Biology subjects

Micheli, F.

Publications and source records attributed to Micheli, F..

14 recordsLinked to original sources

bioRxiv2026

Selective Pharmacological Blockade of GPR39 Markedly Reduces No Reflow and Infarct Volumes in a Rat Model of Acute Myocardial Infarction

Our aim was to determine whether selective pharmacological blockade of GPR39 by the novel drug, VC108, reduces no reflow (NRV) and infarct (INV) volumes during acute myocardial infarction (AMI). Immuocytochemistry and qPCR of isolated rat cardiac cells as well as immunohistochemistry and western blot of rat myocardium was performed for presence of GPR39. Rats underwent 1 h of coronary occlusion and 1 h of reperfusion. Groups 1 and 2 animals received drug/vehicle prior to or during coronary occlusion. Groups 3 and 4 received drug/vehicle 5 min prior to or 30 min after reperfusion. Readouts also included tissue pO2, hemodynamics, and wall thickening. In Groups 5 and 6 animals, drug was injected for measurement of plasma and tissue levels. Immunocytochemistry and qPCR of cells and immunohistochemistry and western blot of tissue revealed GPR39 expression in all cardiac cells analyzed as well as entire myocardial tissue. There was marked reduction in NRV and INV in groups 1 and 3 animals where both were measured and in Group 2 where INV was measured. In contrast, Group 4 animals failed to show reduction in NRV and INV with the drug. The reduction in NRV in all animals was associated with higher tissue pO2 in VC108 compared to vehicle treated animals. Similar results were obtained for INV in only in Group 2 animals. In Group 3 animals direct cardiomyocyte effect of VC108 was seen in myocardium as evidenced by reduced necrosis and apoptosis. We conclude that VC108 is very effective in reducing INV and NRV in an AMI model when given before coronary occlusion or just prior to reperfusion (the latter being clinically more relevant) both in male and female rats. This effect is not seen after reperfusion. VC108 acts by blocking GPR39, resulting in vasodilation through pericyte and VSMC relaxation. It also directly protects cardiomyocytes by preventing downstream effects of GPR39 stimulation. New and NoteworthyGPR39 is the receptor for 15-HETE, which is a vasoconstrictor with direct cardiomyocyte detrimental effects. Pharmacological inhibition of GPR39 by a novel inhibitor, VC108, reduces coronary no reflow after acute myocardial infarction by relaxing contracted pericytes surrounding capillaries, whereby increasing oxygen delivery. GPR39 inhibition also reduces necrosis and ferroptosis by interrupting aberrant downstream signaling responsible for cell death. Hence, pharmacological inhibition of GPR39 by VC108 offers a novel treatment of acute myocardial infarction. Graphical AbstractProposed mechanism of action of VC108 when given prior to and during coronary occlusion based on our results. The drug inhibits the action of the vasoconstrictor, 15-HETE, on GPR39. This causes vasodilation by relaxing contracted pericytes and increasing capillary perfusion, resulting in increased tissue pO2 and reduction in no reflow (left side). When tissue pO2 is not associated with necrosis, GPR39 inhibition by VC108 directly affects cardiomyocytes by inhibiting downstream signaling of GPR39 present in cardiomyocytes that can lead to cell injury and death. Hence, less necrosis and apoptosis are noted in VC108 versus vehicle treated animals. Created in https://BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/699339v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1058995org.highwire.dtl.DTLVardef@8bc0ceorg.highwire.dtl.DTLVardef@11f44e0org.highwire.dtl.DTLVardef@1e2e337_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

15-Hydroxyeicosatetraenoic Acid and GPR39 Together Orchestrate Coronary Autoregulation: A Comprehensive Metabolomic Analysis

