Evaluating the performance of a climate-driven mortality model during heat waves and cold spells in Europe.

The impact of climate change on human health is a serious concern. In particular, changes in the frequency and intensity of heat waves and cold spells are of high relevance in terms of mortality and morbidity. This demonstrates the urgent need for reliable early-warning systems to help authorities prepare and respond to emergency situations. In this study, we evaluate the performance of a climate-driven mortality model to provide probabilistic predictions of exceeding emergency mortality thresholds for heat wave and cold spell scenarios. Daily mortality data corresponding to 187 NUTS2 regions across 16 countries in Europe were obtained from 1998-2003. Data were aggregated to 54 larger regions in Europe, defined according to similarities in population structure and climate. Location-specific average mortality rates, at given temperature intervals over the time period, were modelled to account for the increased mortality observed during both high and low temperature extremes and differing comfort temperatures between regions. Model parameters were estimated in a Bayesian framework, in order to generate probabilistic simulations of mortality across Europe for time periods of interest. For the heat wave scenario (1-15 August 2003), the model was successfully able to anticipate the occurrence or non-occurrence of mortality rates exceeding the emergency threshold (75th percentile of the mortality distribution) for 89% of the 54 regions, given a probability decision threshold of 70%. For the cold spell scenario (1-15 January 2003), mortality events in 69% of the regions were correctly anticipated with a probability decision threshold of 70%. By using a more conservative decision threshold of 30%, this proportion increased to 87%. Overall, the model performed better for the heat wave scenario. By replacing observed temperature data in the model with forecast temperature, from state-of-the-art European forecasting systems, probabilistic mortality predictions could potentially be made several months ahead of imminent heat waves and cold spells

Evaluation of an Early-Warning System for Heat Wave-Related Mortality in Europe: Implications for Sub-seasonal to Seasonal Forecasting and Climate Services.

Heat waves have been responsible for more fatalities in Europe over the past decades than any other extreme weather event. However, temperature-related illnesses and deaths are largely preventable. Reliable sub-seasonal-to-seasonal (S2S) climate forecasts of extreme temperatures could allow for better short-to-medium-term resource management within heat-health action plans, to protect vulnerable populations and ensure access to preventive measures well in advance. The objective of this study is to assess the extent to which S2S climate forecasts could be incorporated into heat-health action plans, to support timely public health decision-making ahead of imminent heat wave events in Europe. Forecasts of apparent temperature at different lead times (e.g., 1 day, 4 days, 8 days, up to 3 months) were used in a mortality model to produce probabilistic mortality forecasts up to several months ahead of the 2003 heat wave event in Europe. Results were compared to mortality predictions, inferred using observed apparent temperature data in the mortality model. In general, we found a decreasing transition in skill between excellent predictions when using observed temperature, to predictions with no skill when using forecast temperature with lead times greater than one week. However, even at lead-times up to three months, there were some regions in Spain and the United Kingdom where excess mortality was detected with some certainty. This suggests that in some areas of Europe, there is potential for S2S climate forecasts to be incorporated in localised heat-health action plans. In general, these results show that the performance of this climate service framework is not limited by the mortality model itself, but rather by the predictability of the climate variables, at S2S time scales, over Europe

Site-Specific DC Surface Signatures Influence CD4⁺ T Cell Co-stimulation and Lung-Homing

Dendritic cells (DCs) that drain the gut and skin are known to favor the establishment of T cell populations that home to the original site of DC-antigen (Ag) encounter by providing soluble "imprinting" signals to T cells in the lymph node (LN). To study the induction of lung T cell-trafficking, we used a protein-adjuvant murine intranasal and intramuscular immunization model to compare in vivo-activated Ag+ DCs in the lung and muscle-draining LNs. Higher frequencies of Ag+ CD11b+ DCs were observed in lung-draining mediastinal LNs (MedLN) compared to muscle-draining inguinal LNs (ILN). Ag+ CD11b+ MedLN DCs were qualitatively superior at priming CD4+ T cells, which then expressed CD49a and CXCR3, and preferentially trafficked into the lung parenchyma. CD11b+ DCs from the MedLN expressed higher levels of surface podoplanin, Trem4, GL7, and the known co-stimulatory molecules CD80, CD86, and CD24. Blockade of specific MedLN DC molecules or the use of sorted DC and T cell co-cultures demonstrated that DC surface phenotype influences the ability to prime T cells that then home to the lung. Thus, the density of dLN Ag+ DCs, and DC surface molecule signatures are factors that can influence the output and differentiation of lung-homing CD4+ T cells

Early-Life Exposure to Outdoor Air Pollution and Respiratory Health, Ear Infections, and Eczema in Infants from the INMA Study

