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Abstract Metabolic dysfunction‐associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver model from primary human hepatocytes and non‐parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease‐relevant endpoints, such as steatosis, inflammation and fibrosis, and multi‐omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls. By combining high‐content imaging with scalable biochemical assays and chemogenomic screening, multiple novel targets with anti‐steatotic, anti‐inflammatory, and anti‐fibrotic effects are identified. Among these, activation of the muscarinic M1 receptor (CHRM1) and inhibition of the TRPM8 cation channel result in strong anti‐fibrotic effects, which are confirmed using orthogonal genetic assays. Strikingly, using biosensors based on bioluminescence resonance energy transfer, a functional interaction along a novel MASH signaling axis in which CHRM1 inhibits TRPM8 via Gq/11 and phospholipase C‐mediated depletion of phosphatidylinositol 4,5‐bisphosphate can be demonstrated. Combined, this study presents the first patient‐derived 3D MASH model, identifies a novel signaling module with anti‐fibrotic effects, and highlights the potential of organotypic culture systems for phenotype‐based chemogenomic drug target identification at scale.

Abstract Facile, durable and biocompatible integration of hybrid Lab‐on‐a‐Chip devices has remained an important challenge in microengineering. Here, the robust and seamless integration of off‐stoichiometry thiol‐ene‐epoxy (OSTE+) thermosets with a diverse range of thermoplastic and glass materials is demonstrated. While direct bonding offers sturdy proprieties for the majority of the material hybrids (up to 1.5 MPa), further surface priming enhances the bonding strength for those of lower surface energy (up to seven‐fold). Using microfluidic devices with a unique configuration of chambers and microchannels down to 100 µm, the impact of various bonding methods on their fluidic functionality is further shown. To investigate the utility of hybrid devices for pharmacological and toxicological studies, both pristine and primed devices are benchmarked against polydimethylsiloxane (PDMS) with regard to cell biocompatibility and drug absorption. While being on par with PDMS in terms of cell viability, pristine OSTE+ devices show an 11‐fold lower absorption of hydrophobic drug molecules. Although surface priming enhances the bonding strength, it compromises other criteria in device performance and biological applications. Combined, results demonstrate a novel integration approach for facile manufacturing of hybrid microfluidic devices using a material toolbox suitable for cell and pharmaceutical studies.

Abstract Obesity and type 2 diabetes are strongly associated with adipose tissue dysfunction and impaired adipogenesis. Understanding the molecular underpinnings that control adipogenesis is thus of fundamental importance for the development of novel therapeutics against metabolic disorders. However, translational approaches are hampered as current models do not accurately recapitulate adipogenesis. Here, a scaffold‐free versatile 3D adipocyte culture platform with chemically defined conditions is presented in which primary human preadipocytes accurately recapitulate adipogenesis. Following differentiation, multi‐omics profiling and functional tests demonstrate that 3D adipocyte cultures feature mature molecular and cellular phenotypes similar to freshly isolated mature adipocytes. Spheroids exhibit physiologically relevant gene expression signatures with 4704 differentially expressed genes compared to conventional 2D cultures (false discovery rate < 0.05), including the concerted expression of factors shaping the adipogenic niche. Furthermore, lipid profiles of >1000 lipid species closely resemble patterns of the corresponding isogenic mature adipocytes in vivo (R2 = 0.97). Integration of multi‐omics signatures with analyses of the activity profiles of 503 transcription factors using global promoter motif inference reveals a complex signaling network, involving YAP, Hedgehog, and TGFβ signaling, that links the organotypic microenvironment in 3D culture to the activation and reinforcement of PPARγ and CEBP activity resulting in improved adipogenesis.

We present here measurements carried out by using a dielectrically loaded copper cavity operating at 7 GHz on MgB2 thin films synthesized by hybrid physical-chemical vapor deposition. Microwave data on samples having critical temperatures above 41 K, very low resistivity values, and residual resistivity ratio between 15 and 17, are presented. The dependence of the nonlinear surface losses and of the third order intermodulation products on the power feeding the cavity is analyzed, with the aim of shedding a light on the primary dissipation mechanisms. At low power, data from both power dependence and third order products seem to indicate that we are observing a nonlinear response which is inherent to the conventional s-wave nature of this novel compound. At intermediate-to-high circulating power values, vortex penetration appears to be the limiting mechanism for the power handling capability of MgB2 films. [ABSTRACT FROM AUTHOR]

The two-tone intermodulation distortion arising in MgB2 thin films synthesized by hybrid physical-chemical vapor deposition is studied in order to probe the influence of the two bands on the nonlinear response of this superconductor. The measurements are carried out by using a dielectrically loaded copper cavity operating at 7 GHz. Microwave data on samples having critical temperatures above 41 K, very low resistivity values, and residual resistivity ratio larger than 10 are shown. The dependence of the nonlinear surface losses and of the third order intermodulation products on the power feeding the cavity and on the temperature is analyzed. At low power, the signal arising from distortion versus temperature shows the intrinsic s-wave behavior expected for this compound. Data are compared with measurements performed on Nb and YBa2Cu3O7-δ thin films using the same technique. [ABSTRACT FROM AUTHOR]