BackgroundCoronary autoregulation is the ability of the normal heart to maintain constant coronary blood flow (CBF) over a wide range of coronary driving pressures (CDP). Despite being vital for survival, the mechanism of coronary autoregulation is unknown. We hypothesized that GPR39, present in vascular smooth muscle cells, together with its endogenous agonist 15- hydroxyeicosatetraenoic acid (15-HETE) orchestrate coronary autoregulation. MethodsWe created coronary stenoses of varying degrees in open-chest, anesthetized dogs where we measured CBF and CDP. In a subset of animals, coronary venous blood was sampled for eicosanoid, adenosine, endothelin-1, polyunsaturated fatty acids, and prostaglandins levels. Stenoses were recreated during intravenous administration of VC108, a specific GPR39 antagonist and systemic, pulmonary, and coronary hemodynamics measured. ResultsGPR39 was identified in coronary arterioles by immunohistochemistry and in heart tissue by western blot. In-vivo, 15-HETE correlated the best (r2=0.4851, p=0.0144) with CDP over the autoregulatory range using a linear mixed-effects model. Prior to administration of VC108, CBF did not change within the autoregulatory range. VC108 had no effect on systemic and pulmonary hemodynamics but increased CBF (p=0.02 versus vehicle) by decreasing coronary microvascular resistance (p=0.01 versus vehicle), indicating that GPR39 participates in control of normal coronary vascular tone. With VC108, coronary autoregulation was abolished and CBF became CDP dependent (r2=0.9562, p=0.0039). ConclusionGPR39 and its endogenous agonist 15-HETE together orchestrate coronary autoregulation when CDP is reduced. These novel findings provide a mechanism for coronary autoregulation and could direct pharmacological treatment of various coronary syndromes in humans. Clinical Perspectives What is new?The new finding from this study is that the vasoconstrictor, 15- hydroxyeicosatetraenoic acid (15-HETE), acting via the G-protein coupled receptor 39 (GPR39) participates in coronary arteriolar tone, and when perfusion pressure falls because of coronary stenosis, 15-HETE levels decrease causing vasodilation to maintain resting coronary blood flow. What are the Clinical implicationsThis mechanism, termed coronary autoregulation, causes patients with coronary artery disease to remain asymptomatic at rest until coronary stenosis is very severe. Pharmacological inhibition of GPR39 causes selective coronary vasodilation and could be used to treat coronary artery disease.

physiology↗

bioRxiv2025

Chromosome-Scale Genome Assembly of Australian Finger Lime and Resequencing Reveal the Hidden Diversity of Oceanian Citrus

Oceanian citrus species, including wild taxa native to Australia and Papua New Guinea, form a genetically distinct clade within the Citrus L. (1753) genus. These species remain largely underexplored, despite their adaptation to diverse environments and relevance for citrus improvement. To support their use in breeding and evolutionary studies, we generated a high-quality, Chromosome-scale genome assembly of an Australian finger lime accession (SRA 1002), a natural interspecific hybrid. The genome was assembled using long-read sequencing, optical mapping, and a high-density genetic map, resulting in nine pseudomolecules covering over 97% of the genome. Using this reference, we analyzed whole-genome resequencing data from 132 accessions representing the diversity of Asian and Oceanian citrus. Variant calling across the dataset produced a high-resolution catalogue of single nucleotide polymorphisms (SNPs) and derived database of SNP fully discriminant of 20 Citrus species (DSNPs), enabling detailed exploration of inter- and intra-specific diversity. The data reveal a strong population structure within the group with clear heterozygosity variation between ancestral species and admixed accessions, reflecting their complex evolutionary history and hybridization patterns. This study provides the first integrated genomic framework for Oceanian citrus diversity, offering essential tools for downstream applications in citrus breeding, conservation, and evolutionary genomics. The resources generated lay the groundwork for future association studies and the targeted introgression of beneficial traits into cultivated citrus.

plant biology↗

bioRxiv2025

Marine heatwaves drive range contraction and alternative states of kelp forests at their warm limit

