Mayaro virus (MAYV) is an arbovirus that circulates in Latin America and is emerging as a potential threat to public health. Infected individuals develop Mayaro fever, a severe inflammatory disease ...characterized by high fever, rash, arthralgia, myalgia and headache. The disease is often associated with a prolonged arthralgia mediated by a chronic inflammation that can last months. Although the immune response against other arboviruses, such as chikungunya virus (CHIKV), dengue virus (DENV) and Zika virus (ZIKV), has been extensively studied, little is known about the pathogenesis of MAYV infection. In this study, we established models of MAYV infection in macrophages and in mice and found that MAYV can replicate in bone marrow-derived macrophages and robustly induce expression of inflammasome proteins, such as NLRP3, ASC, AIM2, and Caspase-1 (CASP1). Infection performed in macrophages derived from Nlrp3-/-, Aim2-/-, Asc-/-and Casp1/11-/-mice indicate that the NLRP3, but not AIM2 inflammasome is essential for production of inflammatory cytokines, such as IL-1β. We also determined that MAYV triggers NLRP3 inflammasome activation by inducing reactive oxygen species (ROS) and potassium efflux. In vivo infections performed in inflammasome-deficient mice indicate that NLRP3 is involved with footpad swelling, inflammation and pain, establishing a role of the NLRP3 inflammasome in the MAYV pathogenesis. Accordingly, we detected higher levels of caspase1-p20, IL-1β and IL-18 in the serum of MAYV-infected patients as compared to healthy individuals, supporting the participation of the NLRP3-inflammasome during MAYV infection in humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this secondary analysis of data from JUPITER, rosuvastatin, as compared with placebo, resulted in a reduced risk of symptomatic venous thromboembolism (including deep-vein thrombosis and pulmonary ...embolism).
In this secondary analysis of data from JUPITER, rosuvastatin, as compared with placebo, resulted in a reduced risk of symptomatic venous thromboembolism (including deep-vein thrombosis and pulmonary embolism).
Venous and arterial thrombosis are common, serious, and strongly age-related events that often occur together
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and share some risk factors.
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Controversies persist regarding the nature and extent of their shared pathways and whether treatments of demonstrated efficacy for one condition, including anticoagulant agents, antiplatelet therapy, thrombolytic agents, and statins, have consistent benefits for the primary or secondary prevention of the other.
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The benefits of statins might accrue not only through their effects on lipid levels but also through their influence on thrombosis and inflammation.
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Two prospective, observational studies showed that substantial and significant reductions in the . . .
Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes
. Their physical origin remains unknown, but dozens of possible models have been postulated
. Some FRB sources exhibit repeat ...bursts
. Although over a hundred FRB sources have been discovered
, only four have been localized and associated with a host galaxy
, and just one of these four is known to emit repeating FRBs
. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source
, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure
further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.
Tropical carbon emissions are largely derived from direct forest clearing processes. Yet, emissions from drought-induced forest fires are, usually, not included in national-level carbon emission ...inventories. Here we examine Brazilian Amazon drought impacts on fire incidence and associated forest fire carbon emissions over the period 2003-2015. We show that despite a 76% decline in deforestation rates over the past 13 years, fire incidence increased by 36% during the 2015 drought compared to the preceding 12 years. The 2015 drought had the largest ever ratio of active fire counts to deforestation, with active fires occurring over an area of 799,293 km
. Gross emissions from forest fires (989 ± 504 Tg CO
year
) alone are more than half as great as those from old-growth forest deforestation during drought years. We conclude that carbon emission inventories intended for accounting and developing policies need to take account of substantial forest fire emissions not associated to the deforestation process.
Summary Background Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients ...given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1·8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis. Methods In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1·9 years), according to on-treatment concentrations of LDL cholesterol (≥1·8 mmol/L or <1·8 mmol/L) and hsCRP (≥2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov , number NCT00239681. Findings Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1·8 mmol/L had a 55% reduction in vascular events (event rate 1·11 vs 0·51 per 100 person-years; hazard ratio HR 0·45, 95% CI 0·34–0·60, p<0·0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0·42 per 100 person-years; HR 0·38, 95% CI 0·26–0·56, p<0·0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients ( r values <0·15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1·8 mmol/L and hsCRP less than 2 mg/L (event rate 0·38 per 100 person-years; adjusted HR 0·35, 95% CI 0·23–0·54), versus a 33% reduction in those who achieved one or neither target (event rate 0·74 per 100 person-years; HR 0·67, 95% CI 0·52–0·87) (p across treatment groups <0·0001). In participants who achieved LDL cholesterol less than 1·8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0·24 per 100 person-years; HR 0·21, 95% CI 0·09–0·52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio. Interpretation For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin. Funding AstraZeneca.
