134 research outputs found
Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK
The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the hostÂŽs cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ÎN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that processFil: Salinas Ojeda, Romina Paola. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas MĂ©dicas. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ortiz Flores, Rodolfo Matias. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas MĂ©dicas. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Distel, JesĂșs SebastiĂĄn. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas MĂ©dicas. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Aguilera, Milton Osmar. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas MĂ©dicas. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas MĂ©dicas. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Beron, Walter. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas MĂ©dicas. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos; Argentin
The Aguablanca Niâ(Cu) sulfide deposit, SW Spain: geologic and geochemical controls and the relationship with a midcrustal layered mafic complex
The Aguablanca Niâ(Cu) sulfide deposit is
hosted by a breccia pipe within a gabbroâdiorite pluton.
The deposit probably formed due to the disruption of a
partially crystallized layered mafic complex at about 12â
19 km depth and the subsequent emplacement of melts and
breccias at shallow levels (<2 km). The ore-hosting breccias
are interpreted as fragments of an ultramafic cumulate,
which were transported to the near surface along with a
molten sulfide melt. Phlogopite ArâAr ages are 341â
332 Ma in the breccia pipe, and 338â334 Ma in the layered
mafic complex, and are similar to recently reported UâPb
ages of the host Aguablanca Stock and other nearby calcalkaline
metaluminous intrusions (ca. 350â330 Ma). Ore
deposition resulted from the combination of two critical
factors, the emplacement of a layered mafic complex deep
in the continental crust and the development of small
dilational structures along transcrustal strike-slip faults that
triggered the forceful intrusion of magmas to shallow
levels. The emplacement of basaltic magmas in the lower
middle crust was accompanied by major interaction with
the host rocks, immiscibility of a sulfide melt, and the
formation of a magma chamber with ultramafic cumulates
and sulfide melt at the bottom and a vertically zoned mafic
to intermediate magmas above. Dismembered bodies of
mafic/ultramafic rocks thought to be parts of the complex
crop out about 50 km southwest of the deposit in a
tectonically uplifted block (Cortegana Igneous Complex,
Aracena Massif). Reactivation of Variscan structures that
merged at the depth of the mafic complex led to sequential
extraction of melts, cumulates, and sulfide magma. Lithogeochemistry
and Sr and Nd isotope data of the Aguablanca
Stock reflect the mixing from two distinct reservoirs, i.e.,
an evolved siliciclastic middle-upper continental crust and a
primitive tholeiitic melt. Crustal contamination in the deep
magma chamber was so intense that orthopyroxene
replaced olivine as the main mineral phase controlling the early fractional crystallization of the melt. Geochemical
evidence includes enrichment in SiO2 and incompatible
elements, and Sr and Nd isotope compositions (87Sr/86Sri
0.708â0.710; 143Nd/144Ndi 0.512â0.513). However, rocks
of the Cortegana Igneous Complex have low initial
87Sr/86Sr and high initial 143Nd/144Nd values suggesting
contamination by lower crustal rocks. Comparison of the
geochemical and geological features of igneous rocks in the
Aguablanca deposit and the Cortegana Igneous Complex
indicates that, although probably part of the same magmatic
system, they are rather different and the rocks of the
Cortegana Igneous Complex were not the direct source of
the Aguablanca deposit. Crustâmagma interaction was a
complex process, and the generation of orebodies was
controlled by local but highly variable factors. The model
for the formation of the Aguablanca deposit presented in
this study implies that dense sulfide melts can effectively
travel long distances through the continental crust and that
dilational zones within compressional belts can effectively
focus such melt transport into shallow environments
Diffuse glioma growth: a guerilla war
In contrast to almost all other brain tumors, diffuse gliomas infiltrate extensively in the neuropil. This growth pattern is a major factor in therapeutic failure. Diffuse infiltrative glioma cells show some similarities with guerilla warriors. Histopathologically, the tumor cells tend to invade individually or in small groups in between the dense network of neuronal and glial cell processes. Meanwhile, in large areas of diffuse gliomas the tumor cells abuse pre-existent âsupply linesâ for oxygen and nutrients rather than constructing their own. Radiological visualization of the invasive front of diffuse gliomas is difficult. Although the knowledge about migration of (tumor)cells is rapidly increasing, the exact molecular mechanisms underlying infiltration of glioma cells in the neuropil have not yet been elucidated. As the efficacy of conventional methods to fight diffuse infiltrative glioma cells is limited, a more targeted (âsearch & destroyâ) tactic may be needed for these tumors. Hopefully, the study of original human glioma tissue and of genotypically and phenotypically relevant glioma models will soon provide information about the Achilles heel of diffuse infiltrative glioma cells that can be used for more effective therapeutic strategies
Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy
Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes
Changing perspectives on the internationalization of R&D and innovation by multinational enterprises: a review of the literature
Internationalization of R&D and innovation by Multinational Enterprises (MNEs) has undergone a gradual and comprehensive change in perspective over the past 50 years. From sporadic works in the late 1950s and in the 1960s, it became a systematically analysed topic in the 1970s, starting with pioneering reports and âfoundation textsâ. Our review unfolds the theoretical and empirical evolution of the literature from dyadic interpretations of centralization versus decentralization of R&D by MNEs to more comprehensive frameworks, wherein established MNEs from Advanced Economies still play a pivotal role, but new players and places also emerge in the global generation and diffusion of knowledge. Hence views of R&D internationalization increasingly rely on concepts, ideas and methods from IB and other related disciplines such as industrial organization, international economics and economic geography. Two main findings are highlighted. First, scholarly research pays an increasing attention to the network-like characteristics of international R&D activities. Second, different streams of literature have emphasized the role of location- specific factors in R&D internationalization. The increasing emphasis on these aspects has created new research opportunities in some key areas, including inter alia: cross-border knowledge sourcing strategies, changes in the geography of R&D and innovation, and the international fragmentation of production and R&D activities
Stroke genetics informs drug discovery and risk prediction across ancestries
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p
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