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Overview

In cryo-electron microscopy, accurate particle localization and classification are imperative. Recent deep learning solutions, though successful, require extensive training datasets. The protracted generation time of physics-based models, often employed to produce these datasets, limits their broad applicability. We introduce FakET, a method based on neural style transfer, capable of simulating the forward operator of any cryo transmission electron microscope. It can be used to adapt a synthetic training dataset according to reference data producing high-quality simulated micrographs or tilt-series. To assess the quality of our generated data, we used it to train a state-of-the-art localization and classification architecture and compared its performance with a counterpart trained on benchmark data. Remarkably, our technique matches the performance, boosts data generation speed 750×, uses 33× less memory, and scales well to typical transmission electron microscope detector sizes. It leverages GPU acceleration and parallel processing. The source code is available at https://github.com/paloha/faket/.

01 Mar 2025·Nature Methods

Challenging the Astral mass analyzer to quantify up to 5,300 proteins per single cell at unseen accuracy to uncover cellular heterogeneity

Article

Author: Mechtler, Karl ; Kagawa, Harunobu ; Slovakova, Jana ; Arrey, Tabiwang N ; Pichler, Peter ; Delanghe, Bernard ; Damoc, Eugen ; Matzinger, Manuel ; Sommer, Theresa M ; Rivron, Nicolas ; Bubis, Julia A

AbstractDespite significant advancements in sample preparation, instrumentation and data analysis, single-cell proteomics is currently limited by proteomic depth and quantitative performance. Here we demonstrate highly improved depth of proteome coverage as well as accuracy and precision for quantification of ultra-low input amounts. Using a tailored library, we identify up to 7,400 protein groups from as little as 250 pg of HeLa cell peptides at a throughput of 50 samples per day. Using a two-proteome mix, we check for optimal parameters of quantification and show that fold change differences of 2 can still be successfully determined at single-cell-level inputs. Eventually, we apply our workflow to A549 cells, yielding a proteome coverage ranging from 1,801 to a maximum of >5,300 protein groups from a single cell depending on cell size and search strategy used, which allows for the study of dependencies between cell size and cell cycle phase. Additionally, our workflow enables us to distinguish between in vitro analogs of two human blastocyst lineages: naive human pluripotent stem cells (epiblast) and trophectoderm-like cells. Our data harmoniously align with transcriptomic data, indicating that single-cell proteomics possesses the capability to identify biologically relevant differences within the blastocyst.

16 Jan 2025·Nature

Cancer cells impair monocyte-mediated T cell stimulation to evade immunity

Article

Author: Fabre, Naomi ; Bai, Xinyu ; Bayerl, Felix ; Cronin, Shona M ; Nguyen, Trung Viet ; Schönlein, Martin ; Novatchkova, Maria ; Lauss, Martin ; Laniti, Denarda Dangaj ; Krecioch, Izabela ; Pottendorfer, Elisabeth ; Bayerl, Jonas ; Rieser, Sarah ; Wiesner, Thomas ; Coukos, George ; Castillon, Leticia ; Andreatta, Francesco ; Quek, Camelia ; Böttcher, Jan P ; Barras, David ; Obenauf, Anna C ; Vulin, Milica ; Muñoz I Ordoño, Miquel ; Estivill, Guillem ; Vanharanta, Sakari ; Zuber, Johannes ; Jönsson, Göran ; Hoffmann-Haas, Lisa ; Holstein, Felix ; Elewaut, Anais ; Pedde, Anna-Marie

AbstractThe tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses1,2. Within the tumour microenvironment, CD8+ T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches3–7. Although interactions with type 1 conventional dendritic cells have been implicated in this process3–5,8–10, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9, Cxcl10 and Il15, but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide–major histocompatibility complex class I complexes from tumour cells through ‘cross-dressing’. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E2 (PGE2), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.

100 Deals associated with Forschungsinstitut für Molekulare Pathologie GmbH

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100 Translational Medicine associated with Forschungsinstitut für Molekulare Pathologie GmbH

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Pipeline

Pipeline Snapshot as of 08 May 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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