The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice

p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. Methodology/Principal Findings: We evaluated osteoblast-specific deletion of p38 alpha to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38 alpha deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38 alpha did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38 alpha disruption after birth by removal of doxycycline. Deletion of p38 alpha at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. Conclusions: Our data demonstrates that, in addition to early skeletogenesis, p38 alpha is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects

SARS-CoV-2 viral load in nasopharyngeal swabs is not an independent predictor of unfavorable outcome

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient’s hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO2, neutrophils > 7.5 × 103/µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

In vitro co-infection by cytomegalovirus improves the antiviral activity of ganciclovir against human adenovirus

Human adenovirus (HAdV) infection has an important clinical impact in the immunosuppressed population and is associated with high morbidity and mortality rates. The lack of a specific, safe and effective antiviral treatment against HAdV makes necessary the search for new therapeutic options. The aim of this study was to evaluate the in vitro activity of ganciclovir (GCV) against HAdV in co-infection by human cytomegalovirus (HCMV) and HAdV in cellular cultures. Quantitative real-time polymerase chain reaction (qPCR) was used to measure HAdV and HCMV DNA replication efficiency in monocultures and in co-infection situations in the presence of both cidofovir (CDV) and GCV. The effects of GCV and CDV were also evaluated in a burst assay (used to measure the production of virus particles) for both viruses, alone and in combination. GCV decreased by 1-log the HAdV DNA replication efficiency in co-infection with HCMV compared with its activity in HAdV monoculture. The burst assay showed that the reductions in virus yield in the presence of GCV were higher for HCMV and co-infection than for HAdV in monoculture (145.2±35.5- vs. 116.4±27.3- vs. 23.0±10.0-fold, respectively, P<0.05). The improved anti-HAdV activity of GCV during co-infection may be because of the more efficient phosphorylation of GCV by the HCMV protein kinase, UL97. Patients treated with GCV as pre-emptive therapy for HCMV infection may be considered as low-risk for developing HAdV infections; however, further evaluations are required to confirm these results.Supported by Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) - co‐financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014‐2020, the Carlos III Health Institute (PI15/00489; DTS17/00130; PI18/01191) and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT) grants

Gulls as vectors for plastics and nutrient transport across natural aquatic environments

2nd Meeting of the Iberian Ecological Society (SIBECOL), 3-8 July 2022, Aveiro, PortugalInterest in plastic contamination in inland aquatic environments due to human activity has been growing greatly. The amount of plastic produced generates severe environmental problems, due to long term deposition, but also because plastic breaks down into smaller pieces that persist and interact with aquatic biota. Many waterbirds (e.g. gulls) have shifted their natural behaviour to exploit constant anthropogenic resources (e.g. rubbish dumps) and may be biovectors of plastics and nutrients between terrestrial and aquatic environments. In south-west Spain Lesser black backed gull (Larus fuscus) and yellow legged gull (Larus michahellis) are opportunistic species exploiting resources at dumps and biovectoring plastics to natural environments (e.g. at Fuente de Piedra Lagoon and Odiel marshlands respectively) through pellet and faecal deposition. However, the role of gulls as plastic vectors has not been quantified so far. Using movement data acquired with GPS devices, combined with censuses and analysis of pellets and faeces collected from the wetlands, we quantify the amounts of plastics, other debris, and nutrients imported by gulls into these two internationally important wetlands. We consider possible management measures to reduce the extent of these biovectoring processesPeer reviewe

The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice

p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. Methodology/Principal Findings: We evaluated osteoblast-specific deletion of p38 alpha to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38 alpha deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38 alpha did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38 alpha disruption after birth by removal of doxycycline. Deletion of p38 alpha at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. Conclusions: Our data demonstrates that, in addition to early skeletogenesis, p38 alpha is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects

The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice

p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. Methodology/Principal Findings: We evaluated osteoblast-specific deletion of p38 alpha to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38 alpha deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38 alpha did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38 alpha disruption after birth by removal of doxycycline. Deletion of p38 alpha at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. Conclusions: Our data demonstrates that, in addition to early skeletogenesis, p38 alpha is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects

The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice

<div><p>Background</p><p>p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified.</p><p>Methodology/Principal Findings</p><p>We evaluated osteoblast-specific deletion of p38α to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38α deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38α did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38α disruption after birth by removal of doxycycline. Deletion of p38α at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months.</p><p>Conclusions</p><p>Our data demonstrates that, in addition to early skeletogenesis, p38α is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects.</p></div

The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice

p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. Methodology/Principal Findings: We evaluated osteoblast-specific deletion of p38 alpha to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38 alpha deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38 alpha did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38 alpha disruption after birth by removal of doxycycline. Deletion of p38 alpha at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. Conclusions: Our data demonstrates that, in addition to early skeletogenesis, p38 alpha is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects

The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice

p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. Methodology/Principal Findings: We evaluated osteoblast-specific deletion of p38 alpha to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38 alpha deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38 alpha did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38 alpha disruption after birth by removal of doxycycline. Deletion of p38 alpha at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. Conclusions: Our data demonstrates that, in addition to early skeletogenesis, p38 alpha is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects