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744 Publications visible to you, out of a total of 744
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 Article

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 …cals 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 Article

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: Conference Paper

Comparison of Bioluminescent Substrates in Natural Infection Models of Neglected Parasitic Diseases

Abstract (Expand)

The application of in vivo bioluminescent imaging in infectious disease research has significantly increased over the past years. The detection of transgenic parasites expressing wildtype firefly … luciferase is however hampered by a relatively low and heterogeneous tissue penetrating capacity of emitted light. Solutions are sought by using codon-optimized red-shifted luciferases that yield higher expression levels and produce relatively more red or near-infrared light, or by using modified bioluminescent substrates with enhanced cell permeability and improved luminogenic or pharmacokinetic properties. In this study, the in vitro and in vivo efficacy of two modified bioluminescent substrates, CycLuc1 and AkaLumine-HCl, were compared with that of D-luciferin as a gold standard. Comparisons were made in experimental and insect-transmitted animal models of leishmaniasis (caused by intracellular Leishmania species) and African trypanosomiasis (caused by extracellular Trypanosoma species), using parasite strains expressing the red-shifted firefly luciferase PpyRE9. Although the luminogenic properties of AkaLumine-HCl and D-luciferin for in vitro parasite detection were comparable at equal substrate concentrations, AkaLumine-HCl proved to be unsuitable for in vivo infection follow-up due to high background signals in the liver. CycLuc1 presented a higher in vitro luminescence compared to the other substrates and proved to be highly efficacious in vivo, even at a 20-fold lower dose than D-luciferin. This efficacy was consistent across infections with the herein included intracellular and extracellular parasitic organisms. It can be concluded that CycLuc1 is an excellent and broadly applicable alternative for D-luciferin, requiring significantly lower doses for in vivo bioluminescent imaging in rodent models of leishmaniasis and African trypanosomiasis.

Authors: Sarah Hendrickx, Dimitri Bulté, Dorien Mabille, Roxanne Mols, Mathieu Claes, Kayhan Ilbeigi, Rokaya Ahmad, Laura Dirkx, Sara I. Van Acker, Guy Caljon

Date Published: 16th Dec 2022

Publication Type: Journal Article

Comparison of Bioluminescent Substrates in Natural Infection Models of Neglected Parasitic Diseases.

Abstract (Expand)

The application of in vivo bioluminescent imaging in infectious disease research has significantly increased over the past years. The detection of transgenic parasites expressing wildtype firefly … luciferase is however hampered by a relatively low and heterogeneous tissue penetrating capacity of emitted light. Solutions are sought by using codon-optimized red-shifted luciferases that yield higher expression levels and produce relatively more red or near-infrared light, or by using modified bioluminescent substrates with enhanced cell permeability and improved luminogenic or pharmacokinetic properties. In this study, the in vitro and in vivo efficacy of two modified bioluminescent substrates, CycLuc1 and AkaLumine-HCl, were compared with that of D-luciferin as a gold standard. Comparisons were made in experimental and insect-transmitted animal models of leishmaniasis (caused by intracellular Leishmania species) and African trypanosomiasis (caused by extracellular Trypanosoma species), using parasite strains expressing the red-shifted firefly luciferase PpyRE9. Although the luminogenic properties of AkaLumine-HCl and D-luciferin for in vitro parasite detection were comparable at equal substrate concentrations, AkaLumine-HCl proved to be unsuitable for in vivo infection follow-up due to high background signals in the liver. CycLuc1 presented a higher in vitro luminescence compared to the other substrates and proved to be highly efficacious in vivo, even at a 20-fold lower dose than D-luciferin. This efficacy was consistent across infections with the herein included intracellular and extracellular parasitic organisms. It can be concluded that CycLuc1 is an excellent and broadly applicable alternative for D-luciferin, requiring significantly lower doses for in vivo bioluminescent imaging in rodent models of leishmaniasis and African trypanosomiasis.

Authors: S. Hendrickx, D. Bulte, D. Mabille, R. Mols, M. Claes, K. Ilbeigi, R. Ahmad, L. Dirkx, S. I. Van Acker, G. Caljon

Date Published: 16th Dec 2022

Publication Type: Journal Article

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 Article

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, …YP 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 Article

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 Article

Impact of pulmonary African trypanosomes on the immunology and function of the lung

Abstract (Expand)

AbstractApproximately 20% of sleeping sickness patients exhibit respiratory complications, however, with a largely unknown role of the parasite. Here we show that tsetse fly-transmitted Trypanosoma … brucei parasites rapidly and permanently colonize the lungs and occupy the extravascular spaces surrounding the blood vessels of the alveoli and bronchi. They are present as nests of multiplying parasites exhibiting close interactions with collagen and active secretion of extracellular vesicles. The local immune response shows a substantial increase of monocytes, macrophages, dendritic cells and γδ and activated αβ T cells and a later influx of neutrophils. Interestingly, parasite presence results in a significant reduction of B cells, eosinophils and natural killer cells. T. brucei infected mice show no infection-associated pulmonary dysfunction, mirroring the limited pulmonary clinical complications during sleeping sickness. However, the substantial reduction of the various immune cells may render individuals more susceptible to opportunistic infections, as evident by a co-infection experiment with respiratory syncytial virus. Collectively, these observations provide insights into a largely overlooked target organ, and may trigger new diagnostic and supportive therapeutic approaches for sleeping sickness.