We report on the discovery and analysis of bursts from nine new repeating fast radio burst (FRB) sources found using the Canadian Hydrogen Intensity Mapping Experiment (CHIME) telescope. These ...sources span a dispersion measure (DM) range of 195-1380 pc cm−3. We detect two bursts from three of the new sources, three bursts from four of the new sources, four bursts from one new source, and five bursts from one new source. We determine sky coordinates of all sources with uncertainties of ∼10′. We detect Faraday rotation measures (RMs) for two sources, with values −20(1) and −499.8(7) rad m−2, that are substantially lower than the RM derived from bursts emitted by FRB 121102. We find that the DM distribution of our events, combined with the nine other repeaters discovered by CHIME/FRB, is indistinguishable from that of thus far non-repeating CHIME/FRB events. However, as previously reported, the burst widths appear statistically significantly larger than the thus far non-repeating CHIME/FRB events, further supporting the notion of inherently different emission mechanisms and/or local environments. These results are consistent with previous work, though are now derived from 18 repeating sources discovered by CHIME/FRB during its first year of operation. We identify candidate galaxies that may contain FRB 190303.J1353+48 (DM = 222.4 pc cm−3).
In this trial, 17,802 healthy men and women with low-density lipoprotein cholesterol levels of less than 130 mg per deciliter and high-sensitivity C-reactive protein levels of 2.0 mg per liter or ...more were randomly assigned to rosuvastatin or placebo. At a median of 1.9 years, the incidence of major cardiovascular events was significantly lower in the rosuvastatin group.
17,802 healthy men and women with LDL cholesterol levels of less than 130 mg per deciliter and high-sensitivity CRP levels of 2.0 mg per liter or more were treated with rosuvastatin or placebo. The incidence of major cardiovascular events was significantly lower in the rosuvastatin group.
Current treatment algorithms for the prevention of myocardial infarction, stroke, and death from cardiovascular causes recommend statin therapy for patients with established vascular disease, diabetes, and overt hyperlipidemia.
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However, half of all myocardial infarctions and strokes occur among apparently healthy men and women with levels of low-density lipoprotein (LDL) cholesterol that are below currently recommended thresholds for treatment.
Measurement of high-sensitivity C-reactive protein, an inflammatory biomarker that independently predicts future vascular events, improves global classification of risk, regardless of the LDL cholesterol level.
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We have previously shown that statin therapy reduces high-sensitivity C-reactive protein levels
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and that . . .
Recent studies have recognised the importance of pulmonary hypertension (PH) in sickle cell disease (SCD). The aim of this study was to determine the prevalence and prognostic impact of PH and its ...features in patients with SCD. 80 patients with SCD underwent baseline clinical evaluation, laboratory testing, 6-min walk tests (6MWTs) and echocardiography. Patients with a peak tricuspid regurgitant jet velocity (TRV) of ≥ 2.5 m·s(-1) were further evaluated through right heart catheterisation (RHC) to assure the diagnosis of PH. Our study evidenced a 40% prevalence of patients with elevated TRV at echocardiography. RHC (performed in 25 out of 32 patients) confirmed PH in 10% (95% CI 3.4-16.5%) of all patients, with a prevalence of post-capillary PH of 6.25% (95% CI 0.95-11.55%) and pre-capillary PH of 3.75% (95% CI -0.4-7.9%). Patients with PH were older, had worse performance in 6MWTs, and more pronounced anaemia, haemolysis and renal dysfunction. Survival was shorter in patients with PH. Our study reinforced the use of echocardiography as a screening tool for PH in SCD and the mandatory role of RHC for proper diagnosis. Our findings confirmed the prognostic significance of PH in SCD as its association to pronounced haemolytic profile.
