Effects of Angiopoietin-2-Blocking Antibody on Endothelial Cell–Cell Junctions and Lung Metastasis

Background: Angiopoietin-2 (Ang2), a ligand for endothelial TEK (Tie2) tyrosine kinase receptor, is induced in hypoxic endothelial cells of tumors, where it promotes tumor angiogenesis and growth. However, the effects of Ang2 on tumor lymphangiogenesis and metastasis are poorly characterized. Methods: We addressed the effect of Ang2 on tumor progression and metastasis using systemic Ang2 overexpression in mice carrying tumor xenografts, endothelium-specific overexpression of Ang2 in VEC-tTA/Tet-OS-Ang2 transgenic mice implanted with isogenic tumors, and administration of Ang2-blocking antibodies to tumor-bearing immunodeficient mice. Fisher's exact test was used for analysis of metastasis occurrence, and repeated measures one-way analysis of variance was used for the analysis of primary tumor growth curves. Unpaired t test was used for all other analyses. All statistical tests were two-sided. Results: Adenoviral expression of Ang2 increased lymph node and lung metastasis in tumor xenografts. The metastatic burden in the lungs was increased in transgenic mice in which Ang2 expression was induced specifically in the vascular endothelium (tumor burden per grid, VEC-tTA/Tet-OS-Ang2 mice [n = 5] vs control mice [n = 4]: 45.23 vs 12.26 mm[superscript 2], difference = 32.67 mm[superscript 2], 95% confidence interval = 31.87 to 34.07, P < .001). Ang2-blocking antibodies reduced lymph node and lung metastasis, as well as tumor lymphangiogenesis, and decreased tumor cell homing to the lungs after intravenous injection. In the lung metastases, Ang2 overexpression decreased endothelial integrity, whereas the Ang2-blocking antibodies improved endothelial cell–cell junctions and basement membrane contacts of metastasis-associated lung capillaries. At the cellular level, the Ang2-blocking antibodies induced the internalization of Ang2-Tie2 receptor complexes from endothelial cell–cell junctions in endothelial–tumor cell cocultures. Conclusion: Our results indicate that blocking Ang2 inhibits metastatic dissemination in part by enhancing the integrity of endothelial cell–cell junctions

Physiological differences between two overlapped breeding Antarctic penguins in a global change perspective

This article is an invited contribution on Life in Antarctica: Boundaries and Gradients in a Changing Environment as the main theme of the XIth SCAR Biology Symposium. J.-M. Gili and R. Zapata Guardiola (Guest Editors).Global change has affected the Antarctic Peninsula influencing the abundance of krill, one of the main preys of penguins. In areas where breeding penguin populations overlap, species with a more diverse diet have generally been less affected than krill-specialist species, which have shown population declines. Human activities can add to these changes, as penguins are sensitive to anthropic impacts such as contamination. Our objective was to assess whether selected physiological parameters of Adélie and Gentoo penguins reflect their contrasting population trends in a colony located at Punta Stranger (25 de Mayo Island/King George, South Shetland Islands) where they breed sympatrically. During 2012, we assessed the leukocyte profile, heterophil to lymphocyte ratio (H/L), erythrocytic nuclear abnormalities (ENAs), hematocrit, biochemical profile, and a measure of immune function (bacterial agglutination) in adults and chicks of both species. Higher values of ENAs, indicative of genotoxic damage caused by contaminants, are in accordance with a greater sensitivity to ongoing global changes by Adélie penguins. Levels of cholesterol and triglycerides strengthen this idea since individuals could be investing more resources in energy reserves to successfully cope with challenging environmental conditions during the breeding season. The remaining physiological parameters did not provide a clear picture. Furthermore, some results could be related to differences in diet. Gentoos show greater prey diversity than Adélie penguins, incorporating a richer parasite fauna, which could explain their higher heterophils and H/L. The physiological parameters measured here serve as baseline for a sustained monitoring of these rapidly changing populations. Further physiological variables, including stress hormone and indices of oxidative stress, remain to be assessed as potential indicators of population susceptibility to global change in this system.AB was supported by the project CTM2011-24425.Peer Reviewe

Phylogenetic analyses reveal that Schellackia parasites (Apicomplexa) detected in American lizards are closely related to the genus Lankesterella: is the range of Schellackia restricted to the Old World?

