Problems Affecting Labor

Much experimental work has been devoted in comparing the folding behavior of proteins sharing the same fold but different sequence. The recent design of proteins displaying very high sequence identities but different 3D structure allows the unique opportunity to address the protein-folding problem from a complementary perspective. Here we explored by ℙ-value analysis the pathways of folding of three different heteromorphic pairs, displaying increasingly high-sequence identity (namely, 30%, 77%, and 88%), but different structures called G A (a 3-α helix fold) and G B (an α/β fold). The analysis, based on 132 site-directed mutants, is fully consistent with the idea that protein topology is committed very early along the pathway of folding. Furthermore, data reveals that when folding approaches a perfect two-state scenario, as in the case of the G A domains, the structural features of the transition state appear very robust to changes in sequence composition. On the other hand, when folding is more complex and multistate, as for the G Bs, there are alternative nuclei or accessible pathways that can be alternatively stabilized by altering the primary structure. The implications of our results in the light of previous work on the folding of different members belonging to the same protein family are discussed

Effectiveness and safety of concurrent beta-blockers and inhaled bronchodilators in COPD with cardiovascular comorbidities

Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease and its prevalence is increasing worldwide, in both industrialised and developing countries. Its prevalence is \ue2\u88\ubc5% in the general population and it is the fourth leading cause of death worldwide. COPD is strongly associated with cardiovascular diseases; in fact, \ue2\u88\ubc64% of people suffering from COPD are treated for a concomitant cardiovascular disease and approximately one in three COPD patients die as a consequence of cardiovascular diseases. Inhaled bronchodilators might have adverse cardiovascular effects, including ischaemic events and arrhythmias, and beta-blockers might adversely influence the respiratory symptoms and the response to bronchodilators. For these reasons, it is important to know the safety profiles and the possible interactions between these two classes of drug, in order to prescribe them with greater awareness. In this article, we review the literature about the epidemiology of COPD, its association with cardiovascular diseases, and the safety of concurrent use of inhaled bronchodilators and beta-blockers, as a tool for improving the approach to complex therapies in clinical practice

The Folding Mechanism of the SH3 Domain from Grb2

SH3 domains are small protein modules involved in the regulation of important cellular pathways. These domains mediate protein-protein interactions recognizing motifs rich in proline on the target protein. The SH3 domain from Grb2 (Grb2-SH3) presents the typical structure of an SH3 domain composed of two-three stranded antiparallel \u3b2-sheets orthogonally packed onto each other, to form a single hydrophobic core. Grb2 interacts, via SH3 domain, with Gab2, a scaffolding disordered protein, triggering some key metabolic pathways involved in cell death and differentiation. In this work we report a mutational analysis (\u3c6-value analysis) of the folding pathway of Grb2-SH3 that, coupled with molecular dynamic simulations, allows us to assess the structure of the transition state and the mechanism of folding of this domain. Data suggest that Grb2-SH3 folds via a native-like, diffused transition state with a concurrent formation of native-like secondary and tertiary structure (nucleation-condensation mechanism) and without the accumulation of folding intermediates. The comparison between our data and previous folding studies on SH3 domains belonging to other proteins, highlights that proteins of this class may fold via alternative pathways, stabilized by different nuclei leading or not to accumulation of folding intermediates. This comparative analysis suggests that the alternative folding pathways for this class of SH3 domains can be selectively regulated by the specific aminoacid sequences

Prevalence and clinical features of celiac disease in a cohort of italian children with autism spectrum disorders

Background: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions whose etiopathogenesis derives from a complex interaction between genetic liability and environmental factors. In this framework, mounting evidence suggests that immune system dysfunction could be a risk factor contributing to the development of ASD in at least a subpopulation of individuals. In particular, some studies suggest an association between celiac disease (CD)—a long‐term autoimmune disorder that primarily affects the small intestine triggered by the ingestion of gluten—and ASD, while others hypothesized a random link. This investigation aimed to evaluate the prevalence of CD in a large sample of school‐aged children with ASD and to characterize their clinical profile. Methods: Medical records of 405 children with ASD aged 5–11 years (mean age: 7.2 years; SD: 1.8 years) consecutively referred to a tertiary‐care university hospital between January 2014 and December 2018 were reviewed; among them, 362 had carried out serological testing for CD. Results: Nine patients with positive CD serology were identified, eight of which satisfied the criteria for CD diagnosis. The estimated CD prevalence in ASD children was 2.18% (95% CI, 0.8–3.7), which was not statistically different (1.58%; p = 0.36) from that of an Italian population, matched for age range, considered as a control group (95% CI, 1.26–1.90). Three out of the eight ASD patients with CD did not have any symptoms suggestive of CD. Conclusions: Our findings did not show a higher prevalence of CD in ASD children than in the control population, but could suggest the utility of routine CD screening, given its frequent atypical clinical presentation in this population

Discovering the characteristics of the surface faulting ancestors of the L’Aquila April 6, 2009 earthquake by paleoseismological investigations

The occurrence of the Mw 6.3, April 6, 2009 earthquake has highlighted how critical is the development of hazard models that incorporate all the information on the long-term seismic behavior of faults (i.e., individual events rupture length and slip, timing, etc.). Under this light we started a campaign of paleoseismological investigations in the epicentral area. The 2009 earthquake occurred on the Paganica normal fault (PF hereinafter) and produced a max 0.15 m high, 3 km-long continuous surface rupture along its central section, as well as several short, discontinuous cracks along the rest of the fault trace; secondary slip along nearby tectonic structures was observed too. The PF consists of a prominent NW-SE striking and SW dipping long-term morphologic scarp formed by the tectonic juxtaposition of Pliocene-middle Pleistocene and late Pleistocene alluvial deposits, and by smaller compound scarps in late Pleistocene-Holocene deposits. The fault runs for a total length of about 20 km along the NE side of the Aterno River valley, a graben-type basin bounded by marked antithetic faults. The limited extent and the small throw of the 2009 surface ruptures, when compared to the size of the Paganica long-term fault scarp, raise questions about the evolution and rupture history of this fault and suggest that the PF may have experienced larger Magnitude earthquakes than the 2009 seismic event. With the aim of defining the Max Magnitude expected for the PF by determining the size of the individual coseismic surface ruptures occurred in the past and their max extent, their frequency and the average rate of displacement we have been excavating new trenches and studied artificial exposures across the PF fault zone, in most of the cases intersecting the 2009 surface ruptures. Preliminary results show evidence for repeated decimetric surface faulting events during the past 3 millennia with the penultimate likely being the 1461 event (Me 6.4); evidence for possible previous larger slip events is found too. Whether the small ruptures are all related to slip at depth on the PF or would represent sympathetic slip triggered by earthquake occurred on nearby faults should be better investigated. Conversely, provided the “double size” slip behavior of the PF is confirmed, to characterize the seismic hazard of the area we should consider a more complex seismogenic model than that presently applied. In particular, we should include also the scenario that the PF produces relatively frequent (each 4-600 yr) 2009-type earthquakes and rare (each 3-4 millennia) larger events, likely in connection with other nearby active structures (i.e., San Demetrio Fault? Pettino Fault?)

Templated folding of intrinsically disordered proteins

Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding

Land subsidence, Ground Fissures and Buried Faults: InSAR Monitoring of Ciudad Guzmán (Jalisco, Mexico)

We study land subsidence processes and the associated ground fissuring, affecting an active graben filled by thick unconsolidated deposits by means of InSAR techniques and fieldwork. On 21 September 2012, Ciudad Guzmán (Jalisco, Mexico) was struck by ground fissures of about 1.5 km of length, causing the deformation of the roads and the propagation of fissures in adjacent buildings. The field survey showed that fissures alignment is coincident with the escarpments produced on 19 September 1985, when a strong earthquake with magnitude 8.1 struck central Mexico. In order to detect and map the spatio-temporal features of the processes that led to the 2012 ground fissures, we applied InSAR multitemporal techniques to process ENVISAT-ASAR and RADARSAT-2 satellite SAR images acquired between 2003 and 2012. We detect up to 20 mm/year of subsidence of the northwestern part of Ciudad Guzmán. These incremental movements are consistent with the ground fissures observed in 2012. Based on interferometric results, field data and 2D numerical model, we suggest that ground deformations and fissuring are due to the presence of areal subsidence correlated with variable sediment thickness and differential compaction, partly driven by the exploitation of the aquifers and controlled by the distribution and position of buried faults

Sulfolobus acidocaldarius terminal oxidase. A kinetic investigation and its structural interpretation.