Marine heatwaves are transforming ecosystems, yet their role in driving alternative states--and the conditions that enable these transitions--remains poorly understood. Using 30 years of satellite and underwater data, we assessed the impact of the 2014-2016 Pacific marine heatwaves on giant kelp forests (Macrocystis pyrifera) at their warm range limit in Mexico. By 2016, 88% of forests were lost, with limited recovery by 2023, including an 80 km range contraction at the southern edge. Surveys revealed three alternative states: replacement by heat-tolerant palm kelp (Eisenia arborea) in warmer regions; urchin barrens due to predator overfishing; and, unexpectedly, persistent giant kelp near the southern limit where high temperatures coincide with low human pressure. Pre-existing conditions, such as high urchin and palm kelp densities, shaped these outcomes. These findings show that responses to marine heatwaves are shaped by local ecological and human contexts, requiring tailored climate-adaptation strategies to promote resilience.

ecology↗

bioRxiv2025

Population Genomics of P. miniata along the Pacific Coastline Reveal Subtly Diverging Genomics Along an Extensive Range Gap

Many marine species exhibit range gaps, patchy distributions, or genetic disjunctions throughout their ranges. These discontinuities can result from various interacting mechanisms, though directly linking ecological and historical factors to observed distributions or genetic disjunctions often proves challenging. Intriguingly, substantial research has demonstrated that these spatial and genetic discontinuities frequently occur in species with long-lived planktonic larvae, which possess the capacity for extensive oceanic dispersal. This study investigates the population genetics of one such species, the bat star Patiria miniata. Despite its long-lived planktonic larval stage of six to ten weeks, P. miniata maintains both a range gap and a, geographically separate, strong genetic disjunction throughout its distribution from Alaska to Baja California. Utilizing low-coverage whole-genome sequencing of over 200 individuals collected throughout P. miniatas range between the early 2000s and 2023, we corroborate previous findings of a significant genetic disjunction across Queen Charlotte Sound, north of Vancouver Island. Additionally, we present new evidence of strong divergence at several genomic loci across an extensive range gap in Washington and Oregon, despite subtle genetic population structure at most loci here. Such differences may reflect more recent ecological or oceanographic barriers, rather than historical processes. Our results demonstrate that while marine invertebrate populations may appear panmictic based on genome-wide metrics of population structure alone, strong local selection for specific gene segments may be maintained in some populations. This research contributes to our understanding of the complex interplay between dispersal potential and local adaptation in marine ecosystems and highlights the importance of considering both genetic structure and finer-scale adaptation in coastal marine populations.

evolutionary biology↗

bioRxiv2024

Passing the quadrat: inferring biodiversity change over time and across investigators

Long-term ecological monitoring inevitably requires a passing of the quadrat from one investigator to another. Here we present the challenge and opportunity of inferring biodiversity change over time and across investigators using a rocky intertidal case study. The intertidal transect was surveyed initially by Willis Hewatt in 1931-1933, then resurveyed in detail by Rafe Sagarin, Sarah Gilman, and their mentors in 1993. In total, the transect has been resurveyed 17 times over the past three decades, with annual surveys nested within five distinct investigator eras. We addressed two goals with our dataset. First, we asked whether temporal change in several biodiversity metrics (species richness, Hill-Shannon and Hill-Simpson diversity, spatial beta diversity) was sensitive to investigator era. Second, we identified recent ecological winners and losers, relative to the historical baseline, and asked whether such designations can change over time (1993-2023). We show that investigators contributed to variable trends in species richness over time, and we hypothesize that sampling effort contributed to this effect. In contrast, we highlight declines in the biodiversity of common species (Hill-Shannon) and dominant species (Hill-Simpson) over time, in the absence of investigator effects. These declines were associated with the rise of a few numerically dominant species and a trend of increasing spatial similarity. Relative to the historical baseline, ecological winners included certain barnacles, anemones, and turban snails, while losers included mussels, urchins, limpets and a host of more cryptic taxa. However, we show that such designations can be complicated by non-linear population trajectories and discuss mechanisms related to climate change versus potential artifacts related to investigator effort. We finish with recommendations and emphasize the value of marine stations in providing a venue for sustained periodic ecological monitoring at small spatial scales, long duration, and fine taxonomic resolution.

