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Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies. Endothelial cells undergo rearrangements during angiogenic sprouting. Gerhardt and colleagues show that the flux in Notch signalling levels in individual cells of sprouting vessels results in differential dynamics of VE-cadherin at junctions to drive functional endothelial cell rearrangements during sprouting. They also find that differential VE-cadherin dynamics are affected in retinopathy and tumour vessels.

Characteristics of vineyard soils and management practices can be assessed to determine the soil trend evolution, risks, and limits of soils for vine production through soil factors and foliar diagnosis. This study was made with soils from a vineyard divided into two plots belonging to the Rías Baixas D.O. The vineyard soils were sampled and characterized for three years. The total and available Cu and Zn contents and the physicochemical characteristics of the soils were determined annually and every four months, respectively. The main objective was to assess edaphic properties, phytosanitary treatments, fertilization, and tillage applied to indicate the quality of the vineyard soils. The soils presented certain limitations associated with mechanization, trafficability, and ease of tillage for cultivation. The soils showed a sandy loam texture, which makes the application of compost necessary to improve water retention and cation exchange capacity. Phytosanitary treatments and fungicides caused phytotoxic contents of Cu and Zn in the soils without being detrimental to the vines. In conclusion, the edaphic factors and foliar analysis were adequate to evaluate the condition of the soils and vines and to establish the necessary measures to improve the edaphic conditions of the vineyard soils to improve plant production.

Background Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. Methods Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as “non-progressors” if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. Results Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P  = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative ( P  = 0.73). Non-progressors’ tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased T REG signatures in gene expression studies in baseline—post-bevacizumab—tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating T REGs in non-progressors. Conclusions This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing T REGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. Trial registration ( www.clinicaltrials.gov): NCT02802098 . Registered on June 16, 2020.

This study investigates the potential use of Lolium perenne L. as a cover crop to improve vineyard soils with varying levels of copper (Cu). Cu-based fungicides are commonly used to control fungal diseases in vineyards, but their accumulation in soils poses environmental risks. This study aims to address this issue by evaluating the influence of soil properties on Cu availability and L. perenne growth. A total of 42 vineyard soils from different Designations of Origin (D.O.s) in Galicia were sampled and their physicochemical properties were analyzed. The results showed most soils exceeded recommended Cu limits due to fungicide applications. Pot experiments were conducted to assess L. perenne growth and Cu accumulation. L. perenne biomass did not vary significantly with total soil Cu content, indicating that other factors such as organic matter and cation exchange capacity were more important for plant growth. While L. perenne showed Cu tolerance, its aerial Cu accumulation was inversely correlated with available Cu. This study provides insight into the potential of L. perenne as a cover crop for sustainable vineyard management and soil improvement and emphasizes the importance of considering Cu accumulation from fungicide applications.

The power flow model performs the analysis of electric distribution and transmission systems. With this statement at hand, in this work we present a summary of those solvers for the power flow equations, in both algebraic and parametric version. The application of the Alternating Search Direction method to the power flow problem is also detailed. This results in a family of iterative solvers that combined with Proper Generalized Decomposition technique allows to solve the parametric version of the equations. Once the solution is computed using this strategy, analyzing the network state or solving optimization problems, with inclusion of generation in real-time, becomes a straightforward procedure since the parametric solution is available. Complementing this approach, an error strategy is implemented at each step of the iterative solver. Thus, error indicators are used as an stopping criteria controlling the accuracy of the approximation during the construction process. The application of these methods to the model IEEE 57-bus network is taken as a numerical illustration.

The inhibition of anabolic pathways, such as aerobic glycolysis, is a metabolic cornerstone of memory T cell differentiation and function. However, the signals that hamper these anabolic pathways are not completely known. Recent evidence pinpoints the chemokine receptor CCR5 as an important player in CD4 + T cell memory responses by regulating T cell antigen receptor (TCR) nanoclustering in an antigen-independent manner. This paper reports that CCR5 specifically restrains aerobic glycolysis in memory-like CD4 + T cells, but not in effector CD4 + T cells. CCR5-deficient memory CD4 + T cells thus show an abnormally high glycolytic/oxidative metabolism ratio. No CCR5-dependent change in glucose uptake nor in the expression of the main glucose transporters was detected in any of the examined cell types, although CCR5-deficient memory cells did show increased expression of the hexokinase 2 and pyruvate kinase M2 isoforms, plus the concomitant downregulation of Bcl-6, a transcriptional repressor of these key glycolytic enzymes. Further, the TCR nanoclustering defects observed in CCR5-deficient antigen-experienced CD4 + T cells were partially reversed by incubation with 2-deoxyglucose (2-DG), suggesting a link between inhibition of the glycolytic pathway and TCR nanoscopic organization. Indeed, the treatment of CCR5-deficient lymphoblasts with 2-DG enhanced IL-2 production after antigen re-stimulation. These results identify CCR5 as an important regulator of the metabolic fitness of memory CD4 + T cells, and reveal an unexpected link between T cell metabolism and TCR organization with potential influence on the response of memory T cells upon antigen re-encounter.

