical names in the biomedical literature. Chemicals are one …erature. Chemicals are one of the most searched biomedical entities in PubMed, and—as highlighted during the coronavirus disease 2019 pandemic—their identification may significantly advance research in multiple biomedical subfields. While previous community challenges focused on identifying chemical names mentioned in titles and abstracts, the full text contains valuable additional detail. We, therefore, organized the BioCreative NLM-Chem track as a community effort to address automated chemical entity recognition in full-text articles. The track consisted of two tasks: (i) chemical identification and (ii) chemical indexing. The chemical identification task required predicting all chemicals mentioned in recently published full-text articles, both span [i.e. named entity recognition (NER)] and normalization (i.e. entity linking), using Medical Subject Headings (MeSH). The chemical indexing task required identifying which chemicals reflect topics for each article and should therefore appear in the listing of MeSH terms for the document in the MEDLINE article indexing. This manuscript summarizes the BioCreative NLM-Chem track and post-challenge experiments. We received a total of 85 submissions from 17 teams worldwide. The highest performance achieved for the chemical identification task was 0.8672 F-score (0.8759 precision and 0.8587 recall) for strict NER performance and 0.8136 F-score (0.8621 precision and 0.7702 recall) for strict normalization performance. The highest performance achieved for the chemical indexing task was 0.6073 F-score (0.7417 precision and 0.5141 recall). This community challenge demonstrated that (i) the current substantial achievements in deep learning technologies can be utilized to improve automated prediction accuracy further and (ii) the chemical indexing task is substantially more challenging. We look forward to further developing biomedical text–mining methods to respond to the rapid growth of biomedical literature. The NLM-Chem track dataset and other challenge materials are publicly available at https://ftp.ncbi.nlm.nih.gov/pub/lu/BC7-NLM-Chem-track/. Database URL https://ftp.ncbi.nlm.nih.gov/pub/lu/BC7-NLM-Chem-track/

Authors: Robert Leaman, Rezarta Islamaj, Virginia Adams, Mohammed A Alliheedi, João Rafael Almeida, Rui Antunes, Robert Bevan, Yung-Chun Chang, Arslan Erdengasileng, Matthew Hodgskiss, Ryuki Ida, Hyunjae Kim, Keqiao Li, Robert E Mercer, Lukrécia Mertová, Ghadeer Mobasher, Hoo-Chang Shin, Mujeen Sung, Tomoki Tsujimura, Wen-Chao Yeh, Zhiyong Lu

Date Published: 2023

Publication Type: Journal

WeLT: Improving Biomedical Fine-tuned Pre-trained Language Models with Cost-sensitive Learning

Abstract

Not specified

Authors: Ghadeer Mobasher, Wolfgang Müller, Olga Krebs, Michael Gertz

Date Published: 2023

Publication Type: InProceedings

Synthesis of Deoxysugars from Aliphatic α-Ketoacids and Aldoses Catalyzed by Thermostable Transketolase Variants from Geobacillus stearothermophilus

Abstract

Not specified

Author: Nazim Ocal, Giuseppe Arbia, Aurélie Lagarde, Muriel Joly, Samantha Gittings, Kirsty M. Graham, Franck Charmantray, Laurence Hecquet

Date Published: 14th Dec 2022

Publication Type: Journal

Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism

Abstract (Expand)

Abstract Little is known about the impact of morphological disorders in distinct zones on metabolic zonation. It was described recently that periportal fibrosis did affect the expression of CYP proteins, …xpression of CYP proteins, a set of pericentrally located drug-metabolizing enzymes. Here, we investigated whether periportal steatosis might have a similar effect. Periportal steatosis was induced in C57BL6/J mice by feeding a high-fat diet with low methionine/choline content for either two or four weeks. Steatosis severity was quantified using image analysis. Triglycerides and CYP activity were quantified in photometric or fluorometric assay. The distribution of CYP3A4, CYP1A2, CYP2D6, and CYP2E1 was visualized by immunohistochemistry. Pharmacokinetic parameters of test drugs were determined after injecting a drug cocktail (caffeine, codeine, and midazolam). The dietary model resulted in moderate to severe mixed steatosis confined to periportal and midzonal areas. Periportal steatosis did not affect the zonal distribution of CYP expression but the activity of selected CYPs was associated with steatosis severity. Caffeine elimination was accelerated by microvesicular steatosis, whereas midazolam elimination was delayed in macrovesicular steatosis. In summary, periportal steatosis affected parameters of pericentrally located drug metabolism. This observation calls for further investigations of the highly complex interrelationship between steatosis and drug metabolism and underlying signaling mechanisms.