Authors: Dorien Mabille, Laura Dirkx, Sofie Thys, Marjorie Vermeersch, Daniel Montenye, Matthias Govaerts, Sarah Hendrickx, Peter Takac, Johan Van Weyenbergh, Isabel Pintelon, Peter Delputte, Louis Maes, David Pérez-Morga, Jean-Pierre Timmermans, Guy Caljon

Date Published: 18th Nov 2022

Publication Type: Journal Article

Impact of pulmonary African trypanosomes on the immunology and function of the lung.

Abstract (Expand)

Approximately 20% of sleeping sickness patients exhibit respiratory complications, however, with a largely unknown role of the parasite. Here we show that tsetse fly-transmitted Trypanosoma brucei … parasites rapidly and permanently colonize the lungs and occupy the extravascular spaces surrounding the blood vessels of the alveoli and bronchi. They are present as nests of multiplying parasites exhibiting close interactions with collagen and active secretion of extracellular vesicles. The local immune response shows a substantial increase of monocytes, macrophages, dendritic cells and gammadelta and activated alphabeta T cells and a later influx of neutrophils. Interestingly, parasite presence results in a significant reduction of B cells, eosinophils and natural killer cells. T. brucei infected mice show no infection-associated pulmonary dysfunction, mirroring the limited pulmonary clinical complications during sleeping sickness. However, the substantial reduction of the various immune cells may render individuals more susceptible to opportunistic infections, as evident by a co-infection experiment with respiratory syncytial virus. Collectively, these observations provide insights into a largely overlooked target organ, and may trigger new diagnostic and supportive therapeutic approaches for sleeping sickness.

Authors: D. Mabille, L. Dirkx, S. Thys, M. Vermeersch, D. Montenye, M. Govaerts, S. Hendrickx, P. Takac, J. Van Weyenbergh, I. Pintelon, P. Delputte, L. Maes, D. Perez-Morga, J. P. Timmermans, G. Caljon

Date Published: 18th Nov 2022

Publication Type: Journal Article

Stochastic modelling of a three-dimensional glycogen granule synthesis and impact of the branching enzyme

Abstract (Expand)

In humans, glycogen storage diseases result from metabolic inborn errors, and can lead to severe phenotypes and lethal conditions. Besides these rare diseases, glycogen is also associated to widely …y spread societal burdens such as diabetes. Glycogen is a branched glucose polymer synthesised and degraded by a complex set of enzymes. Over the past 50 years, the structure of glycogen has been intensively investigated. Yet, the interplay between glycogen structure and the related enzymes is still to be characterised. In this article, we develop a stochastic coarse-grained and spatially resolved model of branched polymer biosynthesis following a Gillespie algorithm. Our study largely focusses on the role of the branching enzyme, and first investigates the properties of the model with generic parameters, before comparing it to in vivo experimental data in mice. It arises that the ratio of glycogen synthase over branching enzyme activities drastically impacts the structure of the granule. We deeply investigate the mechanism of branching and parametrise it using distinct lengths. Not only do we consider various possible sets of values for these lengths, but also distinct rules to apply them. We show how combining them finely tunes glycogen macromolecular structure. Comparing the model with experimental data confirms that we can accurately reproduce glycogen chain length distributions in wild type mice. Additional granule properties obtained for this fit are also in good agreement with typically reported values in the experimental literature. Nonetheless, we find that the mechanism of branching must be more flexible than usually reported. Overall, we demonstrate that the chain length distribution is an imprint of the branching activity and mechanism. Our generic model and methods can be applied to any glycogen data set, and could in particular contribute to characterise the mechanisms responsible for glycogen storage disorders.

