Biology subjects

Larsen, C.

Publications and source records attributed to Larsen, C..

5 recordsLinked to original sources

bioRxiv2025

Drosophila larval Odd neurons process innate and learned information to regulate chemotaxis behavior

Adaptive decision-making emerges from the integration of innate preferences and learned experiences to guide behavior. Using Drosophila larvae as a model, we investigated the neural circuitry underlying olfactory processing, focusing on Odd neurons--a distinct neuronal population that receives innate valence signals from Kenyon cells (KCs) rather than lateral horn inputs. Through larval connectomics, trans-tango labeling, and detailed anatomical analyses, we found that Odd neurons integrate innate valence through dendro-dendritic connections with KCs and learned valence via inhibitory inputs from mushroom body output neurons (MBON-g1 and MBON-g2). Optogenetic silencing of Odd neurons disrupted larval chemotaxis and associative memory by selectively impairing memory retrieval, while sparing memory formation, and by altering the turn rate during navigation. These results suggest that Odd neurons serve as an integrative hub, converging innate olfactory cues with learned reinforcement signals to fine-tune navigational choices. This study illuminates how distinct neural pathways converge in the larval brain to shape behavior, offering novel insights into decision-making circuitry that may extend to more complex nervous systems.

neuroscience↗

bioRxiv2025

HLA-DQ monomer-based enrichment of alloreactive CD4 T cells

Donor-specific T cell responses, particularly against human leukocyte antigen (HLA)-DQ antigens, are critical in transplant immunology as they influence graft survival and rejection. This study investigated HLA-DQ-specific CD4 T cell responses in naive individuals using HLA-DQ monomers, representing common donor HLA-DQ antigens (DQ2.5, DQ5, DQ6, DQ8), as defined alloantigen sources to enrich and detect HLA-DQ-specific T cells. Using a repeated stimulation protocol with HLA-DQ monomers, we achieved an enrichment of HLA-DQ-specific CD4 T cells, evidenced by proliferation and activation marker upregulation. Additionally, in silico epitope prediction identified 15-mer HLA-DQ peptides capable of binding to self-HLA-DRB1 alleles. TCR sequencing demonstrated an enriched, oligoclonal repertoire of HLA-DQ-specific CD4 T cells post-stimulation, with specific TCR clonotypes expanding in response to HLA-DQ monomer stimulation. Together, our study presents an in vitro method for enriching HLA-DQ-specific CD4 T cells using HLA-DQ monomers as an alloantigen source, thereby improving the detection of alloreactive, donor-specific T cells in naive individuals with the potential to mediate immune responses, including graft rejection and donor-specific antibody (DSA) production.

immunology↗

bioRxiv2025

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a rapidly emerging therapeutic strategy for difficult-to-drug cytosolic proteins. PROTACs are heterobifunctional small molecules that bridge the target with an E3 ubiquitin ligase, destining it for degradation by the proteasome. They have the potential to be orally available and to act catalytically, switching the pharmacology from occupancy-driven to event-driven (1-3). Here we present a strategy for targeted degradation of extracellular proteins by reshaping the interaction between the broadly expressed lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation with the target and sortilin, followed by endocytosis and lysosomal degradation. SORTAC activity can be genetically encoded as demonstrated by converting an IgG binding nanobody to an IgG degrading nanobody or by chemical conjugation, enabling single step conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, using structure-based design, we generated small molecule SORTACs against the inflammatory cytokine TNFa with nanomolar range potency and with physicochemical properties like PROTACs. Our results demonstrate that SORTACs constitute a versatile and highly modular platform for rapid generation of degraders of in theory any extracellular target and with the potential to have wide impact in drug discovery.

biochemistry↗

bioRxiv2024

inTRACKtive - A Web-Based Tool for Interactive Cell Tracking Visualization

We introduce inTRACKtive, an innovative web-based tool for interactive visualization and sharing of large 3D cell tracking datasets, eliminating the need for software installations or data downloads. Built with modern web technologies, inTRACKtive enables researchers to explore cell-tracking results from terabyte-scale microscopy data, conduct virtual fate-mapping experiments, and share these results via simple hyperlinks. The platform powers the Virtual Embryo Zoo, an online resource showcasing cell-tracking datasets from state-of-the-art light-sheet embryonic microscopy of six model organisms. inTRACKtives open-source code allows users to visualize their own data or host customized viewer instances. By providing easy access to complex tracking datasets, inTRACKtive offers a versatile, interactive, collaborative tool for developmental biology.

developmental biology↗

bioRxiv2021

Structural basis for Potassium transport by KdpFABC

KdpFABC is an oligomeric K+ transport complex in prokaryotes that maintains ionic homeostasis under stress conditions. The complex comprises a channel-like subunit (KdpA) from the Superfamily of K+ Transporters and a pump-like subunit (KdpB) from the superfamily of P-type ATPases. Recent structural work has defined the architecture and generated contradictory hypotheses for the transport mechanism. Here, we use substrate analogs to stabilize four key intermediates in the reaction cycle and determine the corresponding structures by cryo-EM. We find that KdpB undergoes conformational changes consistent with other representatives from the P-type superfamily, whereas KdpA, KdpC and KdpF remain static. We observe a series of spherical densities that we assign as K+ or water and which define a pathway for K+ transport. This pathway runs through an intramembrane tunnel in KdpA and delivers ions to sites in the membrane domain of KdpB. Our structures suggest a mechanism where ATP hydrolysis is coupled to K+ transfer between alternative sites in the membrane domain of KdpB, ultimately reaching a low-affinity site where a water-filled pathway allows release of K+ to the cytoplasm.

biophysics↗