1,721,131 research outputs found
G12/G13 family G proteins regulate marginal zone B cell maturation, migration, and polarization
No full textG protein-coupled receptors play an important role in the regulation of lymphocyte functions such as migration, adhesion, proliferation, and differentiation. Although the role of G(i) family G proteins has been intensively studied, no in vivo data exist with respect to G12/G13 family G proteins. We show in this study that mice that lack the G protein alpha-subunits G alpha12 and G alpha13 selectively in B cells show significantly reduced numbers of splenic marginal zone B (MZB) cells, resulting in a delay of Ab production in response to thymus-independent Ags. Basal and chemokine-induced adhesion to ICAM-1 and VCAM-1, two adhesion molecules critically involved in MZB localization, is normal in mutant B cells, and the same is true for chemokine-induced migration. However, migration in response to serum and sphingosine 1-phosphate is strongly increased in mutant MZB cells, but not in mutant follicular B cells. Live-cell imaging studies revealed that G alpha12/G alpha13-deficient MZB cells assumed more frequently an ameboid form than wild-type cells, and pseudopod formation was enhanced. In addition to their regulatory role in serum- and sphingosine 1-phosphate-induced migration, G12/G13 family G proteins seem to be involved in peripheral MZB cell maturation, because also splenic MZB cell precursors are reduced in mutant mice, although less prominently than mature MZB cells. These data suggest that G12/G13 family G proteins contribute to the formation of the mature MZB cell compartment both by controlling MZB cell migration and by regulating MZB cell precursor maturation
Lysophospholipids control integrin-dependent adhesion in splenic B cells through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11)
No full textIntegrin-mediated adhesion is a crucial step in lymphocyte extravasation and homing. We show here that not only the chemokines CXCL12 and CXCL13 but also the lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) enhance adhesion of murine follicular and marginal zone B cells to ICAM-1 in vitro. This process involves clustering of integrin LFA-1 and is blocked by pertussis toxin, suggesting that G(i) family G-proteins are involved. In addition, lysophospholipid-induced adhesion on ICAM-1 depends on Rho and Rhokinase, indicative of an involvement of G(12)/G(13), possibly also G(q)/G(11) family G-proteins. We used G(12)/G(13)- or G(q)/G(11)-deficient B cells to study the role of these G-protein families in lysophospholipid-induced adhesion and found that the pro-adhesive effects of LPA and S1P are completely abrogated in G(12)/G(13)-deficient marginal zone B cells, reduced in G(12)/G(13)-deficient follicular B cells, and normal in G(q)/G(11)-deficient B cells. We also show that loss of lysophospholipid-induced adhesion results in disinhibition of migration in response to the follicular chemokine CXCL13, which might contribute to the abnormal localization of splenic B cell populations observed in B cell-specific G(12)/G(13)-deficient mice in vivo. Taken together, this study shows that lysophospholipids regulate integrin-mediated adhesion of splenic B cells to ICAM-1 through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11)
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
AMP-activated protein kinase
No full textAMP-activated protein kinase (AMPK) is a member of the serine/threonine protein kinase family, which modify other proteins (target proteins) by attaching phosphate groups to the side chains of serine or threonine, thus modifying their function. The primary role of AMPK is to sense energy status by monitoring the cellular ratios of AMP:ATP and ADP:AMP. Once activated by energy stress, AMPK acts to restore homeostasis by switching off downstream processes consuming ATP (such as cell growth and proliferation) while switching on catabolic processes generating ATP (such as glucose uptake and mitochondrial biogenesis). AMPK is also involved in regulating whole-body energy balance and has been identified as a key target in treating disorders such as obesity and type 2 diabetes.<br/
Uloga tumorskog endotelnog markera 1 u metastaziranju pluća
No full textCancer relapse is driven by dormant tumor cells that are able to reactivate after perturbations in
the microenvironmental niche. Endothelium-derived protein multimerin 2 (MMRN2) is
hypothesized to induce tumor reawakening through the interaction with tumor endothelial
marker 1 (TEM1). The main objective of this study was to assess the MMRN2-TEM1 axis in
reactivation and proliferation of B16F10 melanoma and E0771 breast cancer cells, and
elucidate function of TEM1 in lung metastasis. The MMRN2-TEM1 axis, induced by a coculture system comprised of endothelial cells and tumor cells, has demonstrated to stimulate
phosphorylation of ERK1/2. Individual addition of PDGFB and MMRN2 fragments to dormant
tumor cells caused their reactivation, conceivably through the TEM1-PDGFRB pathway. In
vivo results have shown that absence of TEM1 does not influence primary tumor growth nor
extravasation, but reduces macrometastasis formation in both intravenous and resection models
of lung metastasis. These in vivo results suggest that TEM1 could be implicated in tumor mass
dormancy. Computational models have shown significant correlation of TEM1 and PDGFRB
as a prediction marker of low survival rates and higher relapse in various tumor types.