Authors: Yvan Rousset, Oliver Ebenhöh, Adélaïde Raguin

Date Published: 1st Nov 2022

Publication Type: Journal Article

Nanoassemblies from Amphiphilic Sb Complexes Target Infection Sites in Models of Visceral and Cutaneous Leishmaniases

Abstract (Expand)

This work aims to evaluate whether nanoassemblies (NanoSb) made from antimony(V) complexes with octanoyl-N-methylglucamide (SbL8) or decanoyl-N-methylglucamide (SbL10) would effectively target the … infection sites in visceral and cutaneous leishmaniases (VL and CL). NanoSb were investigated regarding stability at different pHs, accumulation of Sb in the macrophage host cell and liver, and in vitro and in vivo activities in models of leishmaniasis. The kinetic stability assay showed that NanoSb are stable at neutral pH, but release incorporated lipophilic substance after conformational change in media that mimic the gastric fluid and the parasitophorous vacuole. NanoSb promoted greater accumulation of Sb in macrophages and in the liver of mice after parenteral administration, when compared to conventional antimonial Glucantime®. SbL10 was much more active than Glucantime® against intramacrophage Leishmania amastigotes and less cytotoxic than SbL8 against macrophages. The in vitro SbL10 activity was further enhanced with co-incorporated miltefosine. NanoSb showed high antileishmanial activity in the L. donovani murine VL after parenteral administration and moderate activity in the L. amazonensis murine CL after topical treatment. This study supports the ability of NanoSb to effectively deliver a combination of Sb and co-incorporated drug to host cell and infected tissues, in a better way than Glucantime® does.

Authors: Juliane S. Lanza, Virginia M. R. Vallejos, Guilherme S. Ramos, Ana Carolina B. de Oliveira, Cynthia Demicheli, Luis Rivas, Sébastien Pomel, Philippe M. Loiseau, Frédéric Frézard

Date Published: 21st Aug 2022

Publication Type: Journal Article

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 … 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 Article

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 Article

High non-photochemical quenching of VPZ transgenic potato plants limits CO(2) assimilation under high light conditions and reduces tuber yield under fluctuating light.

Abstract (Expand)

Under natural conditions, photosynthesis has to be adjusted to fluctuating light intensities. Leaves exposed to high light dissipate excess light energy in form of heat at photosystem II (PSII) by a … process called non-photochemical quenching (NPQ). Upon fast transition from light to shade, plants lose light energy by a relatively slow relaxation from photoprotection. Combined overexpression of violaxanthin de-epoxidase (VDE), PSII subunit S (PsbS) and zeaxanthin epoxidase (ZEP) in tobacco accelerates relaxation from photoprotection, and increases photosynthetic productivity. In Arabidopsis, expression of the same three genes (VPZ) resulted in a more rapid photoprotection but growth of the transgenic plants was impaired. Here we report on VPZ expressing potato plants grown under various light regimes. Similar to tobacco and Arabidopsis, induction and relaxation of NPQ was accelerated under all growth conditions tested, but did not cause an overall increased photosynthetic rate or growth of transgenic plants. Tuber yield of VPZ expressing plants was unaltered as compared to control plants under constant light conditions and even decreased under fluctuating light conditions. Under control conditions, levels of the phytohormone abscisic acid (ABA) were found to be elevated, indicating an increased violaxanthin availability in VPZ plants. However, the increased basal ABA levels did not improve drought tolerance of VPZ transgenic potato plants under greenhouse conditions. The failure to benefit from improved photoprotection is most likely caused by a reduced radiation use efficiency under high light conditions resulting from a too strong NPQ induction. Mitigating this negative effect in the future might help to improve photosynthetic performance in VPZ expressing potato plants.

Authors: G. G. Lehretz, A. Schneider, D. Leister, U. Sonnewald

Date Published: 29th Jun 2022

Publication Type: Journal Article

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 Article

Current Treatments to Control African Trypanosomiasis and One Health Perspective

Abstract (Expand)

Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, Trypanosoma brucei. Despite … important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against Trypanosoma brucei spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity.

Authors: Alberto Venturelli, Lorenzo Tagliazucchi, Clara Lima, Federica Venuti, Giulia Malpezzi, George E. Magoulas, Nuno Santarem, Theodora Calogeropoulou, Anabela Cordeiro-da-Silva, Maria Paola Costi

Date Published: 27th Jun 2022

Publication Type: Journal Article

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 Article

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 Article

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 Article

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 Article

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

Abstract (Expand)

Abstract Predicting a multicellular organism’s phenotype quantitatively from its genotype is challenging, as genetic effects must propagate across scales. Circadian clocks are intracellular regulators …ellular 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: 30th May 2022

Publication Type: Journal Article

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 Article

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 Article

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 Article

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 …tures 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 Article

4-Amino-1,8-naphthalimide–ferrocene conjugates as potential multi-targeted anticancer and fluorescent cellular imaging agents

Abstract

Eight ferrocenyl 4-amino-1,8-naphthalimide logic gates for acidity and oxidisability are repurposed as anti-proliferation and cellular imaging agents against MCF-7 and K562 cancer cell lines.

