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Endothelial cells respond to different levels of fluid shear stress through adaptations of their mechanosensitivity. Currently, we lack a good understanding of how this contributes to sculpting of the cardiovascular system. Cerebral cavernous malformation (CCM) is an inherited vascular disease that occurs when a second somatic mutation causes a loss of CCM1/KRIT1, CCM2, or CCM3 proteins. Here, we demonstrate that zebrafish Krit1 regulates the formation of cardiac valves. Expression of heg1, which encodes a binding partner of Krit1, is positively regulated by blood-flow. In turn, Heg1 stabilizes levels of Krit1 protein, and both Heg1 and Krit1 dampen expression levels of klf2a, a major mechanosensitive gene. Conversely, loss of Krit1 results in increased expression of klf2a and notch1b throughout the endocardium and prevents cardiac valve leaflet formation. Hence, the correct balance of blood-flow-dependent induction and Krit1 protein-mediated repression of klf2a and notch1b ultimately shapes cardiac valve leaflet morphology.

Background Cerebral cavernous malformations (CCM) are angiographically occult vascular anomalies of the brain, characterized by dilated capillaries, increased vascular permeability, and loss of endothelial junctional protein complexes. Loss-of-function mutations in one of the three genes, namely KRIT1/CCM1 , CCM2 , and PDCD10/CCM3, have been associated with the disease pathogenesis, although the contribution of other genetic determinants besides CCM genes has been recently identified. Despite recent advances in understanding the molecular mechanism of the disease, the current lack of therapies and its unpredictable clinical behavior represent a significant challenge in the identification of diagnostic biomarkers. ADGRL4/ETLD1 (epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1), a G-protein coupled receptor (GPCR) protein is a known biomarker of angiogenesis and inflammation, and it has been suggested to be a key therapeutic target for stroke and high-grade gliomas. However, the relevance of ELTD1 in CCM pathogenesis remains unexplored. Methods Through different analyses, including whole RNA transcriptome, immunohistochemistry, and real-time PCR, conducted in human CCM patients, cellular and animal models, herein we show the association between CCM disease and ELTD1. Results The whole RNA transcriptome approaches demonstrated ELTD1 is differentially expressed, and gene expression analysis revealed it is significantly upregulated in surgically resected tissue and plasma samples from CCMs, and clinical correlation analysis showed that increased ELTD1 associates with the presence of Focal Neurological Deficits in patients. Immuno-expression showed a strong ELTD1 immunoreactivity in endothelial cells lining affected lesions. According to these elevated levels of ELTD1 in human patients, we also showed a robust increase in the expression level of ELTD1 in cellular and animal models of CCM disease. Conclusions Taken together, our results demonstrate for the first time ELTD1 involvement in CCM pathogenesis, and its tight link with CCM genes. Thanks to this putative new prognostic biomarker, future clinical studies in larger patient cohorts will aim at improving the CCM disease management and risk stratification in patients, as well as placing the basis for targeted therapeutic strategies in CCM.

Divisions that generate one neuronal lineage-committed and one self-renewing cell maintain the balance of proliferation and differentiation for the generation of neuronal diversity. The asymmetric inheritance of apical domains and components of the cell division machinery has been implicated in this process, and might involve interactions with cell fate determinants in regulatory feedback loops of an as yet unknown nature. Here, we report the dynamics of Anillin - an essential F-actin regulator and furrow component - and its contribution to progenitor cell divisions in the developing zebrafish retina. We find that asymmetrically dividing retinal ganglion cell progenitors position the Anillin-rich midbody at the apical domain of the differentiating daughter. anillin hypomorphic conditions disrupt asymmetric apical domain inheritance and affect daughter cell fate. Consequently, the retinal cell type composition is profoundly affected, such that the ganglion cell layer is dramatically expanded. This study provides the first in vivo evidence for the requirement of Anillin during asymmetric neurogenic divisions. It also provides insights into a reciprocal regulation between Anillin and the ganglion cell fate determinant Ath5, suggesting a mechanism whereby the balance of proliferation and differentiation is accomplished during progenitor cell divisions in vivo.

The analysis of genes in evolutionarily distant but morphologically similar species is of major importance to unravel the changes in genomes over millions of years, which led to gene silencing and functional diversification. We report the analysis of Wnt8a gene expression in the medakafish and provide a detailed comparison to other vertebrates. In all teleosts analyzed there are two paralogous Wnt8a copies. These show largely overlapping expression in the early developing zebrafish embryo, an evolutionarily distant relative of medaka. In contrast to zebrafish, we find that both maternal and zygotic expression of particularly one Wnt8a paralog has diverged in medaka. While Wnt8a1 expression is mostly conserved at early embryonic stages, the expression of Wnt8a2 differs markedly. In addition, both genes are distinctly expressed during organogenesis unlike the zebrafish homologs, which may hint at the emergence of functional diversification of Wnt8a ligands during evolution.

The analysis of genes in evolutionarily distant but morphologically similar species is of major importance to unravel the changes in genomes over millions of years, which led to gene silencing and functional diversification. We report the analysis of Wnt8a gene expression in the medakafish and provide a detailed comparison to other vertebrates. In all teleosts analyzed there are two paralogous Wnt8a copies. These show largely overlapping expression in the early developing zebrafish embryo, an evolutionarily distant relative of medaka. In contrast to zebrafish, we find that both maternal and zygotic expression of particularly one Wnt8a paralog has diverged in medaka. While Wnt8a1 expression is mostly conserved at early embryonic stages, the expression of Wnt8a2 differs markedly. In addition, both genes are distinctly expressed during organogenesis unlike the zebrafish homologs, which may hint at the emergence of functional diversification of Wnt8a ligands during evolution.

