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Fifteen years have passed since the cloning and characterization of the interleukin-1 β -converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction.

Inflammasomes are Nod-like receptor(NLR)- and caspase-1-containing cytoplasmic multiprotein complexes, which upon their assembly, process and activate the proinflammatory cytokines interleukin (IL)-1 β and IL-18. The inflammasomes harboring the NLR members NALP1, NALP3 and IPAF have been best characterized. While the IPAF inflammasome is activated by bacterial flagellin, activation of the NALP3 inflammasome is triggered not only by several microbial components, but also by a plethora of danger-associated host molecules such as uric acid. How NALP3 senses these chemically unrelated activators is not known. Here, we provide evidence that activation of NALP3, but not of the IPAF inflammasome, is blocked by inhibiting K + efflux from cells. Low intracellular K + is also a requirement for NALP1 inflammasome activation by lethal toxin of Bacillus anthracis . In vitro , NALP inflammasome assembly and caspase-1 recruitment occurs spontaneously at K + concentrations below 90 m M , but is prevented at higher concentrations. Thus, low intracellular K + may be the least common trigger of NALP-inflammasome activation.

The September 6–10, 2017 two-step magnetic storm was caused by an X9 solar flare followed by a CME. The SSC that occurred at 23:43 UT on day 06 when Sym-H reached about 50 nT, was due to a sudden increase in solar wind. The first step of the storm was caused by a Bz southward incursion on day 07. The magnetic index Kp reached 08, and the Sym-H magnetic index reached a minimum value of − 146 nT on day 08 at 01:08 UT, ending the main phase. On day 07, the solar wind intensified once again and the auroral index AE reached 2500 nT. During the recovery phase of this first storm, there was another Bz southward incursion on day 08 at 13:56 UT when Sym-H reached − 115 nT, and Kp reached a value of 08.33, marking the second step of the storm. In this work, the ionospheric irregularity over São Luís (02.5°S, 44.3°W, dip lat − 04.67°) was studied using data from the VHF, Digisonde and GPS receivers. Electron density data from the satellite SWARM-A were also analyzed for those orbits close to São Luís, and they presented large fluctuations during the storm night of 07/08. To analyze the latitudinal effects of the storm on the plasma irregularities, GPS data from 6 Novatel receivers were used. The vertical plasma drifts during daytime hours were determined using magnetometer data and during the evening using ionogram data. Compared to the ‘quiet’ days of September 2017, the VHF and GPS S4 amplitude scintillation indices increased substantially during the night of 07/08 when there was a strong intensification in the vertical plasma drift due to a prompt penetration under shielding magnetospheric electric field of eastward polarity. On the other hand, on the night of 08/09 the ionospheric scintillation was completely inhibited due to the disturbance dynamo electric field of westward polarity associated with the first and second storms. The irregularity zonal drifts measured by a VHF receiver around 24 UT (21 LT) were eastward on the nights of 05/06 and 06/07; however, during the night of 07/08, it reversed to westward.

The first line of defence The inflammasome is a complex of proteins involved in the activation of the innate immune system, an evolutionarily ancient antimicrobial defence found in most multicelled animals. When activated the inflammasome sets in motion a cascade of events that leads to the production of active molecules including interleukins. Three papers in this issue report the identification of endogenous danger signals and bacterial components that activate inflammasomes containing cryopyrin (also known as NALP3). Mariathasan et al . show that cryopyrin activates the inflammasome in response to bacterial toxins and to ATP. Kanneganti et al . show that cryopyrin is activated by bacterial RNA and by the immune response modifiers R837 and R848. And Martinon et al . show that gout-associated uric acid crystals have a similar effect. In sum these results show that cryopyrin has a vital role in host antibacterial defences and may act as a sensor of cellular stress. In addition, this work provides insight into the mechanisms of autoinflammatory disorders in which abnormalities in the innate immune system have been implicated. Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century 1 and more recently as a ‘danger signal’ released from dying cells 2 , little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1β activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1β receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

The innate immune system has evolved the capacity to detect specific pathogens and to interrogate cell and tissue integrity in order to mount appropriate immune responses. Pathogens are detected by innate immune receptors including NLRs and TLRs. Some NLRs, including NALPs (NLRPs), form molecular machines termed inflammasomes. The recruitment of the adaptor ASC and the enzyme caspase-1 to the inflammasome platform are crucial for its activity that mainly control the proteolytic maturation of a few key inflammatory cytokines such as IL-1beta and IL-18. The mechanisms that regulate the activation of inflammasomes are poorly understood. Here we will discuss how perturbations of cellular homeostasis including endoplasmic reticulum (ER) stress trigger the assembly of the NLRP3 inflammasome. These findings suggest new mechanistic insights linking stress pathways and inflammatory diseases. Disclosure of Interest None Declared

Recently, a biomarker signature consisting of 2-transcript host RNAs was proposed for discriminating bacterial from viral infections in febrile children. We evaluated the performance of this signature in a different disease scenario, namely a cohort of Mexican children ( n  = 174) suffering from acute diarrhea of different infectious etiologies. We first examined the admixed background of the patients, indicating that most of them have a predominantly Native American genetic ancestry with a variable amount of European background (ranging from 0% to 57%). The results confirm that the RNA test can discriminate between viral and bacterial causes of infection (t-test; P -value = 6.94×10 −11 ; AUC = 80%; sensitivity: 68% [95% CI: 55%–79%]; specificity: 84% [95% CI: 78%–90%]), but the strength of the signal differs substantially depending on the causal pathogen, with the stronger signal being that of Shigella ( P -value = 3.14 × 10 −12 ; AUC = 89; sensitivity: 70% [95% CI: 57%–83%]; specificity: 100% [95% CI: 100%–100%]). The accuracy of this test improves significantly when excluding mild cases ( P -value = 2.13 × 10 −6 ; AUC = 85%; sensitivity: 79% [95% CI: 58%–95%]; specificity: 78% [95% CI: 65%–88%]). The results broaden the scope of previous studies by incorporating different pathogens, variable levels of disease severity, and different ancestral background of patients, and add confirmatory support to the clinical utility of these 2-transcript biomarkers.