Authors: Mohamed Albadry, Sebastian Höpfl, Nadia Ehteshamzad, Matthias König, Michael Böttcher, Jasna Neumann, Amelie Lupp, Olaf Dirsch, Nicole Radde, Bruno Christ, Madlen Christ, Lars Ole Schwen, Hendrik Laue, Robert Klopfleisch, Uta Dahmen

Date Published: 1st Dec 2022

Publication Type: Journal

Cardiac PI3K p110alpha attenuation delays aging and extends lifespan.

Abstract (Expand)

Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream … effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend healthspan in humans. We recently demonstrated that reduced PI3K activity in cardiomyocytes delays cardiac growth, causing subnormal contractility and cardiopulmonary functional capacity, as well as increased risk of mortality at young age. In stark contrast, in aged mice, experi-mental attenuation of PI3K signaling reduced the age-dependent decline in cardiac function and extended maximal lifespan, suggesting a biphasic effect of PI3K on cardiac health and survival. The cardiac anti-aging effects of reduced PI3K activity coincided with enhanced oxida-tive phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed in-creased PI3K signaling, as indicated by increased phos-phorylation of the serine/threonine-protein kinase AKT. Hence, late-life cardiac-specific targeting of PI3K might have a therapeutic potential in cardiac aging and related diseases.

Authors: M. Abdellatif, T. Eisenberg, A. M. Heberle, K. Thedieck, G. Kroemer, S. Sedej

Date Published: 30th Nov 2022

Publication Type: Journal

Microalgae and Bacteria Interaction—Evidence for Division of Diligence in the Alga Microbiota

Abstract (Expand)

The current study gives a detailed insight into mutualistic collaboration of microalgae and bacteria, including the involvement of competitive interplay between bacteria. We provide experimental evidence … provide experimental evidence that Gram-negative bacteria belonging to the Dyadobacter , Porphyrobacter , and Variovorax are the key players in a Scenedesmus quadricauda alga-bacteria interaction.

Authors: Yekaterina Astafyeva, Marno Gurschke, Minyue Qi, Lutgardis Bergmann, Daniela Indenbirken, Imke de Grahl, Elena Katzowitsch, Sigrun Reumann, Dieter Hanelt, Malik Alawi, Wolfgang R. Streit, Ines Krohn

Date Published: 1st Aug 2022

Publication Type: Journal

The Arabidopsis Framework Model version 2 predicts the organism-level effects of circadian clock gene mis-regulation

Abstract (Expand)

Predicting a multicellular organism’s phenotype quantitatively from its genotype is challenging, as genetic effects must propagate across scales. Circadian clocks are intracellular regulators that … control temporal gene expression patterns and hence metabolism, physiology and behaviour. Here we explain and predict canonical phenotypes of circadian timing in a multicellular, model organism. We used diverse metabolic and physiological data to combine and extend mathematical models of rhythmic gene expression, photoperiod-dependent flowering, elongation growth and starch metabolism within a Framework Model for the vegetative growth of Arabidopsis thaliana, sharing the model and data files in a structured, public resource. The calibrated model predicted the effect of altered circadian timing upon each particular phenotype in clock-mutant plants under standard laboratory conditions. Altered night-time metabolism of stored starch accounted for most of the decrease in whole-plant biomass, as previously proposed. Mobilization of a secondary store of malate and fumarate was also mis-regulated, accounting for any remaining biomass defect. The three candidate mechanisms tested did not explain this organic acid accumulation. Our results link genotype through specific processes to higher-level phenotypes, formalizing our understanding of a subtle, pleiotropic syndrome at the whole-organism level, and validating the systems approach to understand complex traits starting from intracellular circuits.