Background Wolf-Hirschhorn Syndrome (WHS) is a rare, congenital disease characterized by a distinctive facial phenotype, seizures, intellectual disability and developmental delay, and pre and postnatal growth requiring lifelong care. The psychosocial status of the family caregivers of children diagnosed with WHS is unknown. This study aims to characterize the sociodemographic and psychosocial profile of WHS caregivers and analyze how these variables impact their quality of life (QoL) and well-being. Results The sociodemographic and clinical profile of 22 Spanish caregivers of children with WHS and the characteristics of those affected have been described. Significant relationships were found between sociodemographic and psychosocial characteristics among caregivers. The impact on the parents’ QoL and negative relationship with the symptomatology were assessed. The use of engagement strategies such as problem focused coping was associated with improved psychological QoL and social support. Conclusions WHS caregivers share similarities in their profile and needs with caregivers of children with other rare diseases. Pychosocial support groups involving parents caring for children with the same disease could improve caregivers’ well-being and QoL by strengthening their social support network and using positive coping styles.

Formation of a regularly branched blood vessel network is crucial in development and physiology. Here we show that the expression of the Notch ligand Dll4 fluctuates in individual endothelial cells within sprouting vessels in the mouse retina in vivo and in correlation with dynamic cell movement in mouse embryonic stem cell-derived sprouting assays. We also find that sprout elongation and branching associates with a highly differential phase pattern of Dll4 between endothelial cells. Stimulation with pathologically high levels of Vegf, or overexpression of Dll4, leads to Notch dependent synchronization of Dll4 fluctuations within clusters, both in vitro and in vivo. Our results demonstrate that the Vegf-Dll4/Notch feedback system normally operates to generate heterogeneity between endothelial cells driving branching, whilst synchronization drives vessel expansion. We propose that this sensitive phase transition in the behaviour of the Vegf-Dll4/Notch feedback loop underlies the morphogen function of Vegfa in vascular patterning. Throughout life, blood vessels are constantly remodelled to ensure that oxygen and nutrients reach every part of the body where they are needed. If a tissue is not receiving an adequate blood flow, existing blood vessels may widen or new blood vessels may sprout from their walls. In certain diseases, such as cancer, blood vessels may grow excessively to form disorganized networks, and preventing this growth may help to treat these conditions. However, we do not fully understand how the body controls the size, shape and branching pattern of blood vessels. For a new blood vessel to sprout out of an existing vessel, the tip of the new branch must first develop. The tip forms when the endothelial cells that line the blood vessel are activated by a protein called vascular endothelial growth factor A (Vegfa), which is produced by the surrounding tissue. The activated endothelial cells respond to Vegfa stimulation by producing the protein Dll4, which talks to neighboring endothelial cells to prevent them from also forming new tips. In a way, this process bears all the signs of a competition between cells, as they fight for which one is allowed to take the lead. The losers of this competition, when forced into subordination by the tips, also serve an important function, as they will help to form and elongate the base of the new sprout. Although it is known that changes in the levels of Vegfa in tissues can cause blood vessel branching to alter dramatically, the mechanisms that enable this to occur are not well understood. Computer simulations of the process predicted that an unexpected synchronization of Dll4 dynamics would be triggered when Vegfa levels increased; however, this remained to be observed in real cells. Ubezio, Blanco et al. have now used fluorescent markers to observe the Dll4 production in lab-grown mouse endothelial cells as they formed new vessel sprouts in response to Vegfa. This revealed that the levels of Dll4 fluctuate widely in individual cells. Time-lapse movies of the cells showed that as a new sprout forms, the levels of Dll4 in neighbouring cells fluctuate in an uncoordinated manner. However, increasing the amount of Vegfa in the cells indeed synchronizes these fluctuations. This causes the new sprout to retract and allows the original blood vessel to widen. Increasing the levels of Dll4 had the same effect. Further experiments confirmed that increasing the amount of Vegfa also reduces blood vessel branching in tumours in mice by synchronizing the fluctuations in the levels of Dll4 in neighbouring endothelial cells. In the future, these results could help refine anti-cancer treatments that work by blocking the activity of Vegfa and Dll4.

Telomeres are heterochromatic structures at chromosome ends essential for chromosomal stability. Telomere shortening and the accumulation of dysfunctional telomeres are associated with organismal aging. Using telomerase-deficient TRF2-overexpressing mice $(K5TRF2/Terc^{-/-})$ as a model for accelerated aging, we show that telomere shortening is paralleled by a gradual deregulation of the mammalian transcriptome leading to cumulative changes in a defined set of genes, including up-regulation of the mTOR and Akt survival pathways and down-regulation of cell cycle and DNA repair pathways. Increased DNA damage from dysfunctional telomeres leads to reduced deposition of H3K27me3 onto the inactive X chromosome (Xi), impaired association of the Xi with telomeric transcript accumulations (Tacs), and reactivation of an X chromosome-linked K5TRF2 transgene that is subjected to X-chromosome inactivation in female mice with sufficiently long telomeres. Exogenously induced DNA damage also disrupts Xi-Tacs, suggesting DNA damage at the origin of these alterations. Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging.