Biology subjects

Hirsch, T.

Publications and source records attributed to Hirsch, T..

5 recordsLinked to original sources

bioRxiv2025

Regulatable In Vivo Gene Expression via Adaptamers

Precise, reversible control of transgene expression is essential for safe and durable gene therapy, yet current inducible systems remain difficult to translate in vivo due to large size, limited induction duration, and dependence on immunogenic regulators. Here we present the adaptamer (ADAR modulatable aptamer), a compact (<120 bp) RNA switch that couples an FDA-approved small-molecule-responsive aptamer with endogenous ADAR-mediated RNA editing to regulate expression. Ligand binding stabilizes a double-stranded RNA structure that recruits ADAR to convert a stop codon into a sense codon, restoring downstream protein translation. This cleavage-free, post-transcriptional mechanism enables precise, small-molecule-dependent modulation without exogenous protein machinery. We demonstrate that adaptamers are highly functional across multiple cell lines, including human T-cells. In mice, AAV-delivered adaptamer-controlled FGF21 expression induced metabolic remodeling, significantly increasing energy expenditure and reversing obesity. This minimal, programmable system offers a clinically compatible approach for tunable genetic medicines and safe deployment of pleiotropic and dose-limited proteins.

synthetic biology↗

bioRxiv2024

Clathrin-independent endocytosis and retrograde transport in cancer cells promote cytotoxic CD8 T cell activation

Endophilin A3-mediated clathrin-independent endocytosis (EndoA3-mediated CIE) contributes to the internalization of immunoglobulin-like proteins, including key immune synapse components. Here, we identify ICAM1 as a novel EndoA3-dependent cargo, alongside ALCAM. We demonstrate that both proteins subsequently follow retromer-dependent retrograde transport to the trans-Golgi network (TGN) in cancer cells. From there, we propose that they undergo polarized redistribution to the plasma membrane, where they contribute to immune synapse formation between cancer cells and cytotoxic CD8 T cells. Disruption of EndoA3 or retromer components significantly affects the response of autologous cytotoxic CD8 T cells, as evidenced by reduced cytokine production and secretion, but increased lytic activity, while proliferation and later activation marker expression remain intact. This is accompanied by diminished ICAM1 density at the immune synapse, where we observe it arriving via polarized vesicular transport, indicating altered synapse organization. Indeed, cancer cells lacking EndoA3-mediated CIE or retromer form enlarged immune synapses that fail to sustain full T cell cytokine secretion, suggesting a compensatory attempt by T cells to overcome the defective synapse, while likely promoting more transient contacts that potentially favor serial killing. Together, these findings reveal that EndoA3-mediated CIE and retrograde transport act in concert in cancer cells to relocate immune synapse components via the Golgi, thereby fine-tuning the balance between cytotoxic T cell cytokine secretion and lytic activity. These insights contribute to a better understanding of the mechanisms governing immune synapse formation and organization, providing a necessary foundation for the long-term identification of new strategies to enhance T cell-mediated anti-tumor immunity. Significance StatementThis study uncovers a novel mechanism by which clathrin-independent endocytosis (CIE) and retrograde transport collaborate to regulate immune synapse dynamics in cancer cells. We identify ICAM1 as a new cargo of Endophilin A3-mediated CIE, highlighting its role in the polarized redistribution of immune synapse components critical for cytotoxic CD8 T cell activation. By linking a specific CIE mechanism and retrograde transport to immune synapse function, our findings provide new insights into cancer-immunity interactions and suggest potential therapeutic strategies to enhance immune responses by targeting protein trafficking pathways.

cell biology↗

bioRxiv2024

Making the Monitoring Framework of the Kunming-Montreal Global Biodiversity Framework fit for purpose.