Abstract Background Species of Schellackia Reichenow, 1919 have been described from the blood of reptiles distributed worldwide. Recently, Schellackia spp. detected in European and Asian lizards have been molecularly characterised. However, parasites detected in American lizard hosts remain uncharacterised. Thus, phylogenetic affinities between the Old and New World parasite species are unknown. Methods In the present study, we characterised morphologically and molecularly the hemococcidian parasites (sporozoites) that infect three lizard hosts from North America and two from South America. Results In total, we generated 12 new 18S rRNA gene sequences of hemococcidian parasites infecting New World lizard hosts. By the microscopic examination of the smears we identified Schellackia golvani Rogier & Landau, 1975 (ex Anolis carolinensis Voigt) and Schellackia occidentalis Bonorris & Ball, 1955 (ex Uta stansburiana Baird & Girard and Sceloporus occidentalis Baird & Girard) in some samples, but the phylogenetic analysis indicated that all 18S rDNA sequences are distant from Schellackia species found in Old World lizards. In fact, the hemococcidian parasites detected in the New World lizards (including S. occidentalis and S. golvani) were closely related to the genus Lankesterella Labbé, 1899. Consequently, we suggest these two species to be included within the genus Lankesterella. Conclusions Life history traits of hemococcidian parasites such as the type of host blood cells infected, host species or number of refractile bodies are not valid diagnostic characteristics to differentiate the parasites between the genera Schellackia and Lankesterella. Indeed, lankesterellid parasites with a different number of refractile bodies had a close phylogenetic origin. Based on the phylogenetic results we provide a systematic revision of the North American hemococcidians. Our recommendation is to include the species formerly described in the genus Schellackia that infect American lizards into Lankesterella (Lankesterellidae) as Lankesterella golvani (Rogier & Landau, 1975) n. comb and L. occidentalis (Bonorris & Ball, 1955) n. comb

Dificultades técnicas en el dosaje de testosterona

ResumenObjetivoAnálisis bibliográfico de las limitaciones y dificultades técnicas en el dosaje de testosterona total (TT).Materiales y métodosRevisión de trabajos publicados en diferentes bases de datos desde 2003 hasta el 2014 (PubMed, Biblioteca Virtual de Salud, Cochrane). Evaluación y comparación del dosaje de TT sérica utilizando métodos disponibles en nuestro país, validados por LC-MS/MS y no validados por LC-MS/MS.ResultadosElaboración de una monografía en la que se evalúan los problemas técnicos en el dosaje de TT en la actualidad.AbstractObjectiveBibliographic analysis of the constraints and technical difficulties in the total testosterone (TT) assay.MethodsReview of articles published in various databases from 2003 to 2014. (PubMed, Health Library, Cochrane). Evaluation and comparison of serum TT assays using the different methods available in our country, validated or not validated by LC-MS/MS.ResultsDevelopment of a monograph in which technical problems are evaluated in current TT assays

Tie1 controls angiopoietin function in vascular remodeling and inflammation

The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1- and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability

Author Correction: Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth

Correction to: Nature Communications https://doi.org/10.1038/s41467-020-16618-6, published online 04 June 2020The original version of this Article contained errors in Supplementary Fig. 1d in which the H&amp;E stained sections of lung, heart and liver from the mice were incorrect. These errors have been corrected in the HTML and PDF versions of the Article.</p

Minimum inhibitory concentrations (in μg/mL) of recombinant <i>E</i>. <i>coli</i> producing LRA-12 β-lactamase.

<p>Minimum inhibitory concentrations (in μg/mL) of recombinant <i>E</i>. <i>coli</i> producing LRA-12 β-lactamase.</p

Detail of the active site of LRA-12 β-lactamase.

<p>The <i>2F</i>_<i>0</i> <i>–F</i>_<i>c</i> map was contoured at 1.5 σ (in grey) around the most important amino acid residues that are part of the metal-binding sites in the active site cavity: Gln116-His118-His196 (Site 1; QHH), and Asp120-His121-His263 (Site 2; DHH). Zinc ions (Zn1 and Zn2) are shown as magenta spheres.</p

Sequence analysis on LRA-12 protein.

<p>(a) Multi-alignment of amino acid sequences of LRA-12 and other representative class B3 β-lactamases, using the class B standard numbering scheme. Only the four more conserved segments of the sequences are shown for easier visualization. Location of α-helices and β-sheets is indicated in the upper side (taken from the PDB file), and relative solvent accessibility in the bottom (blue: highly accessible; cyan: poorly accessible; white: hidden or non-accessible). Blue and pink stars indicate the position of conserved residues in metal-binding sites 1 and 2, respectively (see text for further details). The figure was prepared using Espript (<a href="http://espript.ibcp.fr/ESPript/ESPript/" target="_blank">http://espript.ibcp.fr/ESPript/ESPript/</a>). (b) Neighbor joining tree constructed using class B β-lactamases sequences from the three different sub-classes.</p