Background: Prenatal and early-life periods may be critical windows for harmful effects of air pollution on infant health.Objectives: We studied the association of air pollution exposure during pregnancy and the first year of life with respiratory illnesses, ear infections, and eczema during the first 12–18 months of age in a Spanish birth cohort of 2,199 infants.Methods: We obtained parentally reported information on doctor-diagnosed lower respiratory tract infections (LRTI) and parental reports of wheezing, eczema, and ear infections. We estimated individual exposures to nitrogen dioxide (NO2) and benzene with temporally adjusted land use regression models. We used log-binomial regression models and a combined random-effects meta-analysis to estimate the effects of air pollution exposure on health outcomes across the four study locations.Results: A 10-µg/m3 increase in average NO2 during pregnancy was associated with LRTI [relative risk (RR) = 1.05; 95% CI: 0.98, 1.12] and ear infections (RR = 1.18; 95% CI: 0.98, 1.41). The RRs for an interquartile range (IQR) increase in NO2 were 1.08 (95% CI: 0.97, 1.21) for LRTI and 1.31 (95% CI: 0.97, 1.76) for ear infections. Compared with NO2, the association for an IQR increase in average benzene exposure was similar for LRTI (RR = 1.06; 95% CI: 0.94, 1.19) and slightly lower for ear infections (RR = 1.17; 95% CI: 0.93, 1.46). Associations were slightly stronger among infants whose mothers spent more time at home during pregnancy. Air pollution exposure during the first year was highly correlated with prenatal exposure, so we were unable to discern the relative importance of each exposure period.Conclusions: Our findings support the hypothesis that early-life exposure to ambient air pollution may increase the risk of upper and lower respiratory tract infections in infants

Involvement of G-quadruplex regions in mammalian replication origin activity.

Genome-wide studies of DNA replication origins revealed that origins preferentially associate with an Origin G-rich Repeated Element (OGRE), potentially forming G-quadruplexes (G4). Here, we functionally address their requirements for DNA replication initiation in a series of independent approaches. Deletion of the OGRE/G4 sequence strongly decreased the corresponding origin activity. Conversely, the insertion of an OGRE/G4 element created a new replication origin. This element also promoted replication of episomal EBV vectors lacking the viral origin, but not if the OGRE/G4 sequence was deleted. A potent G4 ligand, PhenDC3, stabilized G4s but did not alter the global origin activity. However, a set of new, G4-associated origins was created, whereas suppressed origins were largely G4-free. In vitro Xenopus laevis replication systems showed that OGRE/G4 sequences are involved in the activation of DNA replication, but not in the pre-replication complex formation. Altogether, these results converge to the functional importance of OGRE/G4 elements in DNA replication initiation

Identification of transcriptional regulatory variants in pig duodenum, liver, and muscle tissues

Background In humans and livestock species, genome-wide association studies (GWAS) have been applied to study the association between variants distributed across the genome and a phenotype of interest. To discover genetic polymorphisms affecting the duodenum, liver, and muscle transcriptomes of 300 pigs from 3 different breeds (Duroc, Landrace, and Large White), we performed expression GWAS between 25,315,878 polymorphisms and the expression of 13,891 genes in duodenum, 12,748 genes in liver, and 11,617 genes in muscle. Results More than 9.68 × 1011 association tests were performed, yielding 14,096,080 significantly associated variants, which were grouped in 26,414 expression quantitative trait locus (eQTL) regions. Over 56% of the variants were within 1 Mb of their associated gene. In addition to the 100-kb region upstream of the transcription start site, we identified the importance of the 100-kb region downstream of the 3′UTR for gene regulation, as most of the cis-regulatory variants were located within these 2 regions. We also observed 39,874 hotspot regulatory polymorphisms associated with the expression of 10 or more genes that could modify the protein structure or the expression of a regulator gene. In addition, 2 motifs (5′-GATCCNGYGTTGCYG-3′ and a poly(A) sequence) were enriched across the 3 tissues within the neighboring sequences of the most significant single-nucleotide polymorphisms in each cis-eQTL region. Conclusions The 14 million significant associations obtained in this study are publicly available and have enabled the identification of expression-associated cis-, trans-, and hotspot regulatory variants within and across tissues, thus shedding light on the molecular mechanisms of regulatory variations that shape end-trait phenotypes.info:eu-repo/semantics/publishedVersio

Mutations on a conserved distal enhancer in the porcine C-reactive protein gene impair its expression in liver

