https://hdl.handle.net/20.500.14178/908 2026-05-11T15:52:45Z 2026-05-11T15:52:45Z Jirků, Jaroslav Vilhelm, Jan https://hdl.handle.net/20.500.14178/3799 2026-05-08T01:00:11Z 2025-01-01T00:00:00Z

Forward Modeling in ERT Employing Resistor Network - Alternative to Standard Approaches Jirků, Jaroslav; Vilhelm, Jan This paper uses an orthogonal resistor network model instead of traditional finite-difference or finite-element methods to explore an alternative approach to forward modeling in Electrical Resistivity Tomography (ERT). A resistor network is advantageous for modeling high-contrast resistivity environments, particularly in crystalline rock scenarios with thin conductive fractures. The key idea is to represent the resistivity problem as a network of resistors, where each resistor corresponds to a unit cell edge with assigned resistance values. The study compares this approach with existing numerical methods and analytical solutions for 2D conductive dipping faults, showing that the resistor network method produces comparable results for shallow depths while offering better resolution for thin conductive fractures. This study demonstrates that a resistor network can serve as an auxiliary tool for qualitatively assessing the effects of thin conductive fractures in crystalline rock environments or masonry.

2025-01-01T00:00:00Z Musil, Dominik Krhutová, Markéta Blažková, Kristýna Kramná, Anežka Brázdová, Andrea Výmolová, Barbora Houdová Megová, Magdalena Hadzima, Martin Kryštůfek, Robin Šubr, Vladimír Kostka, Libor Etrych, Tomáš Ormsby, Tereza Sácha, Pavel Ambramson, Jakub Konvalinka, Jan https://hdl.handle.net/20.500.14178/3798 2026-05-08T01:00:20Z 2026-01-01T00:00:00Z

CD64-Targeted Polymer-Drug Conjugates Exploit Cathepsin K-Dependent Payload Release for Selective Elimination of Immunosuppressive Macrophages Musil, Dominik; Krhutová, Markéta; Blažková, Kristýna; Kramná, Anežka; Brázdová, Andrea; Výmolová, Barbora; Houdová Megová, Magdalena; Hadzima, Martin; Kryštůfek, Robin; Šubr, Vladimír; Kostka, Libor; Etrych, Tomáš; Ormsby, Tereza; Sácha, Pavel; Ambramson, Jakub; Konvalinka, Jan Selective depletion of immunosuppressive macrophages in the tumor microenvironment is a promising strategy in cancer therapy. CD64 is broadly expressed on myeloid cells, including both pro-inflammatory M1-like and immunosuppressive M2-like macrophages that resemble tumor-associated macrophages (TAMs), and thus represents an attractive entry receptor for targeted payload delivery. We developed HPMA-based CD64-targeted polymer-drug conjugates (CD64-TPDCs) that combine multivalent receptor engagement with enzyme-responsive payload release. These copolymers are decorated with the CD64-binding cyclic peptide cp33 and carry the cytotoxic payload mertansine (DM1) bound via cathepsin-cleavable peptide linkers. Multivalent cp33 presentation on the polymer markedly increased the apparent affinity for human CD64, resulting in subnanomolar binding and selective recognition of CD64-expressing cells, significantly improving the binding potency of monovalent cp33 peptide. In polarized M2-like human monocyte-derived macrophages (MDMs), we showed that cytotoxic Gly-Phe-Leu-Gly-DM1 CD64-TPDCs selectively induced apoptosis. In contrast, M1-like MDMs were largely spared despite expressing higher levels of CD64. In M2-like MDMs, CD64-TPDCs rapidly accumulated in lysosomes, whereas in M1-like cells, they remained largely confined to endosomes. To elucidate the basis of this selectivity, we profiled expression of cathepsins in polarized MDMs. We found that M2-like MDMs display substantially higher levels of cathepsin K, establishing a model in which cathepsin K is the major protease responsible for Gly-Phe-Leu-Gly linker cleavage and DM1 release in M2-like macrophages. These findings demonstrate that CD64-TPDCs can be engineered to exploit subset-specific trafficking and cathepsin K-dependent linker cleavage for the selective elimination of M2-like macrophages. This work provides a generalizable design principle for stimuli-responsive PDCs that may actively target immunosuppressive myeloid cells in tumors.