The Gulf Stream (GS) plays a key role in shaping the North Atlantic climate. Moreover, the associated sea surface temperature (SST) front undergoes interannual-to-decadal variability that is thought to force significant atmospheric circulation anomalies. However, general circulation models do not accurately reproduce the atmospheric response to SST front variability as estimated from observations. In this work we analyze the atmospheric response to the GS SST front (GSF) shifts in a multimodel ensemble of atmosphere-only simulations forced with observed SSTs (1950–2014). The atmospheric response is found to be resolution dependent. Only the high-resolution simulations produce a wintertime response similar to observed anomalies. More specifically, (i) analysis of the atmospheric thermodynamic balance close to the GSF showed that the anomalous diabatic heating associated to the GSF displacement is mainly balanced by vertical motion and by meridional transient eddy heat transport (not the case for low-resolution models), while (ii) the large-scale response includes a meridional shift of the North Atlantic eddy-driven jet and storm track homodirectional to the GSF displacement. This atmospheric response is accompanied by changes in low-level baroclinicity close to and north of the GSF, resulting from the oceanic forcing and the zonal atmospheric circulation anomalies respectively. The low-level baroclinicity anomalies lead to changes in baroclinic eddy activity and, ultimately, in the jet via eddy–mean flow interaction. Considering the two-way nature of air–sea interactions, using historical atmosphere-only simulations is a powerful way to isolate the impact of realistic oceanic variability on the atmosphere. Our results suggest that interannual-to-decadal predictability may be higher than what low-resolution models currently indicate.

While it is accepted that extracellular vesicles (EVs)-mediated transfer of microRNAs contributes to intercellular communication, the knowledge about molecular mechanisms controlling the selective and dynamic miRNA-loading in EVs is still limited to few specific RNA-binding proteins interacting with sequence determinants. Moreover, although mutagenesis analysis demonstrated the presence/function of specific intracellular retention motifs, the interacting protein/s remained unknown. Here, PCBP2 was identified as a direct interactor of an intracellular retention motif: CLIP coupled to RNA pull-down and proteomic analysis demonstrated that it binds to miRNAs embedding this motif and mutagenesis proved the binding specificity. Notably, PCBP2 binding requires SYNCRIP, a previously characterized miRNA EV-loader as indicated by SYNCRIP knock-down. SYNCRIP and PCBP2 may contemporarily bind to miRNAs as demonstrated by EMSA assays and PCBP2 knock-down causes EV loading of intracellular microRNAs. This evidence highlights that multiple proteins/miRNA interactions govern miRNA compartmentalization and identifies PCBP2 as a dominant inhibitor of SYNCRIP function in murine hepatocytes.

The interaction between the North Atlantic Oscillation (NAO) and the latitudinal shifts of the Gulf Stream sea surface temperature front (GSF) has been the subject of extensive investigations. There are indications of nonstationarity in this interaction, but differences in the methodologies used in previous studies make it difficult to draw consistent conclusions. Furthermore, there is a lack of consensus on the key mechanisms underlying the response of the GSF to the NAO. This study assesses the possible nonstationarity in the NAO–GSF interaction and the mechanisms underlying this interaction during 1950–2020, using reanalysis data. Results show that the NAO and GSF indices covary on the decadal time scale but only during 1972–2018. A secondary peak in the NAO–GSF covariability emerges on multiannual time scales but only during 2005–15. The nonstationarity in the decadal NAO–GSF covariability is also manifested in variations in their lead–lag relationship. Indeed, the NAO tends to lead the GSF shifts by 3 years during 1972–90 and by 2 years during 1990–2018. The response of the GSF to the NAO at the decadal time scale can be interpreted as the joint effect of the fast response of wind-driven oceanic circulation, the response of deep oceanic circulation, and the propagation of Rossby waves. However, there is evidence of Rossby wave propagation only during 1972–90. Here it is suggested that the nonstationarity of Rossby wave propagation caused the time lag between the NAO and the GSF shifts on the decadal time scale to differ between the two time periods.

A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species. Furthermore, our rat model confirmed that vitamin E in the prostate has a powerful booster effect on CYP enzymes associated with the generation of oxidative stress, thereby favoring lipid-derived electrophile spread that covalently modifies proteins. We show that vitamin E not only causes DNA damage but also promotes cell transformation frequency induced by the PAH-prototype benzo[a]pyrene. Our findings might explain why dietary supplementation with vitamin E increases the prostate cancer risk among healthy men.

Sustainability and circular economy are increasingly pushing for the search of natural materials to foster antiparasitic treatments, especially in the case of economically relevant agricultural cultivations, such as grapevine. In this work, we propose to deliver neem oil, a natural biopesticide loaded into novel nanovectors (nanocapsules) which were fabricated using a scalable procedure starting from Kraft lignin and grapeseed tannins. The obtained formulations were characterized in terms of size and Zeta potential, showing that almost all the nanocapsules had size in the suitable range for delivery purposes (mean diameter 150–300 nm), with low polydispersity and sufficient stability to ensure long shelf life. The target microorganisms were three reference fungal pathogens of grapevine ( Botrytis cinerea , Phaeoacremonium minimum , Phaeomoniella chlamydospora ), responsible for recurrent diseases on this crop: grey mold or berry rot by B. cinerea and diseases of grapevine wood within the Esca complex of diseases. Results showed that grapeseed tannins did not promote inhibitory effects, either alone or in combination with Kraft lignin. On the contrary, the efficacy of neem oil against P. minimum was boosted by more than 1–2 orders of magnitude and the parasite growth inhibition was higher with respect to a widely used commercial pesticide, while no additional activity was detected against P. chlamydospora and B. cinerea .