The Kunming-Montreal Global Biodiversity Framework (GBF) is the most ambitious agreement on biodiversity conservation and sustainable use to date. It calls for a whole-of government and whole-of-society approach to halt and reverse biodiversity loss worldwide. The Monitoring Framework of the GBF lays out how Parties to the Convention on Biological Diversity (CBD) are expected to report their progress. A CBD expert group provided guidance on its implementation, including a gap analysis to identify the strengths and limitations of the indicators in the Monitoring Framework. We present the results of the gap analysis, highlight where more work is needed and provide recommendations on implementing and improving monitoring to allow effective and comprehensive tracking of the GBFs ambition. We find that with the headline and binary indicators, which Parties are required to use, the Monitoring Framework fully covers 19% of the GBFs ambition and partially covers an additional 40%. Including disaggregations of the headline indicators improves coverage to 22% fully and an additional 41% partially. Adding optional (component and complementary) indicators brings full coverage to 29% with an additional 47% partial coverage. No indicators are available for 12% of the GBF. In practice, the coverage of the Monitoring Framework will depend on which indicators (headline and binary as well as component and complementary) and disaggregations are used by countries. Disaggregations are particularly relevant to monitor the cross-cutting considerations defined under section C. Substantial investment is required to collect the necessary data to compute indicators, infer change, and effectively monitor progress. We highlight important next steps to progressively improve the efficacy of the Monitoring Framework.

ecology↗

bioRxiv2022

The Global Register of Introduced and Invasive Species: Country Compendium

The Country Compendium of the Global Register of Introduced and Invasive Species (GRIIS) is a collation of data across 196 individual country checklists of alienspecies, along with a designation of those species with evidence of impact at a country level. The Compendium provides a baseline for monitoring the distribution and invasion status of all major taxonomic groups, and can be used for the purpose of global analyses of Introduced (alien, non-native, exotic) and Invasive species (invasive alien species), including regional, single and multi-species taxon assessments and comparisons. It enables exploration of gaps and inferred absences of species for countries, and provides a means for short to medium term refinement of GRIIS Checklists. The Country Compendium is, for example, instrumental, along with data on first records of introduction, for assessing and reporting on invasive alien species targets, including for the Convention on Biological Diversity and Sustainable Development Goals. The GRIIS Country Compendium provides a baseline and mechanism for tracking the spread of introduced and invasive alien species across countries globally. O_TBL View this table: org.highwire.dtl.DTLVardef@eb30fdorg.highwire.dtl.DTLVardef@dd338aorg.highwire.dtl.DTLVardef@62b8daorg.highwire.dtl.DTLVardef@1561763org.highwire.dtl.DTLVardef@119988e_HPS_FORMAT_FIGEXP M_TBL C_TBL

ecology↗

bioRxiv2021

Antiviral activity of influenza A virus defective interfering particles against SARS-CoV-2 replication in vitro through stimulation of innate immunity

SARS-CoV-2 causing COVID-19 emerged in late 2019 and resulted in a devastating pandemic. Although the first approved vaccines were already administered by the end of 2020, worldwide vaccine availability is still limited. Moreover, immune escape variants of the virus are emerging against which the current vaccines may confer only limited protection. Further, existing antivirals and treatment options against COVID-19 only show limited efficacy. Influenza A virus (IAV) defective interfering particles (DIPs) were previously proposed not only for antiviral treatment of the influenza disease but also for pan-specific treatment of interferon (IFN)-sensitive respiratory virus infections. To investigate the applicability of IAV DIPs as an antiviral for the treatment of COVID-19, we conducted in vitro co-infection experiments with cell culture-derived DIPs and the IFN-sensitive SARS-CoV-2 in human lung cells. We show that treatment with IAV DIPs leads to complete abrogation of SARS-CoV-2 replication. Moreover, this inhibitory effect was dependent on janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. Further, our results suggest boosting of IFN-induced antiviral activity by IAV DIPs as a major contributor in suppressing SARS-CoV-2 replication. Thus, we propose IAV DIPs as an effective antiviral agent for treatment of COVID-19, and potentially also for suppressing the replication of new variants of SARS-CoV-2.

microbiology↗