Biology subjects

Scherer, L.

Publications and source records attributed to Scherer, L..

3 recordsLinked to original sources

bioRxiv2025

Development of conditional-siRNA programmable riboswitch for targeting adverse cardiac remodeling

Heart Failure (HF) remains a global epidemic and a significant healthcare burden, with an unmet need for novel therapies to target the preceding pathological hypertrophy in vulnerable patients. Here we report the development of novel conditional-siRNA (Cond- siRNA) constructs that are selectively activated by disease-specific RNA biomarkers to enable cell-specific inhibition of a target disease-causing RNA. We designed a Cond- siRNA that can be activated by nppa mRNA, upregulated specifically in CMs under pathological stress, to silence the key pro-hypertrophic gene calcineurin by the effector siRNA. In cellular models including neonatal rat ventricular myocyte (NRVM) and rat cardiomyocyte cell-line (H9C2), Cond-siRNA exhibited low baseline activity in the absence of the disease biomarker but achieved targeted calcineurin silencing upon nppa mRNA induction by phenylephrine (PE)-induced stress in a two-dimensional (2D) cell culture system and pressure overload in three-dimensional (3D) heart-on a chip system. NRVM transfection with the Cond-siRNA resulted in a decreased expression of calcineurin mRNA specifically after PE or pressure-overload treatment, but not after vehicle treatment, proving nppa mRNA-specific activation of the effector siRNA against calcineurin. Specificity was confirmed as Cond-siRNA did not significantly silence calcineurin in cardiac fibroblasts and T cells, lacking nppa expression. Reduced calcineurin protein levels and NFATc1 nuclear translocation correlated with decreased NRVM hypertrophy after PE treatment, confirming Cond-siRNAs efficacy. This study offers proof-of-concept for Cond-siRNA as a targeted therapy to mitigate hypertrophic progression, paving the way for novel HF treatments. One sentence summaryConditional-siRNA targeting adverse cardiac remodeling GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/633434v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1b6532borg.highwire.dtl.DTLVardef@10e3836org.highwire.dtl.DTLVardef@8c839eorg.highwire.dtl.DTLVardef@1152883_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Land-use impacts on plant functional diversity throughout Europe

AimGlobal biodiversity loss resulting from anthropogenic land-use activities is a pressing concern, requiring precise assessments of impacts at large spatial extents. Existing models mainly focus on species richness and abundance, lacking insights into ecological mechanisms and species roles in ecosystem functioning. To bridge this gap, we conducted an extensive analysis of the impact of human land use on vascular plant functional diversity, across diverse land-use classes and bioregions in Europe, comparing it to traditional metrics. Location: Europe Time period: 1992-2019 Major taxa studied: Vascular plants MethodsIntegrating extensive databases of vegetation plots with spatial data on land use and land cover, we paired plots from areas actively used and modified by humans with plots from natural habitats under similar environmental conditions. Using species occurrences and traits, in each plot we computed three complementary functional diversity metrics (functional richness, evenness, and divergence), species richness and abundance. We assessed the impact of land use by comparing the metrics in the paired plots. ResultsOur findings revealed that, compared to natural habitats, anthropogenic land use exhibits lower functional richness and divergence but higher functional evenness across most land-use classes and bioregions. The response of functional richness was more marked than the other two metrics and especially pronounced in croplands and urban areas and in northern bioregions. Functional richness exhibited a pattern that did not fully overlap with the trend in species richness, providing useful complementary information. Main conclusionsWe provide a large-scale precise assessment of anthropogenic land-use impacts on functional diversity across Europe. Our findings indicate that: (i) human disturbance significantly alters plant functional diversity compared to natural habitats; (ii) this alteration goes in the direction of functional homogenization; (i) functional diversity metrics complement traditional metrics by offering deeper insights into the ecological mechanisms in response to anthropogenic land use.

ecology↗

bioRxiv2023

Embryo-restricted responses to maternal IL-17A promote neurodevelopmental disorders in mouse offspring

Prenatal imprinting to interleukin 17A (IL-17A) triggers behavioral disorders in offspring. However, reported models of maternal immune activation utilizing immunostimulants, lack specificity to elucidate the anatomical compartments of IL-17As action and the distinct behavioral disturbances it causes. By combining transgenic IL-17A overexpression with maternal deficiency in its receptor, we established a novel model of prenatal imprinting to maternal IL-17A (acronym: PRIMA-17 model). This model allowed us to study prenatal imprinting established exclusively through embryo-restricted IL-17A responses. We demonstrated IL-17A transfer across the placental barrier and subsequent development of selected behavioral deficits in mouse offspring. More specifically, embryonic responses to IL-17A resulted in communicative impairment in early-life measured by reduced numbers of nest retrieval calls. In adulthood, IL-17A-imprinted offspring displayed an increase in anxiety-like behavior. We advocate our PRIMA-17 model as a useful tool to study neurological deficits in mice.

neuroscience↗