C-reactive protein (CRP) is an evolutionary highly conserved protein. Like humans, CRP acts as a major acute phase protein in pigs. While CRP regulatory mechanisms have been extensively studied in humans, little is known about the molecular mechanisms that control pig CRP gene expression. The main goal of the present work was to study the regulatory mechanisms and identify functional genetic variants regulating CRP gene expression and CRP blood levels in pigs. The characterization of the porcine CRP proximal promoter region revealed a high level of conservation with both cow and human promoters, sharing binding sites for transcription factors required for CRP expression. Through genome-wide association studies and fine mapping, the most associated variants with both mRNA and protein CRP levels were localized in a genomic region 39.3 kb upstream of CRP. Further study of the region revealed a highly conserved putative enhancer that contains binding sites for several transcriptional regulators such as STAT3, NF-kB or C/EBP-β. Luciferase reporter assays showed the necessity of this enhancer-promoter interaction for the acute phase induction of CRP expression in liver, where differences in the enhancer sequences significantly modified CRP activity. The associated polymorphisms disrupted the putative binding sites for HNF4α and FOXA2 transcription factors. The high correlation between HNF4α and CRP expression levels suggest the participation of HNF4α in the regulatory mechanism of porcine CRP expression through the modification of its binding site in liver. Our findings determine, for the first time, the relevance of a distal regulatory element essential for the acute phase induction of porcine CRP in liver and identify functional polymorphisms that can be included in pig breeding programs to improve immunocompetence.The authors declare financial support was received for the research, authorship, and/or publication of this article. The study was funded by grants AGL2016-75432-R and PID2020-112677RB-C21 awarded by MCIN/AEI/10.13039/501100011033 and GENE-SWitCH project (https://www.gene-switch.eu), which is funded by the European Union’s Horizon 2020 Research and Innovation Programme under the grant agreement n°817998. T. Jové-Juncà was funded with an IRTA fellowship (CPI1221) and C. Hernández-Banqué was supported by a FPI grant (PRE2021-097825) granted by the Spanish Ministry of Science and Innovation. YR-C was financially supported by a Ramon y Cajal contract (RYC2019-027244-I) from the Spanish Ministry of Science and Innovation. The authors are part to a Consolidated Research Group AGAUR, with the reference 2021-SGR-01552.info:eu-repo/semantics/publishedVersio

Revisiting the use of Live Attenuated viruses as models to study the pathogenesis and the mechanisms involved in protection against African swine fever

Trabajo presentado en el 8th EPIZONE Annual Meeting "Primed for tomorrow", celebrado en Copenhague (Dinamarca) del 23 al 25 de septiembre de 2014.The meeting is entitled: "Primed for tomorrow" and will address the latest developments aimed at monitoring and understanding the evolution, emergence, transmission and spread of epizootic viruses. The focus will remain on the EPIZONE themes aimed at improved disease control through integration and collaboration of research in diagnosis, intervention strategies, risk assessment, surveillance and epidemiology. A stimulating scientific programme will be provided by invited speakers and selected poster and oral presentations describing recent research on epizootic diseases of cattle, pigs, poultry, sheep, goats, fish and horses. This meeting builds on previous highly successful EPIZONE meetings and will provide extensive opportunities for networking, scientific exchange and fostering collaboration

Author Correction: Involvement of G-quadruplex regions in mammalian replication origin activity

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Swine, human or avian influenza viruses differentially activates porcine dendritic cells cytokine profile

Swine influenza virus (SwIV) is considered a zoonosis and the fact that swine may act as an intermediate reservoir for avian influenza virus, potentially infectious for humans, highlights its relevance and the need to understand the interaction of different influenza viruses with the porcine immune system. Thus, in vitro porcine bone marrow-derived dendritic cell (poBMDCs) were infected with a circulating SwIV A/Swine/Spain/SF32071/2007(H3N2), 2009 human pandemic influenza virus A/Catalonia/63/2009(H1N1), low pathogenic avian influenza virus (LPAIV) A/Anas plathyrhynchos/Spain/1877/2009(aH7N2) or high pathogenic avian influenza virus (HPAIV) A/Chicken/Italy/5093/1999(aH7N1). Swine influenza virus H3N2 infection induced an increase of SLA-I and CD80/86 at 16 and 24 h post infection (hpi), whereas the other viruses did not. All viruses induced gene expression of NF-κB, TGF-β, IFN-β and IL-10 at the mRNA level in swine poBMDCs to different extents and in a time-dependent manner. All viruses induced the secretion of IL-12 mostly at 24 hpi whereas IL-18 was detected at all tested times. Only swH3N2 induced IFN-α in a time-dependent manner. Swine H3N2, aH7N2 and aH7N1 induced secretion of TNF-α also in a time-dependent manner. Inhibition of NF-κB resulted in a decrease of IFN-α and IL-12 secretion by swH3N2-infected poBMDC at 24 hpi, suggesting a role of this transcription factor in the synthesis of these cytokines. Altogether, these data might help in understanding the relationship between influenza viruses and porcine dendritic cells in the innate immune response in swine controlled through soluble mediators and transcription factors.This work was partly funded by the Project No. CSD 2006-00007, AGL2006-13809-C03-01, AGL2009-12945-C02-01 and AGL2010-22200-C02-01 by the Spanish Government. PhD studies of Mrs. Tufária Mussá and Masssimiliano Baratelli are funded by doctoral grants from the AECID and MICIN respectively.Peer reviewe