Therefore, this study presents a pioneering research in defining the MMRN2-TEM1
reactivation axis as a potential target for state-of-the-art, personalized therapies intended for
patients in remission.Ponovnu pojavu tumora uzrokuju dormantne tumorske stanice koje su sposobne reaktivirati se
uslijed promjena u mikrookolišnoj niši. Za endotelni protein multimerin 2 (MMRN2) se
pretpostavlja da inducira nastanak tumora, stupanjem u interakciju s tumorskim endotelnim
markerom 1 (TEM1). Glavni cilj ovoga rada bio je procijeniti ulogu osi MMRN2-TEM1 u
reaktivaciji i proliferaciji stanica melanoma B16F10 i stanica tumora dojke E0771 te razjasniti
funkciju proteina TEM1 u metastaziranju pluća. Pokazano je da os MMRN2-TEM1, inducirana
kokulturom endotelnih stanica i tumorskih stanica, može stimulirati fosforilaciju proteina
ERK1/2. Pojedinačni dodaci proteina PDGFRB i fragmenata MMRN2 dormantnim tumorskim
stanicama uzrokovali su njihovu reaktivaciju, potencijalno signalnim putem TEM1-PDGFRB.
Rezultati in vivo su pokazali da nedostatak proteina TEM1 ne utječe na rast primarnog tumora
ni proces ekstravazacije, ali smanjuje formaciju makrometastaza u intravenoznom i
resekcijskom modelu plućnog metastaziranja. Navedeni rezultati in vivo upućuju na to da
protein TEM1 može biti uključen u regulaciju tumorske mase tijekom dormancije. Računalni
modeli su ukazali na značajnu povezanost proteina TEM1 i proteina PDGFRB kao
predikcijskog markera smanjenog preživljenja i češće ponovne pojave tumora kod brojnih
tipova tumora. Ovaj rad predstavlja inicijalno istraživanje u definiranju reaktivacijske osi
MMRN2-TEM1, kao potencijalne mete suvremenih, personaliziranih terapija namijenjenih
pacijentima u remisiji
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Proteinase-activated receptors (PARs)
No full textProteinase-activated receptors (PARs) are a unique family of G-protein-coupled receptors (GPCRs) that are activated in response to serine proteinases. There are four PAR family members; PAR-1 through to PAR-4. PAR-1 and PAR-3 respond to thrombin, PAR-2 responds to trypsin, whilst PAR-4 is sensitive to both thrombin- and trypsin-related proteinases
The Amyloid Precursor Protein Family and its Functional Role in Endothelium
Full text linkAmyloid Precursor Protein (APP), Amyloid Precursor-like Protein 1 (APLP1) and APLP2, are part of the APP protein family. They are characterized as type 1 single-pass transmembrane proteins. APP and APLP2 are ubiquitously expressed, whereas APLP1 is restricted to neuronal tissue. Consequently, I decided to focus solely on APP and APLP2 in my studies. The strong conservation of APP and APLP2 from invertebrates to humans implies they have fundamental roles in cellular function. They show high structural similarities. However, the amyloid β (Aβ) sequence, which is known to play a critical role in the development of Alzheimer’s disease, is not expressed in APLP2. Several studies have suggested that APP and APLP2 might act like cell surface receptor-like proteins or ligands. The suggested functions range from playing a role in transcriptional regulation to synaptic functions or involvement in cell adhesion. In contrast to the single App or Aplp2 knockout mice, gene deficiency for both genes is perinatal lethal. Therefore, it is assumed that both genes have, at least in part, overlapping functions during development. Apart from its involvement in Alzheimer’s disease, the function of APP and APLP2 remain poorly understood.
According to our RNA sequencing data, APP and APLP2 are among the most highly expressed genes in endothelial cells. Therefore, I hypothesized that they have a critical, yet unknown role in either the development or functionality of blood vessels. The aim of this study was to unravel the function of APP and APLP2 within the endothelium. APP and APLP2 can potentially affect a wide array of endothelial cell-related processes, such as inflammation, vessel remodeling and regulation of blood homeostasis and vascular permeability. To identify the most suitable mouse model for App and/or Aplp2 endothelial-specific knockout (KO) mice, I initiated a series of in vitro experiments. The particular focus on the role of APP and/or APLP2 in angiogenesis stemmed from my intriguing observation of compromised tube formation in HUVECs subsequent to the double knockdown (KD) of both APP and APLP2 in an in vitro matrigel assay. As a next step, I used
different in vivo models to investigate a potential role of the protein family in angiogenesis in vivo. Hereby, I observed fewer muscle fibers, less proliferation and a dilated vessel perimeter in double KO mice 28 days after femoral artery ligation. However, no significant differences directly related to the KO of App and Aplp2 in the endothelium were detected.
Overall, these results describe an important role of APP in angiogenesis in vitro that could not be compensated by APLP2. However, the underlying mechanisms in vivo appear to be much more complex and could potentially be compensated by as-yet-unkown backup mechanisms. Future studies in other tissues and other species would certainly help to unravel the physiological role of App and Aplp2 within the endothelium
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