Abstract The thermoacidophilic archaebacterium Sulfolobus acidocaldarius possesses a very unusual terminal oxidase. We report original kinetic experiments on membranes of this microorganism carried out by stopped flow, using time-resolved optical spectroscopy combined with singular value decomposition analysis. The reduced-oxidized kinetic difference spectrum of the Sulfolobus membranes is characterized by three significant peaks in the visible region at 605, 586, and 560 nm. The 605-nm peak and part of the 586-nm peak (cytochrome aa3-type quinol oxidase) are reduced synchronously by both ascorbate plus N,N,N',N'-tetramethyl-p-phenylendiamine (TMPD) and dithionite, and they are very rapidly oxidized by molecular oxygen. A second pool of cytochromes seems to contribute to the 586-nm peak which is not reduced by ascorbate plus TMPD and reacts very slowly with dithionite. The b-type cytochromes (560 nm peak) are reduced by both reductants and are essentially "non-autoxidizable" at room temperature. Only one CO binding site with spectral features, kinetic properties, and ligand affinity not very dissimilar from those of mammalian cytochrome oxidase can be detected in the ascorbate-reduced membranes. On the contrary, a second CO binding site having unusual properties for aa3 terminal oxidases can be detected in the dithionite-reduced membranes

Position paper on the safety/efficacy profile of Direct Oral Anticoagulants in patients with Chronic Kidney Disease: Consensus document of Società Italiana di Nefrologia (SIN), Federazione Centri per la diagnosi della trombosi e la Sorveglianza delle terapie Antitrombotiche (FCSA) and Società Italiana per lo Studio dell’Emostasi e della Trombosi (SISET)

Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism and an increased use of DOAC in daily practice is recorded also in elderly patients. Aging is associated with a reduction of glomerular filtration rate and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. There is uncertainty on the safety profile of DOAC in patients with CKD, particularly in those with severely impaired renal function or end stage renal disease, due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD

The VELISAR initiative for the measurement of ground velocity in italian seismogenic areas

VELISAR (Ground VELocity in Italian Seismogenic Areas) is a scientific research initiative aimed at producing a map of the ground deformation over most of the seismogenic areas of Italy, using the space-based technique of multitemporal Synthetic Aperture Radar Interferometry (InSAR). The ground velocities derived from InSAR data will be validated by means of ground based data obtained from GPS, optical leveling, seismological and neotectonic studies. The scope of the project is to produce a high-resolution ground deformation dataset useful to model the seismic cycle of strain accumulation and release at the scale of the single faults. The main objective of VELISAR is to produce maps of ground velocity with the following characteristics: - A ground resolution better than 100 m. - Average uncertainty of LoS velocity measurements smaller than 2 mm/yr . - Temporal coverage of at least 7 years. - Retrieval of East and Up components from ascending and descending LoS. VELISAR will exploit the potential of the long time series (1992-2000) of ERS InSAR data maintained in the ESA archives; over 4000 ERS images will have to be processed to accomplish its objectives. Presently, two InSAR techniques for the measurement of slow ground deformation are used in VELISAR: the Permanent Scatterers (PS) technique developed by the Politecnico of Milano (POLIMI), and the Small Baseline Subset (SBAS) technique, developed by the Institute for Remote Sensing of Environment (IREA-CNR), in Napoli. The PS technique is applied by TRE preferably over areas characterised by diffuse temporal decorrelation due to, for instance, erodible lithologies, agricultural land use and strong vegetation cover. In these areas we expect to obtain good temporal coherence mainly on sparse point scatterers. The SBAS technique is applied by IREA and INGV mostly over areas where limited temporal decorrelation is expected: urban areas, scarcely vegetated areas. The ground resolution at which these data are originally processed is 80 m. An important goal of the VELISAR initiative is to disseminate the information on the InSAR-derived ground velocity measurements, to the scientific community and to the public in general. Such goal is accomplished through a dedicated web site, where the velocity maps of the italian seismogenic areas will be progressively published. We will present the initiative, its scope and objectives, the technical details and the data processing strategies, and some examples of ground velocity maps.PublishedVienna, Austriaope