Biology subjects

Grossmann, R.

Publications and source records attributed to Grossmann, R..

4 recordsLinked to original sources

bioRxiv2026

Serotonin induces DOWN states across the anesthetized mouse forebrain

Serotonergic neurons in the dorsal raphe nucleus (DRN) project extensively throughout the forebrain, yet their influence on global network states remains controversial. Serotonin is implicated in regulating slow-oscillations, so-called UP and DOWN states, which occur during sleep and light anesthesia. While optogenetic fMRI suggests that serotonin (5-HT) suppresses brain-wide activity, classical electrical stimulation studies report the induction of cortical UP states. To resolve this discrepancy, we combined optogenetic 5-HT stimulation with large-scale Neuropixel recordings across the forebrain of lightly anesthetized mice. We demonstrate that selective 5-HT release consistently induces DOWN states across the cortex and striatum, while leaving midbrain dynamics largely unaffected. A multi-area computational model constrained by biologically plausible connectivity, indicates that in certain regions the transitions arises from network-level synchronization rather than direct DRN input.

neuroscience↗

bioRxiv2026

Coiled-coil domain kinking controls laminin-332 cleavage by elastase

Laminins are trimeric glycoproteins and essential components of basement membranes, where they provide structural support and mediate cell-matrix adhesion. Their -, {beta}-, and {gamma}-chains combine into a flexible trimeric coiled-coil domain forming the laminin long arm, which links the N-terminal short arms and the C-terminal globular domains. However, ultrastructural insight into the laminin coiled-coil domain remains limited, and the function of coiled-coil flexibility remains unclear. Using high-speed atomic force microscopy (HS-AFM) imaging, we previously investigated the ultrastructure of laminin-332 and observed dynamic kinking around a putative molecular hinge in the center of the coiled-coil domain. In this study, we integrate HS-AFM time-lapse imaging with AlphaFold structure prediction and normal-mode flexible fitting (NMFF) to generate dynamic models of the laminin-332 hinge during coiled-coil domain kinking, providing atomic-scale insight into the underlying molecular rearrangements. Furthermore, we use HS-AFM to visualize, in real time, the digestion of individual laminin-332 molecules by pancreatic elastase and show that coiled-coil kinking directs elastase cleavage to the hinge site, thereby ensuring reliable generation of the elastase 8 (E8) fragment containing the integrin binding site. In contrast, laminin molecules with extended coiled-coil conformations are cleaved at arbitrary sites, resulting in complete coiled-coil removal and degradation. Our results thus identify a novel conformational control mechanism directing proteolytic processing of laminin-332 through defined coiled-coil kinking. Besides expanding the understanding of dynamic laminin coiled-coil function, the gained ultrastructural insight into trimeric coiled-coil bending may aid the rational design of flexible coiled-coil modules for future protein engineering applications.

cell biology↗

bioRxiv2024

Chemically induced dislocation and mutation of essential cytoskeletal proteins: A case study focusing on Coronin-A

Actin is one of the most highly conserved proteins--the actin cytoskeleton or actin-like structures are found in all kingdoms of life. In this work, Coronin-A, a central player involved in actin dynamics, is considered as an example to compare the effect of four mutation strategies on its function in Dictyostelium discoideum. Two distinct genetic knockout methods (selection-linked integration and classical gene disruption), RNAi knockdown, and sudden loss-of-function generated by chemically induced dislocation (CID) are compared and the cell lines are characterized according to actin dependent processes: appearance, development, and motility. These phenotypic features are affected to different degrees in the mutant cell lines, providing a basis to discuss the strengths and weaknesses of each approach. This comparative study highlights the advantages of the newly introduced selection-linked integration method to knock out genes over commonly used gene disruption, and for expressing a CID-based knock-sideways system under the native promotor of the protein of interest.

cell biology↗

bioRxiv2021

Integrated phospho-proteogenomic and single-cell transcriptomic analysis of meningiomas establishes robust subtyping and reveals subtype-specific immune invasion

Meningiomas are the most frequent primary intracranial tumors. They can follow a wide clinical spectrum from benign to highly aggressive clinical course. No specific therapy exists for refractory cases or cases not amenable to resection and radiotherapy. Identification of risk of recurrence and malignant transformation for the individual patients is challenging. However, promising molecular markers and prognostic subgrouping by DNA methylation are emerging. Still, the biological underpinnings of these diagnostic subgroups are elusive, and, consequently, no novel therapeutic options arise thereof. Here we establish robust subgroups across the full landscape of meningiomas, consistent through DNA methylation, mutations, the transcriptomic, proteomic and phospho-proteomic level. Pronounced proliferative stress and DNA damage repair signals in malignant cells and in clusters exclusive to recurrent tumors are in line with their higher mitotic activity, but also provide an explanation for the accumulation of genomic instability in anaplastic meningiomas. Although homozygous deletion of CDKN2A/B is a diagnostic marker of high-grade meningioma, the expression of its gene product increased from low to non-deleted high-grade cases. Differences between subgroups in lymphocyte and myeloid cell infiltration, representing a majority of tumor mass in low-grade NF2 tumors, could be assigned to cluster-specific interaction with tumor cells. Activation to a more proinflammatory phenotype and decreased infiltration of myeloid cells in high-grade cases correlated with lower expression of CSF1, located on chromosome arm 1p, whose deletion is known as prognostic marker, with no proposed mechanism before. Our results demonstrate a robust molecular subclassification of a tumor type across multiple layers, provide insight into heterogeneous growth dynamics despite shared pathognomonic mutations, and highlight immune infiltration modulation as a novel target for meningioma therapy.

genomics↗