Authors: Yin Hoon Chew, Daniel D Seaton, Virginie Mengin, Anna Flis, Sam T Mugford, Gavin M George, Michael Moulin, Alastair Hume, Samuel C Zeeman, Teresa B Fitzpatrick, Alison M Smith, Mark Stitt, Andrew J Millar

Date Published: 1st Jul 2022

Publication Type: Journal

Stochastic LCA Model of Upscaling the Production of Microalgal Compounds

Abstract

Not specified

Authors: Pierre Jouannais, Stefan Hindersin, Sarah Löhn, Massimo Pizzol

Date Published: 28th Jun 2022

Publication Type: Journal

Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.

Abstract (Expand)

BACKGROUND: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 … signaling on cardiac aging remains controversial. METHODS: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. RESULTS: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. CONCLUSIONS: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.

Authors: M. Abdellatif, V. Trummer-Herbst, A. M. Heberle, A. Humnig, T. Pendl, S. Durand, G. Cerrato, S. J. Hofer, M. Islam, J. Voglhuber, J. M. Ramos Pittol, O. Kepp, G. Hoefler, A. Schmidt, P. P. Rainer, D. Scherr, D. von Lewinski, E. Bisping, J. R. McMullen, A. Diwan, T. Eisenberg, F. Madeo, K. Thedieck, G. Kroemer, S. Sedej

Date Published: 21st Jun 2022

Publication Type: Journal

In vitro grafting of hepatic spheroids and organoids on a microfluidic vascular bed.

Abstract (Expand)

With recent progress in modeling liver organogenesis and regeneration, the lack of vasculature is becoming the bottleneck in progressing our ability to model human hepatic tissues in vitro. Here, we … introduce a platform for routine grafting of liver and other tissues on an in vitro grown microvascular bed. The platform consists of 64 microfluidic chips patterned underneath a 384-well microtiter plate. Each chip allows the formation of a microvascular bed between two main lateral vessels by inducing angiogenesis. Chips consist of an open-top microfluidic chamber, which enables addition of a target tissue by manual or robotic pipetting. Upon grafting a liver microtissue, the microvascular bed undergoes anastomosis, resulting in a stable, perfusable vascular network. Interactions with vasculature were found in spheroids and organoids upon 7 days of co-culture with space of Disse-like architecture in between hepatocytes and endothelium. Veno-occlusive disease was induced by azathioprine exposure, leading to impeded perfusion of the vascularized spheroid. The platform holds the potential to replace animals with an in vitro alternative for routine grafting of spheroids, organoids, or (patient-derived) explants.

Authors: F. Bonanini, D. Kurek, S. Previdi, A. Nicolas, D. Hendriks, S. de Ruiter, M. Meyer, M. Clapes Cabrer, R. Dinkelberg, S. B. Garcia, B. Kramer, T. Olivier, H. Hu, C. Lopez-Iglesias, F. Schavemaker, E. Walinga, D. Dutta, K. Queiroz, K. Domansky, B. Ronden, J. Joore, H. L. Lanz, P. J. Peters, S. J. Trietsch, H. Clevers, P. Vulto

Date Published: 16th Jun 2022

Publication Type: Journal

AnthraxKP: a knowledge graph-based, Anthrax Knowledge Portal mined from biomedical literature.