ecology↗

bioRxiv2024

A super-pangenome for cultivated citrus reveals evolutive features during the allopatric phase of their reticulate evolution

Most of the rich genetic diversity observed in cultivated citrus results from a reticulate evolution involving four ancestral taxa, C. medica, C. reticulata, C. maxima and C. micrantha, whose radiation occurred in allopatry. In such an evolutive context, genome diversity studies, GWAS analysis and transcriptomic studies will be significantly enhanced through pangenome approaches. We report the implementation of a super-pangenome for cultivated citrus, established with de novo assemblies in pseudochromosomes of C. medica (346 Mb), C. reticulata (332 Mb) and C. micrantha (333 Mb), released for the first time alongside a previously published chromosome-scale assembly of C. maxima. Gene annotation of these four genome assemblies revealed 28,090, 29,477, 29,258 and 30,101 genes, respectively, with a focus on pattern recognition receptors. Repetitive element annotation revealed that nearly half of each genome consisted of transposable elements or DNA-satellites. The 3 new genome assemblies display strong synteny and collinearity, while significant discrepancies are observed with the C. maxima assembly. Resequencing information (single nucleotide polymorphisms [SNPs], small indels and gene presence-absence variation [PAV]) from 55 accessions were used to explore the intra- and interspecific diversity of the four ancestral taxa and their relationships with the main horticultural groups resulting from reticulate evolution. Diagnostic SNPs of the ancestral taxa, all over the four genomes assemblies, revealed interspecific introgressions in several accessions representative of C. reticulata, C. maxima and C. medica as well as insights into the origin and phylogenomic structures of modern horticultural groups. PAV analysis revealed a gene whose absence or presence was specific to one of the ancestral taxa (dPAV). Interestingly, diagnostic PAV (dPAV) analysis uncovered a large chloroplastic introgression in chromosome 4 of C. medica, inherited in horticultural groups and recent hybrids having this species as the male parent. Implementing the super-pangenome combined the identification of orthologous genes across the four genome assemblies and the PAV information from the resequencing data. Significant inter- and intraspecific variations were highlighted, including 25,291 core, 2,431 soft-core and 5,171 dispensable genes. The analysis of the functional enrichment and species-specific adaptations in the citrus super-pangenome revealed distinct functional specializations. This highlights the evolutionary paths that have shaped each species, contributing to the diversity in the citrus super-pangenome while maintaining a shared foundation of essential biological processes. The development of this super-pangenome is a significant milestone in citrus genomics, providing a comprehensive resource that captures the extensive genetic diversity of modern cultivated citrus. Additionally, we established a dedicated Genome Hub, offering a platform for continuous genomic research and allowing for ongoing updates and future inclusion of additional ancestral species.

genomics↗

bioRxiv2024

Intensifying marine heatwaves and limited protection threaten global kelp forests

Kelp forests are one of the earths most productive ecosystems and are at the greatest risk from climate change, yet little is known regarding their future threats and current conservation status. By combining a global remote sensing dataset of floating kelp forests with climate data and projections, we find that exposure to projected marine heatwaves will increase [~]8 times compared to contemporary (2001-2020) exposure for intermediate climate scenarios. While exposure will intensify for all forests, climate refugia emerge for some southern hemisphere kelp forests, which have lower exposure to contemporary and projected marine heatwaves. Under these escalating threats, less than 3% of global kelp forests are currently within highly restrictive marine protected areas, the most effective conservation measure for providing climate resilience. Our findings emphasize the urgent need to increase the global protection of kelp forests and set bolder climate adaptation goals.

