136 research outputs found
Una figurita de guerrero, con espada al hombro, procedente del castro del Cerro del Berrueco, Salamanca.
62 (3-4) Jul.-Dez. 1952, p. 233-243
Enhancement of CD8(+) T-cell memory by removal of a vaccinia virus nuclear factor-ÎşB inhibitor.
Factors influencing T-cell responses are important for vaccine development but are incompletely understood. Here, vaccinia virus (VACV) protein N1 is shown to impair the development of both effector and memory CD8(+) T cells and this correlates with its inhibition of nuclear factor-κB (NF-κB) activation. Infection with VACVs that either have the N1L gene deleted (vΔN1) or contain a I6E mutation (vN1.I6E) that abrogates its inhibition of NF-κB resulted in increased central and memory CD8(+) T-cell populations, increased CD8(+) T-cell cytotoxicity and lower virus titres after challenge. Furthermore, CD8(+) memory T-cell function was increased following infection with vN1.I6E, with more interferon-γ production and greater protection against VACV infection following passive transfer to naive mice, compared with CD8(+) T cells from mice infected with wild-type virus (vN1.WT). This demonstrates the importance of NF-κB activation within infected cells for long-term CD8(+) T-cell memory and vaccine efficacy. Further, it provides a rationale for deleting N1 from VACV vectors to enhance CD8(+) T-cell immunogenicity, while simultaneously reducing virulence to improve vaccine safety.This work was supported by grants from the Wellcome Trust and the Medical Research Council. GLS is a Wellcome Trust Principal Research Fellow.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/imm.1242
HIV-2/SIV Vpx antagonises NF-ÎşB activation by targeting p65
BACKGROUND: The NF-ÎşB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-ÎşB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-ÎşB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins targeting the NF-ÎşB pathway to mitigate the anti-viral effects of NF-ÎşB-dependent host immunity. RESULTS: In this study we have demonstrated using a variety of assays, in a number of different cell types including primary cells, that plasmid-encoded or virus-delivered simian immunodeficiency virus (SIV) accessory protein Vpx is a broad antagonist of NF-ÎşB signalling active against diverse innate NF-ÎşB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-ÎşB transcription factor p65, but not NF-ÎşB family members p50 or p100, preventing nuclear translocation of p65. We found that broad antagonism of NF-ÎşB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity. CONCLUSIONS: We have discovered a novel mechanism by which lentiviruses antagonise NF-ÎşB activation by targeting p65. These findings extend our knowledge of how lentiviruses manipulate universal regulators of immunity to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists. Importantly our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of NF-ÎşB
HIV-2/SIV Vpx antagonises NF-ÎşB activation by targeting p65.
BACKGROUND: The NF-ÎşB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-ÎşB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-ÎşB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins targeting the NF-ÎşB pathway to mitigate the anti-viral effects of NF-ÎşB-dependent host immunity. RESULTS: In this study we have demonstrated using a variety of assays, in a number of different cell types including primary cells, that plasmid-encoded or virus-delivered simian immunodeficiency virus (SIV) accessory protein Vpx is a broad antagonist of NF-ÎşB signalling active against diverse innate NF-ÎşB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-ÎşB transcription factor p65, but not NF-ÎşB family members p50 or p100, preventing nuclear translocation of p65. We found that broad antagonism of NF-ÎşB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity. CONCLUSIONS: We have discovered a novel mechanism by which lentiviruses antagonise NF-ÎşB activation by targeting p65. These findings extend our knowledge of how lentiviruses manipulate universal regulators of immunity to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists. Importantly our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of NF-ÎşB
Forest growth responses to drought at short- and long-term scales in Spain: squeezing the stress memory from tree rings
Drought-triggered declines in forest productivity and associated die-off events have increased considerably due to climate warming in the last decades. There is an increasing interest in quantifying the resilience capacity of forests against climate warming and drought to uncover how different stands and tree species will resist and recover after more frequent and intense droughts. Trees form annual growth rings that represent an accurate record of how forest growth responded to past droughts. Here we use dendrochronology to quantify the radial growth of different forests subjected to contrasting climatic conditions in Spain during the last half century. Particularly, we considered four climatically contrasting areas where dominant forests showed clear signs of drought-induced dieback. Studied forests included wet sites dominated by silver fir (Abies alba) in the Pyrenees and beech (Fagus sylvatica) stands in northern Spain, and drought-prone sites dominated by Scots pine (Pinus sylvestris) in eastern Spain and black pine (Pinus nigra) in the semi-arid south-eastern Spain. We quantified the growth reduction caused by different droughts and assessed the short-and long-term resilience capacity of declining vs. non-declining trees in each forest. In all cases, drought induced a marked growth reduction regardless tree vigor. However, the capacity to recover after drought (resilience) at short- and long-term scales varied greatly between declining and non-declining individuals. .
Miniatures from domestic contexts in Iron age Iberia
This article reviews a set of miniatures from domestic contexts in Iron Age eastern Iberia, and interprets them in terms of their role in forging social personae. After an introduction to the historical case under consideration, the miniatures are described in terms of their typology and their contexts of provenance are outlined. Though not abundant, they tend to occur in central places in the landscape; specifically, they are often found in houses of the powerful. The vast majority are miniatures of pottery and tools, though some miniature weapons are recorded. We contend that these objects were used as a means of enculturation and for the learning of values and norms. It is no coincidence that they emerge in the archaeological record of Iron Age Iberia at the same time as the rise of a social structure based on hereditary power
Persistence of long-term COVID-19 sequelae in patients with cancer: An analysis from the OnCovid registry
Co-infections and superinfections complicating COVID-19 in cancer patients: A multicentre, international study
Background: We aimed to describe the epidemiology, risk factors, and clinical outcomes of co-infections and superinfections in onco-hematological patients with COVID-19. Methods: International, multicentre cohort study of cancer patients with COVID-19. All patients were included in the analysis of co-infections at diagnosis, while only patients admitted at least 48 h were included in the analysis of superinfections. Results: 684 patients were included (384 with solid tumors and 300 with hematological malignancies). Co-infections and superinfections were documented in 7.8% (54/684) and 19.1% (113/590) of patients, respectively. Lower respiratory tract infections were the most frequent infectious complications, most often caused by Streptococcus pneumoniae and Pseudomonas aeruginosa. Only seven patients developed opportunistic infections. Compared to patients without infectious complications, those with infections had worse outcomes, with high rates of acute respiratory distress syndrome, intensive care unit (ICU) admission, and case-fatality rates. Neutropenia, ICU admission and high levels of C-reactive protein (CRP) were independent risk factors for infections. Conclusions: Infectious complications in cancer patients with COVID-19 were lower than expected, affecting mainly neutropenic patients with high levels of CRP and/or ICU admission. The rate of opportunistic infections was unexpectedly low. The use of empiric antimicrobials in cancer patients with COVID-19 needs to be optimized
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