Abstract (Expand)

Anthrax is a zoonotic infectious disease caused by Bacillus anthracis (anthrax bacterium) that affects not only domestic and wild animals worldwide but also human health. As the study develops in-depth, … a large quantity of related biomedical publications emerge. Acquiring knowledge from the literature is essential for gaining insight into anthrax etiology, diagnosis, treatment and research. In this study, we used a set of text mining tools to identify nearly 14 000 entities of 29 categories, such as genes, diseases, chemicals, species, vaccines and proteins, from nearly 8000 anthrax biomedical literature and extracted 281 categories of association relationships among the entities. We curated Anthrax-related Entities Dictionary and Anthrax Ontology. We formed Anthrax Knowledge Graph (AnthraxKG) containing more than 6000 nodes, 6000 edges and 32 000 properties. An interactive visualized Anthrax Knowledge Portal(AnthraxKP) was also developed based on AnthraxKG by using Web technology. AnthraxKP in this study provides rich and authentic relevant knowledge in many forms, which can help researchers carry out research more efficiently. Database URL: AnthraxKP is permitted users to query and download data at http://139.224.212.120:18095/.

Authors: B. Feng, J. Gao

Date Published: 2nd Jun 2022

Publication Type: Journal

SALARECON connects the Atlantic salmon genome to growth and feed efficiency

Abstract (Expand)

Atlantic salmon (Salmo salar) is the most valuable farmed fish globally and there is much interest in optimizing its genetics and rearing conditions for growth and feed efficiency. Marine feed ingredients … must be replaced to meet global demand, with challenges for fish health and sustainability. Metabolic models can address this by connecting genomes to metabolism, which converts nutrients in the feed to energy and biomass, but such models are currently not available for major aquaculture species such as salmon. We present SALARECON, a model focusing on energy, amino acid, and nucleotide metabolism that links the Atlantic salmon genome to metabolic fluxes and growth. It performs well in standardized tests and captures expected metabolic (in)capabilities. We show that it can explain observed hypoxic growth in terms of metabolic fluxes and apply it to aquaculture by simulating growth with commercial feed ingredients. Predicted limiting amino acids and feed efficiencies agree with data, and the model suggests that marine feed efficiency can be achieved by supplementing a few amino acids to plant- and insect-based feeds. SALARECON is a high-quality model that makes it possible to simulate Atlantic salmon metabolism and growth. It can be used to explain Atlantic salmon physiology and address key challenges in aquaculture such as development of sustainable feeds.

Authors: Maksim Zakhartsev, Filip Rotnes, Marie Gulla, Ove Oyas, Jesse van Dam, Maria Suarez Diez, Fabian Grammes, Robert Hafthorsson, Wout van Helvoirt, Jasper Koehorst, Peter Schaap, Yang Jin, Liv Torunn Mydland, Arne Gjuvsland, Sandve Simen, Vitor Martins dos Santos, Jon Olav Vik

Date Published: 1st Jun 2022

Publication Type: Journal

Health benefits of microalgae and their microbiomes

Abstract (Expand)

Microalgae comprise a phylogenetically very diverse group of photosynthetic unicellular pro- and eukaryotic organisms growing in marine and other aquatic environments. While they are well explored for … the generation of biofuels, their potential as a source of antimicrobial and prebiotic substances have recently received increasing interest. Within this framework, microalgae may offer solutions to the societal challenge we face, concerning the lack of antibiotics treating the growing level of antimicrobial resistant bacteria and fungi in clinical settings. While the vast majority of microalgae and their associated microbiota remain unstudied, they may be a fascinating and rewarding source for novel and more sustainable antimicrobials and alternative molecules and compounds. In this review, we present an overview of the current knowledge on health benefits of microalgae and their associated microbiota. Finally, we describe remaining issues and limitation, and suggest several promising research potentials that should be given attention.

