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1. A novel peptide inhibitor of Dll4‐Notch1 signalling and its pro‐angiogenic functions

   https://doi.org/10.1111/bph.15743  

   Zhu, Guofu ; Lin, Ying ; Ge, Tandi ; Singh, Shekhar ; Liu, Hao ; Fan, Linlin ; Wang, Shumin ; Rhen, Jordan ; Jiang, Dongyang ; Lyu, Yuyan ; et al ( January 2022 , British Journal of Pharmacology)

   The Dll4‐Notch1 signalling pathway plays an important role in sprouting angiogenesis, vascular remodelling and arterial or venous specificity. Genetic or pharmacological inhibition of Dll4‐Notch1 signalling leads to excessive sprouting angiogenesis. However, transcriptional inhibitors of Dll4‐Notch1 signalling have not been described.

   We designed a new peptide targeting Notch signalling, referred to as TAT‐ANK, and assessed its effects on angiogenesis. In vitro, tube formation and fibrin gel bead assay were carried out, using human umbilical vein endothelial cells (HUVECs). In vivo, Matrigel plug angiogenesis assay, a developmental retinal model and tumour models in mice were used. The mechanisms underlying TAT‐ANK activity were investigated by immunochemistry, western blotting, immunoprecipitation, RT‐qPCR and luciferase reporter assays.

   The amino acid residues 179–191 in the G‐protein‐coupled receptor‐kinase‐interacting protein‐1 (GIT1‐ankyrin domain) are crucial for GIT1 binding to the Notch transcription repressor, RBP‐J. We designed the peptide TAT‐ANK, based on residues 179–191 in GIT1. TAT‐ANK significantly inhibited Dll4 expression and Notch 1 activation in HUVECs by competing with activated Notch1 to bind to RBP‐J. The analyses of biological functions showed that TAT‐ANK promoted angiogenesis in vitro and in vivo by inhibiting Dll4‐Notch1 signalling.

   We synthesized and investigated the biological actions of TAT‐ANK peptide, a new inhibitor of Notch signalling. This peptide will be of significant interest to research on Dll4‐Notch1 signalling and to clinicians carrying out clinical trials using Notch signalling inhibitors. Furthermore, our findings will have important conceptual and therapeutic implications for angiogenesis‐related diseases.

    

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2. Pericyte heterogeneity identified by 3D ultrastructural analysis of the microvessel wall

   https://doi.org/10.3389/fphys.2022.1016382  

   Abdelazim, Hanaa ; Payne, Laura Beth ; Nolan, Kyle ; Paralkar, Karan ; Bradley, Vanessa ; Kanodia, Ronak ; Gude, Rosalie ; Ward, Rachael ; Monavarfeshani, Aboozar ; Fox, Michael A. ; et al ( December 2022 , Frontiers in Physiology)

   Confident identification of pericytes (PCs) remains an obstacle in the field, as a single molecular marker for these unique perivascular cells remains elusive. Adding to this challenge is the recent appreciation that PC populations may be heterogeneous, displaying a range of morphologies within capillary networks. We found additional support on the ultrastructural level for the classification of these PC subtypes—“thin-strand” (TSP), mesh (MP), and ensheathing (EP)—based on distinct morphological characteristics. Interestingly, we also found several examples of another cell type, likely a vascular smooth muscle cell, in a medial layer between endothelial cells (ECs) and pericytes (PCs) harboring characteristics of the ensheathing type. A conserved feature across the different PC subtypes was the presence of extracellular matrix (ECM) surrounding the vascular unit and distributed in between neighboring cells. The thickness of this vascular basement membrane was remarkably consistent depending on its location, but never strayed beyond a range of 150–300 nm unless thinned to facilitate closer proximity of neighboring cells (suggesting direct contact). The density of PC-EC contact points (“peg-and-socket” structures) was another distinguishing feature across the different PC subtypes, as were the apparent contact locations between vascular cells and brain parenchymal cells. In addition to this thinning, the extracellular matrix (ECM) surrounding EPs displayed another unique configuration in the form of extensions that emitted out radially into the surrounding parenchyma. Knowledge of the origin and function of these structures is still emerging, but their appearance suggests the potential for being mechanical elements and/or perhaps signaling nodes via embedded molecular cues. Overall, this unique ultrastructural perspective provides new insights into PC heterogeneity and the presence of medial cells within the microvessel wall, the consideration of extracellular matrix (ECM) coverage as another PC identification criteria, and unique extracellular matrix (ECM) configurations (i.e., radial extensions) that may reveal additional aspects of PC heterogeneity. 