Authors: Alex D. Johnson, Joseph A. Buhagiar, David C. Magri

Date Published: 15th Dec 2021

Publication Type: Journal Article

Effect of graphite oxide on the catalytic behavior of (S)-selective amine transaminases

Abstract (Expand)

Graphite oxide (GO) has been used for the immobilization of several classes of enzymes, exhibiting very interesting properties as immobilization matrix. However, the effect the nanomaterial has on the … enzyme cannot be predicted. Herein, the effect GO has on the catalytic behavior of several (S)-selective amine transaminases ((S)-ATAs) has been investigated. These enzymes were the focus of this work as they are homodimers with pyridoxal 5’-phosphate in their active site, significantly more complex systems than other enzymes previously studied. Addition of GO (up to 0.1 mg/mL) in the reaction medium leads to activation (up to 50% improved activity) for most enzymes studied, while they maintain their temperature profile (they perform better between 40-45ºC), and their stability. However, the effect is not universal and there are enzymes that are negatively influenced by the presence of the nanomaterial. More profound is the effect on the (S)-ATA from Chromobacterium violaceum which loses almost 50% of its activity in the presence of 0.1 mg/mL GO, while the stability was significantly decreased, losing its activity after 2 h incubation at 40°C, in the presence of 25 μg/mL GO. This negative effect seems to rise from minor secondary structure alterations; namely, a loss of α-helices and subsequent increase in random coil (~3% in the presence of 25 μg/mL GO). We hypothesize that the effect the GO has on (S)-ATAs is correlated to the surface chemistry of the enzymes; the less negatively-charged enzymes are deactivated from the interaction with GO. This insight will aid the rationalization of ATA immobilization onto carbon-based nanomaterials.

Authors: Nikolaos Kaloudis, Panagiota Zygouri, Nikolaos Chalmpes, Konstantinos Spyrou, Dimitrios Gournis, Ioannis Pavlidis

Date Published: 6th Dec 2021

Publication Type: Journal Article

The chemical defensome of five model teleost fish

Abstract (Expand)

How an organism copes with chemicals is largely determined by the genes and proteins that collectively function to defend against, detoxify and eliminate chemical stressors. This integrative network … includes receptors and transcription factors, biotransformation enzymes, transporters, antioxidants, and metal- and heat-responsive genes, and is collectively known as the chemical defensome. Teleost fish is the largest group of vertebrate species and can provide valuable insights into the evolution and functional diversity of defensome genes. We have previously shown that the xenosensing pregnane x receptor (pxr, nr1i2) is lost in many teleost species, including Atlantic cod (Gadus morhua) and three-spined stickleback (Gasterosteus aculeatus), but it is not known if compensatory mechanisms or signaling pathways have evolved in its absence. In this study, we compared the genes comprising the chemical defensome of five fish species that span the teleosteii evolutionary branch often used as model species in toxicological studies and environmental monitoring programs: zebrafish (Danio rerio), medaka (Oryzias latipes), Atlantic killifish (Fundulus heteroclitus), Atlantic cod, and three-spined stickleback. Genome mining revealed evolved differences in the number and composition of defensome genes that can have implication for how these species sense and respond to environmental pollutants, but we did not observe any candidates of compensatory mechanisms or pathways in cod and stickleback in the absence of pxr. The results indicate that knowledge regarding the diversity and function of the defensome will be important for toxicological testing and risk assessment studies.

Authors: Marta Eide, Xiaokang Zhang, Odd André Karlsen, Jared V. Goldstone, John Stegeman, Inge Jonassen, Anders Goksøyr

Date Published: 1st Dec 2021

Publication Type: Journal Article

Virus structure and structure-based antivirals

Abstract (Expand)

Structure-based antiviral developments in the past two years have been dominated by the structure determination and inhibition of SARS-CoV-2 proteins and new lead molecules for picornaviruses. The … SARS-CoV-2 spike protein has been targeted successfully with antibodies, nanobodies, and receptor protein mimics effectively blocking receptor binding or fusion. The two most promising non-structural proteins sharing strong structural and functional conservation across virus families are the main protease and the RNA-dependent RNA polymerase, for which design and reuse of broad range inhibitors already approved for use has been an attractive avenue. For picornaviruses, the increasing recognition of the transient expansion of the capsid as a critical transition towards RNA release has been targeted through a newly identified, apparently widely conserved, druggable, interprotomer pocket preventing viral entry. We summarize some of the key papers in these areas and ponder the practical uses and contributions of molecular modeling alongside empirical structure determination.

Authors: Zlatka Plavec, Ina Pöhner, Antti Poso, Sarah J Butcher

Date Published: 1st Dec 2021

Publication Type: Journal Article

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