Authors: Ines Krohn, Simon Menanteau‐Ledouble, Gunhild Hageskal, Yekaterina Astafyeva, Pierre Jouannais, Jeppe Lund Nielsen, Massimo Pizzol, Alexander Wentzel, Wolfgang R. Streit

Date Published: 29th May 2022

Publication Type: Journal

Fermentative Indole Production via Bacterial Tryptophan Synthase Alpha Subunit and Plant Indole-3-Glycerol Phosphate Lyase Enzymes

Abstract (Expand)

Indole is produced in nature by diverse organisms and exhibits a characteristic odor described as animal, fecal, and floral. In addition, it contributes to the flavor in foods, and it is applied in the … fragrance and flavor industry. In nature, indole is synthesized either from tryptophan by bacterial tryptophanases (TNAs) or from indole-3-glycerol phosphate (IGP) by plant indole-3-glycerol phosphate lyases (IGLs). While it is widely accepted that the tryptophan synthase α-subunit (TSA) has intrinsically low IGL activity in the absence of the tryptophan synthase β-subunit, in this study, we show that Corynebacterium glutamicum TSA functions as a bona fide IGL and can support fermentative indole production in strains providing IGP. By bioprospecting additional bacterial TSAs and plant IGLs that function as bona fide IGLs were identified. Capturing indole in an overlay enabled indole production to titers of about 0.7 g L-1 in fermentations using C. glutamicum strains expressing either the endogenous TSA gene or the IGL gene from wheat.

Authors: Lenny Ferrer, Melanie Mindt, Maria Suarez-Diez, Tatjana Jilg, Maja Zagorščak, Jin-Ho Lee, Kristina Gruden, Volker F. Wendisch, Katarina Cankar

Date Published: 11th May 2022

Publication Type: Journal

Black soldier fly larvae (BSFL) and their affinity for organic waste processing.

Abstract (Expand)

There are two major problems that we are facing currently. Firstly, a growing human population continues to contribute to the increased food demand. Secondly, the volume of organic waste produced will … threaten human health and the quality of the environment. Recently, there is an increasing number of efforts placed into farming insect biomass to produce alternative feed ingredients. Black soldier fly larvae (BSFL), Hermetia illucens have proven to convert organic waste into high-quality nutrients for pet foods, fish and poultry feeds, as well as residue fertilizer for soil amendment. However, better BSFL feed formulation and feeding approaches are necessary for yielding a higher nutrient content of the insect body, and if performed efficiently, whilst converting waste into higher value biomass. Lastly, this paper reveals that BSFL, in fact, thrives in various ranges of organic matter composition and with simple rearing systems.

Authors: S. A. Siddiqui, B. Ristow, T. Rahayu, N. S. Putra, N. Widya Yuwono, K. Nisa', B. Mategeko, S. Smetana, M. Saki, A. Nawaz, A. Nagdalian

Date Published: 1st Mar 2022

Publication Type: Journal

Gene Network Inference from Single-Cell Omics Data and Domain Knowledge for Constructing COVID-19-Specific ICAM1-Associated Pathways

Abstract (Expand)

Abstract ICAM-1 is critical for interactions between cells. Previous studies have suggested that ICAM-1 triggers cell-to-cell transmission of HIV-1 or HTLV-1. SARS-CoV-2 shares several features with … several features with these viruses in interactions between cells, and SARS-CoV-2 cell-to-cell transmission is associated with COVID-19 severity. However, ICAM-1 and its associated pathways are not identified as essential factors in interactions between cells in COVID-19. For example, the current COVID-19 Disease Map has no entry for those pathways. Therefore, discovering unknown ICAM-1 pathways will be indispensable for clarifying the mechanism of COVID-19. This study builds ICAM1-associated pathways by gene network inference from single-cell omics data and multiple knowledge bases. First, data analyses extracted coexpressed genes with significant differences in expression levels with spurious correlations removed. Second, knowledge bases validate models. Finally, mapping the models onto existing pathways identifies new ICAM1-associated pathways. These pathways indicate that (1) upstream pathways include proteins in noncanonical NF-kappaB pathway and that (2) downstream pathways contain integrins and cytoskeleton or motor proteins for cell transformation. In this way, data-driven and knowledge-based approaches are integrated into gene network inference for ICAM1-associated pathway construction. The results can contribute to repairing and completing the COVID-19 Disease Map, thereby improving our understanding of the mechanisms of COVID-19.

Authors: Mitsuhiro Odaka, Morgan Magnin, Katsumi Inoue

Date Published: 11th Feb 2022

Publication Type: Journal

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