Disentangling the effects of traffic-related noise and air pollution on blood pressure: indoor noise levels and protections

Outdoor road traffic noise levels are associated with hypertension (HT). Studies on blood pressure (BP) are inconsistent and the true indoor traffic noise exposure may differ due to protections against noise. We analysed the effects of long-term exposure to outdoor and indoor traffic noise levels on HT, systolic (SBP) and diastolic BP (DBP, mmHg), adjusting for outdoor annual average concentrations of near-road traffic-related air pollution (nitrogen dioxide, NO2) among 1926 participants (aged 36-82) from the Catalan REGICOR study. Long-term outdoor residential levels of traffic noise at night (Lnight, in A-weighted dB) and annual averages of NO2 (in µg/m3 ) were estimated at the postal addresses’ façades with a city-specific noise model and a land-use regression model, respectively. Indoor traffic noise was calculated from outdoor noise levels subtracting the attenuations in dB according to reported noise protections. Median noise levels were 56.7 dB outdoors and 27.1 dB indoors. Spearman correlations between outdoor and indoor noise with NO2 were 0.75 and 0.23, respectively. Outdoor noise was only associated with HT (OR=1.19, 95%CI: 1.02, 1.40), whereas there was a suggestive association of indoor noise with both HT (OR=1.06, 95%CI: 0.99, 1.13) and SBP (ß=0.38, 95%CI: -0.08, 0.83) per 5 dB increase in outdoor noise levels. NO2 was also associated with both outcomes after adjustment for indoor noise. Findings for indoor traffic noise levels are more plausible than those for outdoor traffic noise. The use of indoor traffic noise estimates help to disentangle the effects from those of traffic-related air pollution.Postprint (author's final draft

Cross-sectional association between road traffic noise and hypertension in a population-based sample in Girona, Spain (REGICOR-AIR project)

Peer ReviewedPostprint (published version

Transportation noise (in particular railway noise) and blood pressure in REGICOR compared to SAPALDIA

Peer ReviewedPostprint (author's final draft

The Trypanosoma brucei MISP family of invariant proteins is co-expressed with BARP as triple helical bundle structures on the surface of salivary gland forms, but is dispensable for parasite development within the tsetse vector

Trypanosoma brucei spp. develop into mammalian-infectious metacyclic trypomastigotes inside tsetse salivary glands. Besides acquiring a variant surface glycoprotein (VSG) coat, little is known about the metacyclic expression of invariant surface antigens. Proteomic analyses of saliva from T. brucei-infected flies identified, in addition to VSG and Brucei Alanine-Rich Protein (BARP) peptides, a family of GPI-anchored surface proteins herein named as Metacyclic Invariant Surface Proteins (MISP) because of its predominant expression on the surface of metacyclic trypomastigotes. The MISP family is encoded by five paralog genes with >80% protein identity, which are exclusively expressed by salivary gland stages of the parasite and peak in metacyclic stage, as shown by confocal microscopy and immuno-high resolution scanning electron microscopy. Crystallographic analysis of a MISP isoform (MISP360) and a high confidence model of BARP revealed a triple helical bundle architecture commonly found in other trypanosome surface proteins. Molecular modelling combined with live fluorescent microscopy suggests that MISP N-termini are potentially extended above the metacyclic VSG coat, and thus could be tested as a transmission-blocking vaccine target. However, vaccination with recombinant MISP360 isoform did not protect mice against a T. brucei infectious tsetse bite. Lastly, both CRISPR-Cas9-driven knock out and RNAi knock down of all MISP paralogues suggest they are not essential for parasite development in the tsetse vector. We suggest MISP may be relevant during trypanosome transmission or establishment in the vertebrate’s skin

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Cross-sectional association between road traffic noise and hypertension in a population-based sample in Girona, Spain (REGICOR-AIR project)

Peer Reviewe

Transportation noise (in particular railway noise) and blood pressure in REGICOR compared to SAPALDIA

Peer Reviewe

Proteomic analysis reveals different composition of extracellular vesicles released by two Trypanosoma cruzi strains associated with their distinct interaction with host cells

Trypanosoma cruzi, the aetiologic agent of Chagas disease, releases vesicles containing a wide range of surface molecules known to affect the host immunological responses and the cellular infectivity. Here, we compared the secretome of two distinct strains (Y and YuYu) of T. cruzi, which were previously shown to differentially modulate host innate and acquired immune responses. Tissue culture-derived trypomastigotes of both strains secreted extracellular vesicles (EVs), as demonstrated by electron scanning microscopy. EVs were purified by exclusion chromatography or ultracentrifugation and quantitated using nanoparticle tracking analysis. Trypomastigotes from YuYu strain released higher number of EVs than those from Y strain, enriched with virulence factors trans-sialidase (TS) and cruzipain. Proteomic analysis confirmed the increased abundance of proteins coded by the TS gene family, mucin-like glycoproteins, and some typical exosomal proteins in the YuYu strain, which also showed considerable differences between purified EVs and vesicle-free fraction as compared to the Y strain. To evaluate whether such differences were related to parasite infectivity, J774 macrophages and LLC-MK2 kidney cells were preincubated with purified EVs from both strains and then infected with Y strain trypomastigotes. EVs released by YuYu strain caused a lower infection but higher intracellular proliferation in J774 macrophages than EVs from Y strain. In contrast, YuYu strain-derived EVs caused higher infection of LLC-MK2 cells than Y strain-derived EVs. In conclusion, quantitative and qualitative differences in EVs and secreted proteins from different T. cruzi strains may correlate with infectivity/virulence during the host–parasite interaction

Association of long-term exposure to traffic-related air pollution with blood pressure and hypertension in an adult population-based cohort in Spain (the REGICOR study)

Background: Long-term exposure to traffic-related air pollution may increase blood pressure (BP) and induce hypertension. However, evidence supporting these associations is limited, and they may be confounded by exposure to traffic noise and biased due to inappropriate control for use of BP-lowering medications. Objectives: We evaluated the associations of long-term traffic-related air pollution with BP and prevalent hypertension, adjusting for transportation noise and assessing different methodologies to control for BP-lowering medications. Methods: We measured systolic (SBP) and diastolic BP (DBP) at baseline (years 2003–2005) in 3,700 participants, 35–83 years of age, from a population-based cohort in Spain. We estimated home outdoor annual average concentrations of nitrogen dioxide (NO2) with a land-use regression model. We used multivariate linear and logistic regression. Results: A 10-µg/m3 increase in NO2 levels was associated with 1.34 mmHg (95% CI: 0.14, 2.55) higher SBP in nonmedicated individuals, after adjusting for transportation noise. Results were similar in the entire population after adjusting for medication, as commonly done, but weaker when other methods were used to account for medication use. For example, when 10 mmHg were added to the measured SBP levels of medicated participants, the association was ß = 0.78 (95% CI: –0.43, 2.00). NO2 was not associated with hypertension. Associations of NO2 with SBP and DBP were stronger in participants with cardiovascular disease, and the association with SBP was stronger in those exposed to high traffic density and traffic noise levels = 55 dB(A). Conclusions: We observed a positive association between long-term exposure to NO2 and SBP, after adjustment for transportation noise, which was sensitive to the methodology used to account for medication.Peer Reviewe