2026-01-01T00:00:00Z Bruštíková, Kateřina Forstová, Jitka Holajová, Barbora Huerfano Meneses, Sandra https://hdl.handle.net/20.500.14178/3736 2026-04-14T01:00:16Z 2026-01-01T00:00:00Z

Remodeling of the cellular membrane architecture in response to BK polyomavirus infection Bruštíková, Kateřina; Forstová, Jitka; Holajová, Barbora; Huerfano Meneses, Sandra BK polyomavirus (BKPyV) is a human pathogen that causes severe disease in immunocompromised individuals. Although discovered in the 1970s, important gaps in our understanding of BKPyV biology persist. Key unresolved areas include the precise molecular mechanisms governing viral latency and reactivation, the specific host and viral factors determining the virus tropism towards the urinary track, and the intricate virus-host interactions that drive clinical pathogenesis. These unresolved biological questions have stalled the development of targeted therapeutics; as a result, no specific antiviral therapy is currently available for BKPyV-related diseases. In this review, we examined findings from both experimental models and clinical samples that investigate how BKPyV remodels host organelles and the molecular pathways underlying these alterations. We focus on BKPyV-driven changes in cellular membranes, including endoplasmic reticulum remodeling, mitochondrial disruption, the formation of endoplasmic reticulum-derived tubuloreticular structures, vacuoles, and autophagosomes, as well as the accumulation of lipid droplets. Collectively, these organelle-specific modifications highlight membrane remodeling as a central feature of BKPyV replication and pathogenesis. Addressing the key knowledge gaps in the molecular basis of virus-induced membrane remodeling will be critical for guiding the development of effective antiviral strategies.

2026-01-01T00:00:00Z Březina, Jiří Brabec, Tomáš Machač, David Vobořil, Matouš Ballek, Ondřej Pačes, Jan Sýkora, Vojtěch Jančovičová, Kristína Valter, Evgeny Kováčová, Katarína Manning, Jasper Tahtahová, Valerie Čepková, Adéla Dobešová, Martina Dobeš, Jan Kubovčiak, Jan Kolář, Michal Kašpárek, Petr Sedlacek, Radislav Štepánek, Ondřej Černý, Jan Tsukita, Sachiko Malissen, Bernard Anderson, Graham Filipp, Dominik https://hdl.handle.net/20.500.14178/3734 2026-04-14T01:00:09Z 2026-01-01T00:00:00Z

Claudin 1 – mediated positioning of DC1 to mTECs is essential for maintenance of central tolerance Březina, Jiří; Brabec, Tomáš; Machač, David; Vobořil, Matouš; Ballek, Ondřej; Pačes, Jan; Sýkora, Vojtěch; Jančovičová, Kristína; Valter, Evgeny; Kováčová, Katarína; Manning, Jasper; Tahtahová, Valerie; Čepková, Adéla; Dobešová, Martina; Dobeš, Jan; Kubovčiak, Jan; Kolář, Michal; Kašpárek, Petr; Sedlacek, Radislav; Štepánek, Ondřej; Černý, Jan; Tsukita, Sachiko; Malissen, Bernard; Anderson, Graham; Filipp, Dominik Central tolerance, which relies on the presentation of self-antigens by mTECs and DCs, prevents autoimmunity by eliminating self-reactive T cells. While mTECs produce self-antigens autonomously, DCs acquire them from mTECs via cooperative antigen transfer (CAT). We previously showed that mTEC and DC subsets exhibit preferential pairing in CAT, providing a rationale for the existence of molecular determinants underpinning this pairing and its outcome. Here, we compared the transcriptomes of CAT-experienced and CAT-inexperienced DCs and identified Claudin 1 as a molecule involved in CAT and type 1 DC (DC1) maturation. DC1-specific ablation of Claudin 1 resulted in decreased CAT to late mature DC1s and dramatically diminished DC1 maturation. These phenotypes correlated with the displacement of DC1s from mTECs and their decreased expression of MHCII pathway genes. This translated into impaired Treg selection and clonal deletion, ultimately manifesting in symptoms of multiorgan autoimmunity and shortened lifespan. Collectively, our results identify thymic DC1-derived Claudin 1 as a regulator of immune tolerance.

2026-01-01T00:00:00Z