Total Electron Content (TEC) maps allow the evaluation of the state of the ionosphere. There are many providers/sources of worldwide or regional TEC maps for the continuous monitoring of the ionosphere, which employ different GNSS monitoring networks for data acquisition, TEC calculation or interpolation methods for generating the maps, or different spatial and temporal resolutions and coverage. How reliable are TEC maps over Brazil? We employed TEC maps from four different providers for 2022–2024, in the growing phase of the current solar cycle 25. Seasonality is also taken into account. A systematic comparison of TEC maps over Brazil was performed using correlation and similarity analysis between maps of different sources. Significant differences were found. Even for the same source there are differences in the density of monitoring stations according to the region. An example of bubble signature in TEC maps is also analyzed. Ground truth validation of TEC is performed by comparing TEC point values extracted from the maps with values derived from a set of GNSS stations over Brazil. As a result, no TEC maps of these sources were deemed reliable, due to low spatial and/or temporal resolution, low monitoring station density, or inadequate interpolation scheme.

Rotavirus gastroenteritis is a vaccine-preventable disease that confers a high medical and economic burden in more developed countries and can be fatal in less developed countries. Two vaccines with high efficacy and good safety profiles were approved and made available in Europe in 2006. We present an overview of the status of rotavirus vaccination in Europe. We discuss the drivers (including high effectiveness and effect of universal rotavirus vaccination) and barriers (including low awareness of disease burden, perception of unfavourable cost-effectiveness, and potential safety concerns) to the implementation of universal rotavirus vaccination in Europe. By February, 2014, national universal rotavirus vaccination had been implemented in Belgium, Luxembourg, Austria, Finland, Greece, Luxembourg, Norway, and the UK. Four other German states have issued recommendations and reimbursement is provided by sickness funds. Other countries were at various stages of recommending or implementing universal rotavirus vaccination.

Background Diabetes is one of the underlying risk factors for developing community-acquired pneumonia (CAP). The high prevalence of diabetes among population and the rising incidence of this illness, converts it as an important disease to better control and manage, to prevent its secondary consequences as CAP. The objective of this research is to describe the characteristics of the patients with diabetes and the differences with the no diabetes who have had an episode of CAP in the context of the primary care field. Methods A retrospective, observational study in adult patients (> 18 years-old) who suffer from CAP and attended at primary care in Spain between 2009 and 2013 was developed using the Computerized Database for Pharmacoepidemiological Studies in Primary Care (BIFAP). We carried out a descriptive analysis of the first episodes of CAP, in patients with or without diabetes as comorbidity. Other morbidity (CVA, Anaemia, Arthritis, Asthma, Heart disease, Dementia, Depression, Dysphagia, Multiple sclerosis, Epilepsy, COPD, Liver disease, Arthrosis, Parkinson’s disease, Kidney disease, HIV) and life-style factors were also included in the study. Results A total of 51,185 patients were included in the study as they suffer from the first episode of CAP. Of these, 8012 had diabetes as comorbidity. There were differences between sex and age in patients with diabetes. Patients without diabetes were younger, and had less comorbidities including those related to lifestyles such as smoking, alcoholism, social and dental problems than patients with diabetes. Conclusions Patients who developed an episode of CAP with diabetes have more risk factors which could be reduced with an appropriate intervention, including vaccination to prevent successive CAP episodes and hospitalization. The burden of associated factors in these patients can produce an accumulation of risk. Health care professional should know this for treating and control these patients in order to avoid complications. Diabetes and those other risk factors associated could be reduced with an appropriate intervention, including vaccination to prevent the first and successive CAP episodes and the subsequent hospitalization in severe cases.

The autoinflammatory disorders Muckle–Wells syndrome, familial cold urtecaria and chronic infantile neurological cutaneous and articular syndrome are associated with mutations in the NALP3 (Cryopyrin) gene, which is the central platform of the proinflammatory caspase-1 activating complex, named the inflammasome. In patients with another autoinflammatory disorder, familial Mediterranean fever (FMF), mutations in the SPRY domain of the Pyrin protein are frequently found. Recent evidence suggests that Pyrin associates with ASC, an inflammasome component, via its Pyrin domain, thereby halting the inflammatory response. This interaction, however, does not explain the effects of mutations of the SPRY domain found in FMF patients. Here we show that the Pyrin SPRY domain not only interacts with NALP3, but also with caspase-1 and its substrate pro-interleukin(IL)-1 β . Whereas a Pyrin knockdown results in increased caspase-1 activation and IL-1 β secretion, overexpression of the SPRY domain alone blocks these processes. Thus Pyrin binds to several inflammasome components thereby modulating their activity.