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5. Thymic epithelial organoids mediate T-cell development.

Author

Hübscher, Tania, Lorenzo-Martıń, L. Francisco, Barthlott, Thomas, Tillard, Lucie, Langer, Jakob J., Rouse, Paul, Blackburn, C. Clare, Holländer, Georg, and Lutolf, Matthias P.

Subjects
DEVELOPMENTAL biology, EPITHELIAL cells, CELL populations, PROGENITOR cells, TRANSLATIONAL research
Abstract

Although the advent of organoids has opened unprecedented perspectives for basic and translational research, immune system-related organoids remain largely underdeveloped. Here, we established organoids from the thymus, the lymphoid organ responsible for T-cell development. We identified conditions enabling mouse thymic epithelial progenitor cell proliferation and development into organoids with diverse cell populations and transcriptional profiles resembling in vivo thymic epithelial cells (TECs) more closely than traditional TEC cultures. In contrast to these two-dimensional cultures, thymic epithelial organoids maintained thymus functionality in vitro and mediated physiological T-cell development upon reaggregation with T-cell progenitors. The reaggregates showed in vivo-like epithelial diversity and the ability to attract T-cell progenitors. Thymic epithelial organoids are the first organoids originating from the stromal compartment of a lymphoid organ. They provide new opportunities to study TEC biology and T-cell development in vitro, paving the way for future thymic regeneration strategies in ageing or acute injuries. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Thymic epithelial organoids mediate T cell development

Author

Hübscher, Tania, primary, Lorenzo-Martín, L. Francisco, additional, Barthlott, Thomas, additional, Tillard, Lucie, additional, Langer, Jakob J., additional, Rouse, Paul, additional, Blackburn, C. Clare, additional, Holländer, Georg, additional, and Lutolf, Matthias P., additional

Published
2024
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16. An engineered Sox17 induces somatic to neural stem cell fate transitions independently from pluripotency reprogramming

Author

Weng, Mingxi, primary, Hu, Haoqing, additional, Graus, Matthew S., additional, Tan, Daisylyn Senna, additional, Gao, Ya, additional, Ren, Shimiao, additional, Ho, Derek Hoi Hang, additional, Langer, Jakob, additional, Holzner, Markus, additional, Huang, Yuhua, additional, Ling, Guang Sheng, additional, Lai, Cora Sau Wan, additional, Francois, Mathias, additional, and Jauch, Ralf, additional

Published
2023
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18. Room for improvement in current influenza vaccines? A systematic literature review on the humanistic and economic burden of influenza in older (≥65 years old) adults

Author

Langer, Jakob, primary, Welch, Verna, additional, Moran, Mary, additional, Cane, Alejandro, additional, Lopez, Santiago, additional, Srivastava, Amit, additional, Enstone, Ashley, additional, Sears, Amy, additional, Markus, Kristen, additional, Heuser, Maria, additional, Kewley, Rachel, additional, and Whittle, Isabelle, additional

Published
2023
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24. c-MAF coordinates enterocyte zonation and nutrient uptake transcriptional programs

Author

González-Loyola, Alejandra, primary, Bernier-Latmani, Jeremiah, additional, Roci, Irena, additional, Wyss, Tania, additional, Langer, Jakob, additional, Durot, Stephan, additional, Munoz, Olivia, additional, Prat-Luri, Borja, additional, Delorenzi, Mauro, additional, Lutolf, Matthias P., additional, Zamboni, Nicola, additional, Verdeil, Grégory, additional, and Petrova, Tatiana V., additional

Published
2022
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32. Developing a health economic model for Asians with type 2 diabetes based on the Japan Diabetes Complications Study and the Japanese Elderly Diabetes Intervention Trial

Author

Tanaka, Shiro, primary, Langer, Jakob, additional, Morton, Tim, additional, Hoskins, Nicki, additional, Wilkinson, Lars, additional, Tanaka-Mizuno, Sachiko, additional, Kawasaki, Ryo, additional, Moriya, Tatsumi, additional, Horikawa, Chika, additional, Aida, Rei, additional, Araki, Atsushi, additional, Fujihara, Kazuya, additional, and Sone, Hirohito, additional

Published
2021
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33. Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

Author

Lundsgaard, Annemarie, Fritzen, Andreas Mæchel, Nicolaisen, Trine Sand, Carl, Christian Strini, Sjøberg, Kim Anker, Raun, Steffen Henning, Klein, Anders Bue, Sanchez-Quant, Eva, Langer, Jakob, Ørskov, Cathrine, Clemmensen, Christoffer, Tschöp, Matthias H, Richter, Erik A, Kiens, Bente, Kleinert, Maximilian, Lundsgaard, Annemarie, Fritzen, Andreas Mæchel, Nicolaisen, Trine Sand, Carl, Christian Strini, Sjøberg, Kim Anker, Raun, Steffen Henning, Klein, Anders Bue, Sanchez-Quant, Eva, Langer, Jakob, Ørskov, Cathrine, Clemmensen, Christoffer, Tschöp, Matthias H, Richter, Erik A, Kiens, Bente, and Kleinert, Maximilian

Abstract

Excessive circulating fatty acids (FAs) have been proposed to promote insulin resistance of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate insulin resistance. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor Etomoxir, in combination with short-term 45% high fat diet feeding to increase FA availability. Etomoxir acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in liver and heart within hours. Several days of FAOX inhibition by daily Etomoxir administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by Etomoxir. Reduced whole body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) UCP1 protein content, diminished BAT glucose clearance, and an increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat insulin resistance and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function.