In the last decades, several discoveries have uncovered the complexity of mammalian evolution during the Mesozoic Era, including important Gondwanan lineages: the australosphenidans, ...gondwanatherians, and meridiolestidans (Dryolestoidea). Most often, their presence and diversity is documented by isolated teeth and jaws. Here, we describe a new meridiolestidan mammal, Orretherium tzen gen. et sp. nov., from the Late Cretaceous of southern Chile, based on a partial jaw with five cheek teeth in locis and an isolated upper premolar. Phylogenetic analysis places Orretherium as the earliest divergence within Mesungulatidae, before other forms such as the Late Cretaceous Mesungulatum and Coloniatherium, and the early Paleocene Peligrotherium. The in loco tooth sequence (last two premolars and three molars) is the first recovered for a Cretaceous taxon in this family and suggests that reconstructed tooth sequences for other Mesozoic mesungulatids may include more than one species. Tooth eruption and replacement show that molar eruption in mesungulatids is heterochronically delayed with regard to basal dryolestoids, with therian-like simultaneous eruption of the last premolar and last molar. Meridiolestidans seem endemic to Patagonia, but given their diversity and abundance, and the similarity of vertebrate faunas in other regions of Gondwana, they may yet be discovered in other continents.
The current COVID-19 pandemic presents one of the greatest challenges in human history. There is a consensus that the rapid and accurate diagnosis of COVID-19 directly affects procedures to avoid ...dissemination, promote treatments, and favor the prognosis of infected patients. This interdisciplinary study aims at designing new synthetic peptides inspired by the SARS-CoV-2 spike protein (SARS-CoV-2S) to produce rapid detection tests relying on nanomaterial-based colorimetric properties. Hence,
in silico
analyses of SARS-CoV-2S were performed using advanced bioinformatic simulation tools and algorithms. Five novel peptide sequences were proposed, and three were selected (P2, J4, and J5) based on their prospective reactivity against positive serum from naturally COVID-19-infected humans. Next, hyperimmune sera against the selected peptides were produced in rabbits. Concurrently, gold nanoparticles (AuNP) were synthesized using a green aqueous method under mild conditions through
in situ
reduction by trisodium citrate salt. They were extensively characterized by their morphological, physicochemical, and optical properties. The AuNPs demonstrated colloidal chemical stability in aqueous media, with an average size of approximately 29 nm (metallic core), and zeta potential before and after bioconjugation of −43 mV and −31 mV, respectively. Moreover, they presented an intense reddish-bluish color due to the surface plasmon resonance (SPR) effect, with maxima at
λ
= 525 nm and 536 nm, before and after bioconjugation, respectively, evidencing their applicability as colorimetric biomarkers for antigen-antibody immunoassay detection. To develop a rapid COVID-19 diagnosis test using lateral flow assay (LFA), semi-purified anti-SARS-CoV-2S sera against the three selected peptides were bioconjugated to the AuNPs as the highly optically sensitive agents using a considerably low antibody concentration (0.2 mg mL
−1
). All tested peptide sequences (P2, J4, and J5) induced antibodies capable of identifying the presence of SARS-CoV-2 virus inactivate suspensions (1 : 10, 1 : 100, or 1 : 1000 dilutions). For LFA positive test control, an anti-rabbit antibody was used. In summary, this research comprises several contributions and advances to the broad and multidisciplinary field of nanomaterials-based immunodiagnosis tools, encompassing: (a) the novelty of designing and synthesizing new immunogenic peptides inspired by SARS-CoV-2 virus epitopes using
in silico
bioinformatics; (b) the peptides induced the immune response in rabbit animal model producing hyperimmune serum; (c) the semi-purified hyperimmune serum rendered effective antibodies to detect SARS-CoV-2 virus in cell suspension; (d) colloidal gold nanoparticles were produced and bioconjugated to the antibodies for qualitative colorimetric detection. As the overall result of this study, it was designed, developed, produced, and validated a new simple, rapid, and sensitive LFA diagnostic test for the SARS-CoV-2 virus using a nanotechnology-based qualitative colorimetric assay, which can be envisioned as promising nanoplatforms for detecting other diseases.
The current COVID-19 pandemic presents one of the greatest challenges in human history.
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