ecology↗

bioRxiv2024

Recovery mode: Marine protected areas enhance the resilience of kelp species from marine heatwaves

Marine protected areas (MPAs) can promote population recovery from climate change impacts by reducing local stressors, such as fishing. However, with extreme climatic events such as marine heatwaves (MHWs) increasing in frequency and duration, it remains unclear whether MPAs enhance recovery following these acute perturbations, and how recovery varies across species and ecological traits (e.g., sedentary vs mobile species). We used 16 years (2007-2022) of kelp forest monitoring data in Isla Natividad, Baja California Sur, Mexico, to assess the impact of the 2014-2016 MHWs on fish and invertebrate communities. Then we evaluated the impact and recovery from the MHWs of economically and ecologically important invertebrate species inside and outside two fully protected marine reserves. We found that the 2014-2016 MHWs, which were the most intense and persistent ever observed in Isla Natividad, impacted invertebrates but not fish biomass. Marine reserves did not confer resistance to the MHWs, however, reserves did enhance the recovery of some species after the MHWs. Inside marine reserves, abalone (Haliotis spp.) and wavy turban snail (Megastraea spp.) (benthic sedentary invertebrates) recovered to pre-heatwave biomass after two years and spiny lobster (Panulirus interruptus) (benthic mobile invertebrate) after four years. Outside the reserves, abalone recovered after three years, while the other two species never recovered. The warty sea cucumber (Apostichopus parvimensis) population collapsed after the MHWs and never recovered inside nor outside the reserve. Remarkably, abalone biomass had an outstanding and sustained recovery inside reserves, with a 5.6-fold increase in biomass after the MHWs, which was over three times higher than the recovery reported outside the reserve. Our analysis of long-term monitoring data shows that marine reserves cannot prevent adverse impacts from extreme climatic events but can enhance species recovery following these events. Benefits conferred by marine reserves, however, are species-specific and may be limited to species with limited dispersal and localized population dynamics.

ecology↗

bioRxiv2024

Marine protected areas promote resilience of kelp forests to marine heatwaves by preserving trophic cascades

Under accelerating threats from climate change impacts, marine protected areas (MPAs) have been proposed as climate adaptation tools to enhance the resilience of marine ecosystems. Yet, debate persists as to whether and how MPAs may promote resilience to climate shocks. Here, we empirically assess whether a network of 85 temperate MPAs in coastal waters promotes resilience against marine heatwaves in Central and Southern California. We use 38 years of satellite-derived kelp cover to test whether MPAs enhance the resistance of kelp forest ecosystems to, and recovery from, the unprecedented 2014-2016 marine heatwave regime. We also leverage a 20-year time series of subtidal community surveys to understand whether protection and recovery of sea urchin predators within MPAs explain emergent patterns in kelp forest resilience through trophic cascades. We find that fully protected MPAs (i.e. no-take marine reserves) significantly enhance the resistance to and recovery of kelp forests to marine heatwaves in Southern California, but not in Central California. Differences in regional responses to the heatwaves may be partly explained by three-level trophic interactions comprising kelp, urchins, and predators of urchins. Urchin abundances in Southern California MPAs are significantly lower within fully protected MPAs during and after the heatwave, while the abundance of their predators are higher. In Central California, there is no significant difference in urchin abundances within protected areas as the current urchin predator, sea otters, are unilaterally protected. Therefore, we provide evidence that fully protected MPAs can be effective climate adaptation tools, but their ability to enhance resilience to extreme climate events depends upon region-specific environmental and ecological dynamics. As nations progress to protect 30% of the oceans by 2030 scientists and managers should consider whether protection will increase resilience to climate-change impacts given their local ecological contexts, and what additional measures may be needed.

ecology↗

bioRxiv2022

Towards transboundary networks of climate-smart marine reserves in the Southern California Bight