Published
2020

35. Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

Author

Lundsgaard, Anne-Marie, primary, Fritzen, Andreas M., additional, Nicolaisen, Trine S., additional, Carl, Christian S., additional, Sjøberg, Kim A., additional, Raun, Steffen H., additional, Klein, Anders B., additional, Sanchez-Quant, Eva, additional, Langer, Jakob, additional, Ørskov, Cathrine, additional, Clemmensen, Christoffer, additional, Tschöp, Matthias H., additional, Richter, Erik A., additional, Kiens, Bente, additional, and Kleinert, Maximilian, additional

Published
2020
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37. Clinical inertia in patients with type 2 diabetes treated with oral antidiabetic drugs: Results from a Japanese cohort study (JDDM53).

Author

Maegawa, Hiroshi, Ishigaki, Yasushi, Langer, Jakob, Saotome‐Nakamura, Ai, and Andersen, Marc

Subjects
TYPE 2 diabetes, GLYCOSYLATED hemoglobin, GLUCAGON-like peptide-1 receptor, HYPOGLYCEMIC agents, GLUCAGON-like peptide-1 agonists, GLYCEMIC control
Abstract

Aims/Introduction: Treatment intensification is commonly delayed in people with type 2 diabetes, resulting in poor glycemic control for an unacceptable length of time and increased risk of complications. Materials and Methods: This retrospective study investigated clinical inertia in 33,320 Japanese adults with type 2 diabetes treated with oral antidiabetic drugs (OADs) between 2009 and 2018, using data from the Computerized Diabetes Care (CoDiC®) database. Results: The median time from first reported glycated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol) to treatment intensification was considerably longer and HbA1c levels were higher the more OADs the patient was exposed to. For patients receiving three OADs, the median times from HbA1c ≥7.0% (53 mmol/mol) to intensification with OAD, glucagon‐like peptide‐1 receptor agonist or insulin were 8.1, 9.1 and 6.7 months, with a mean HbA1c level at the time of intensification of 8.4%, 8.9% and 9.3%, respectively. The cumulative incidence for time since the first reported HbA1c ≥7.0% (≥53 mmol/mol) to intensification confirmed the existence of clinical inertia, identifying patients whose treatment was not intensified despite poor glycemic control. HbA1c levels ≥7.0% (≥53 mmol/mol) after ≥6 months on one, two or three OADs were observed in 42%, 51% and 58% of patients, respectively, showing that approximately 50% of patients are above HbA1c target regardless of how many OADs they take. Conclusions: Real‐world data here show clinical inertia in Japanese adults with type 2 diabetes from early diabetes stages when they are receiving OADs, and illustrate a need for earlier, more effective OADs or injectable treatment intensification and better communication around the existence of clinical inertia. [ABSTRACT FROM AUTHOR]

Published
2021
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39. Developing a Health Economic Model for Asians with Type 2 Diabetes Based on the Japan Diabetes Complications Study and the Japanese Elderly Diabetes Intervention Trial

Author

TANAKA, SHIRO, primary, LANGER, JAKOB, additional, MORTON, TIM, additional, WILKINSON, LARS, additional, TANAKA, SACHIKO, additional, KAWASAKI, RYO, additional, MORIYA, TATSUMI, additional, HORIKAWA, CHIKA, additional, AIDA, REI, additional, ARAKI, ATSUSHI, additional, and SONE, HIROHITO, additional

Published
2018
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50. Protein Spin Labeling with a Photocaged Nitroxide Using Diels–Alder Chemistry

Author

Kugele, Anandi, Silkenath, Bjarne, Langer, Jakob, Wittmann, Valentin, and Drescher, Malte

Subjects
Nitroxide mediated radical polymerization, 010402 general chemistry, 01 natural sciences, Biochemistry, chemistry.chemical_compound, EPR spectroscopy, Cycloaddition, Bioorthogonal chemistry, non-canonical amino acids, Site-directed spin labeling, Humans, Moiety, Amino Acids, Spin label, Protecting group, Molecular Biology, cycloaddition, noncanonical amino acids, Cycloaddition Reaction, 010405 organic chemistry, Communication, Organic Chemistry, Electron Spin Resonance Spectroscopy, Proteins, Site-directed spin labeling, bioorthogonal chemistry, Combinatorial chemistry, Communications, Cycloaddition, site-directed spin labeling, 3. Good health, 0104 chemical sciences, chemistry, ddc:540, Molecular Medicine, Nitrogen Oxides, Spin Labels, Bioorthogonal chemistry, Ethylene glycol, EPR spectroscopy
Abstract

EPR spectroscopy of diamagnetic bio‐macromolecules is based on site‐directed spin labeling (SDSL). Herein, a novel labeling strategy for proteins is presented. A nitroxide‐based spin label has been developed and synthesized that can be ligated to proteins by an inverse‐electron‐demand Diels–Alder (DAinv) cycloaddition to genetically encoded noncanonical amino acids. The nitroxide moiety is shielded by a photoremovable protecting group with an attached tetra(ethylene glycol) unit to achieve water solubility. SDSL is demonstrated on two model proteins with the photoactivatable nitroxide for DAinv reaction (PaNDA) label. The strategy features high reaction rates, combined with high selectivity, and the possibility to deprotect the nitroxide in Escherichia coli lysate., PaNDA proteins: The photoactivatable nitroxide for DAinv reaction (PaNDA; DAinv: inverse‐electron‐demand Diels–Alder) is a novel spin label for proteins. This newly developed nitroxide‐based spin label can be ligated to proteins through a DAinv cycloaddition to genetically encoded noncanonical amino acids.

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