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3. Cell force-mediated matrix reorganization underlies multicellular network assembly

   https://doi.org/10.1038/s41598-018-37044-1  

   Davidson, Christopher D. ; Wang, William Y. ; Zaimi, Ina ; Jayco, Danica Kristen P. ; Baker, Brendon M. ( January 2019 , Scientific Reports)

   Vasculogenesis is thede novoformation of a vascular network from individual endothelial progenitor cells occurring during embryonic development, organogenesis, and adult neovascularization. Vasculogenesis can be mimicked and studiedin vitrousing network formation assays, in which endothelial cells (ECs) spontaneously form capillary-like structures when seeded in the appropriate microenvironment. While the biochemical regulators of network formation have been well studied using these assays, the role of mechanical and topographical properties of the extracellular matrix (ECM) is less understood. Here, we utilized both natural and synthetic fibrous materials to better understand how physical attributes of the ECM influence the assembly of EC networks. Our results reveal that active cell-mediated matrix recruitment through actomyosin force generation occurs concurrently with network formation on Matrigel, a reconstituted basement membrane matrix regularly used to promote EC networks, and on synthetic matrices composed of electrospun dextran methacrylate (DexMA) fibers. Furthermore, modulating physical attributes of DexMA matrices that impair matrix recruitment consequently inhibited the formation of cellular networks. These results suggest an iterative process in which dynamic cell-induced changes to the physical microenvironment reciprocally modulate cell behavior to guide the formation and stabilization of multicellular networks.

    

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4. Increasing phylogenetic stochasticity at high elevations on summits across a remote North American wilderness

   https://doi.org/10.1002/ajb2.1328  

   Marx, Hannah E. ; Richards, Melissa ; Johnson, Grahm M. ; Tank, David C. ( July 2019 , American Journal of Botany)

   At the intersection of ecology and evolutionary biology, community phylogenetics can provide insights into overarching biodiversity patterns, particularly in remote and understudied ecosystems. To understand community assembly of the high alpine flora in the Sawtooth National Forest,USA, we analyzed phylogenetic structure within and between nine summit communities.

   We used high‐throughput sequencing to supplement existing data and infer a nearly completely sampled community phylogeny of the alpine vascular flora. We calculated mean nearest taxon distance (MNTD) and mean pairwise distance (MPD) to quantify phylogenetic divergence within summits, and assessed whether maximum elevation explains phylogenetic structure. To evaluate similarities between summits, we quantified phylogenetic turnover, taking into consideration microhabitats (talus vs. meadows).

   We found different patterns of community phylogenetic structure within the six most species‐rich orders, but across all vascular plants phylogenetic structure was largely not different from random. There was a significant negative correlation between elevation and tree‐wide phylogenetic diversity (MPD) within summits: overdispersion degraded as elevation increased. Between summits, we found high phylogenetic turnover driven by greater niche heterogeneity on summits with alpine meadows.

   Our results provide further evidence that stochastic processes may also play an important role in the assembly of vascular plant communities in high alpine habitats at regional scales. However, order‐specific patterns suggest that adaptations are still important for assembly of specific sectors of the plant tree of life. Further studies quantifying functional diversity will be important in disentangling the interplay of eco‐evolutionary processes that likely shape broad community phylogenetic patterns in extreme environments.

    

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5. Bryophytes in fir waves: Forest canopy indicator species and functional diversity decline in canopy gaps

   https://doi.org/10.1111/jvs.12718  

   Berdugo, Monica B. ; Dovciak, Martin ; Nakashizuka, ed., Tohru ( March 2019 , Journal of Vegetation Science)

   Bryophytes can cover three quarters of the ground surface, play key ecological functions, and increase biodiversity in mesic high‐elevation conifer forests of the temperate zone. Forest gaps affect species coexistence (and ecosystem functions) as suggested by the gap and gap‐size partitioning hypotheses (GPH,G_SPH). Here we test these hypotheses in the context of high‐elevation forest bryophyte communities and their functional attributes.

   Spruce–fir forests on Whiteface Mountain, NY,USA.

   We characterized canopy openness, microclimate, forest floor substrates, vascular vegetation cover, and moss layer (cover, common species, and functional attributes) in three canopy openness environments (gap, gap edge, forest canopy) across 20 gaps (fir waves) (n = 60); the functional attributes were based on 16 morphologic, reproductive, and ecological bryophyte plant functional traits (PFTs). We testedGPHandG_SPHrelative to bryophyte community metrics (cover, composition), traits, and trait functional sensitivity (functional dispersion;FDis) using indicator species analysis, ordination, and regression.

   Canopy openness drove gradients in ground‐level temperature, substrate abundance and heterogeneity (beta diversity), and understory vascular vegetation cover. TheGPHwas consistent with (a) the abundance patterns of forest canopy indicator species (Dicranum fuscescens,Hypnum imponens, andTetraphis pellucida), and (b)FDisbased on threePFTs (growth form, fertility, and acidity), both increasing with canopy cover. We did not find support forGPHin the remaining species or traits, or forG_SPHin general; gap width (12–44 m) was not related to environmental or bryophyte community gradients.

   The observed lack of variation in most bryophyte metrics across canopy environments suggests high resistance of the bryophyte layer to natural canopy gaps in high‐elevation forests. However, responses of forest canopy indicator species suggest that canopy mortality, potentially increased by changing climate or insect pests, may cause declines in some forest canopy species and consequently in the functional diversity of bryophyte communities.

    

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