Climate-smart conservation addresses the vulnerability of biodiversity to climate change impacts but may require transboundary considerations. Here, we adapt and refine 16 biophysical guidelines for climate-smart marine reserves for the transboundary California Bight ecoregion. We link several climate-adaptation strategies (e.g., maintaining connectivity, representing climate refugia, and forecasting effectiveness of protection) by focusing on kelp forests and associated species. We quantify transboundary larval connectivity along [~]800 km of coast and find that the number of connections and the average density of larvae dispersing through the network under future climate scenarios could decrease by [~]50%, highlighting the need to protect critical steppingstone nodes. We also find that although focal species will generally recover with 30% protection, marine heatwaves could hinder subsequent recovery in the following 50 years, suggesting that protecting climate refugia and expanding the coverage of marine reserves is a priority. Together, these findings provide a first comprehensive framework for integrating climate resilience for networks of marine reserves and highlight the need for a coordinated approach in the California Bight ecoregion.

ecology↗

bioRxiv2021

Data-Poor Ecological Risk Assessment of Multiple Stressors

O_LIEcological Risk Assessment is a formal process widely applied to terrestrial, marine, and freshwater ecosystems to evaluate the likelihood of adverse ecological effects occurring as a result of exposure to natural or anthropogenic stressors. For many species, data is sparse and semi-quantitative methodologies provide valuable insight for ecosystem management. Recent statistical developments have improved the quality of these analyses yet a rigorous theoretical framework to assess the cumulative impact of multiple stressors is lacking. C_LIO_LIWe present EcoRAMS, a web application and open-source software module that provides easy-to-use, statistically-robust ecological risk assessments of multiple stressors in data-poor contexts. The software receives attribute scores for two variables (e.g. exposure-sensitivity, productivity-susceptibility, severity-likelihood) via CSV templates and outputs results according to a probabilistic metric of risk. C_LIO_LIWe demonstrate comparative results across a range of assumptions, using simulated and empirical datasets including up to five stressors. Accounting for multiple stressors even when data is limited provides a more detailed analysis of risk that may otherwise be understated in single stressor analyses. C_LIO_LIThis application will allow quantification of risk across data-poor contexts for which statistical results have been previously unavailable. The web app format of EcoRAMS.net lowers the barrier of use for practitioners and scientists at any level of statistical training. C_LI

ecology↗

bioRxiv2020

Uneven protection of persistent giant kelp forest in the Northeast Pacific Ocean

In most regions, the distribution of marine forests and the efficacy of their protection is unknown. We mapped the persistence of giant kelp forests across ten degrees of latitude in the Northeast Pacific Ocean and found that 7.7% of giant kelp is fully protected, with decreasing percentages from north to south. Sustainability goals should prioritize kelp mapping and monitoring, while protection and climate adaption targets should account for habitat dynamics.

ecology↗

bioRxiv2018

Prawn aquaculture as a method for schistosomiasis control and poverty alleviation: a win-win approach to address a critical infectious disease of poverty

Recent evidence suggests crustacean snail predators may aid schistosomiasis control programs by targeting the environmental component of the parasites life cycle through predation of the snail species that serve as intermediate hosts of the parasite. We evaluate costs, benefits, and potential synergies between schistosomiasis control and aquaculture of giant prawns using an integrated bio-economic-epidemiologic model. We identified combinations of stocking density and aquaculture cycle length that maximize profit and offer disease control benefits for sustainable schistosomiasis control. We consider two prawn species in sub-Saharan Africa: the endemic, non-domesticated Macrobrachium vollenhovenii, and the non-native, domesticated Macrobrachium rosenbergii. We find that, at profit-optimal densities, both M. rosenbergii and M. vollenhovenii can complement conventional control approaches (mass drug treatment of people) and lead to sustainable schistosomiasis control. We conclude that integrated aquaculture strategies can be a win-win strategy in terms of health and sustainable development in schistosomiasis endemic regions of the world.

epidemiology↗