Imaging the dome of Santa Maria del Fiore using cosmic rays Guardincerri, E; Bacon, J D; Barros, N ...
Philosophical transactions of the Royal Society of London. Series A: Mathematical, physical, and engineering sciences,
12/2018, Letnik:
377, Številka:
2137
Journal Article
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The dome of Santa Maria del Fiore, Florence Cathedral, was built between 1420 and 1436 by architect Filippo Brunelleschi and it is now cracking under its own weight. Engineering efforts are under way ...to model the dome's structure and reinforce it against further deterioration. According to some scholars, Brunelleschi might have built reinforcement structures into the dome itself; however, the only known reinforcement is a wood chain 7.75 m above the springing of the Cupola. Multiple scattering muon radiography is a non-destructive imaging method that can be used to image the interior of the dome's wall and therefore ascertain the layout and status of any iron substructure in it. A demonstration measurement was performed at the Los Alamos National Laboratory on a mock-up wall to show the feasibility of the work proposed, and a lightweight and modular imaging system is currently under construction. We will discuss here the results of the demonstration measurement and the potential of the proposed technique, describe the imaging system under construction and outline the plans for the measurement.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.
TLQP-21, a VGF-encoded peptide is emerging as a novel target for obesity-associated disorders. TLQP-21 is found in the sympathetic nerve terminals in the adipose tissue and targets the ...G-protein-coupled receptor complement-3a receptor1 (C3aR1). The mechanisms of TLQP-21-induced receptor activation remain unexplored. Here, we report that TLQP-21 is intrinsically disordered and undergoes a disorder-to-order transition, adopting an α-helical conformation upon targeting cells expressing the C3aR1. We determined that the hot spots for TLQP-21 are located at the C terminus, with mutations in the last four amino acids progressively reducing the bioactivity and, a single site mutation (R21A) or C-terminal amidation abolishing its function completely. Additionally, the human TLQP-21 sequence carrying a S20A substitution activates the human C3aR1 receptor with lower potency compared to the rodent sequence. These studies reveal the mechanism of action of TLQP-21 and provide molecular templates for designing agonists and antagonists to modulate C3aR1 functions.
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•TLQP-21 activates the C3aR1 receptor through a folding-upon-binding mechanism•C3aR1 inhibitor competes with TLQP-21 binding preventing its transition to α helix•The C-terminal amino acids constitute the hot spots for TLQP-21 biological activity•Rodent TLQP-21 sequence actives human C3aR1 with higher potency than human TLQP-21
Cero et al. report that TLQP-21, a peptide implicated in obesity, undergoes disorder-to-order transition and adopts an α helix upon targeting the C3aR1-receptor. They examine what molecular features govern TLQP-21 activity and thus provide a template for designing C3aR1 agonists and antagonists.
To summarize evidence from randomized controlled trials (RCTs) on the effectiveness of virtual reality technology (VRT), as used by patients, for reducing pain during outpatient hysteroscopy.
...Electronic databases and clinical registers were searched until June 21, 2023. The review protocol was registered in PROSPERO before the data extraction (CRD42023434340).
We included RCTs of patients receiving VRT compared with controls receiving routine care during outpatient hysteroscopy.
The primary outcome was average pain during hysteroscopy. Pooled results were expressed as mean differences (MDs) with 95% confidence interval (CI). Sources of heterogeneity were investigated through sensitivity and subgroups analysis. Five RCTs were included (435 participants). The comparison between the intervention and control groups showed a borderline difference in perceived pain during hysteroscopy (MD -0.88, 95% CI -1.77 to 0.01). Subgroup analysis based on the type of VRT (active or passive) indicated that active VRT potentially reduced the perception of pain (MD -1.42, 95% CI -2.21 to -0.62), whereas passive VRT had no effect (MD -0.06, 95% CI -1.15 to 1.03).
Patients' use of active VRT may be associated with a reduction in pain during outpatient hysteroscopy (evidence Grading of Recommendations Assessment, Development, and Evaluation 2/4). Future research should focus on conducting methodologically robust studies with larger sample sizes and more homogeneous populations.
The San Salvador volcanic complex (El Salvador) and Nejapa-Chiltepe volcanic complex (Nicaragua) have been characterized by a significant variability in eruption style and vent location. Densely ...inhabited cities are built on them and their surroundings, including the metropolitan areas of San Salvador (∼2.4 million people) and Managua (∼1.4 million people), respectively. In this study we present novel vent opening probability maps for these volcanic complexes, which are based on a multi-model approach that relies on kernel density estimators. In particular, we present thematic vent opening maps, i.e., we consider different hazardous phenomena separately, including lava emission, small-scale pyroclastic density currents, ejection of ballistic projectiles, and low-intensity pyroclastic fallout. Our volcanological dataset includes: (1) the location of past vents, (2) the mapping of the main fault structures, and (3) the eruption styles of past events, obtained from critical analysis of the literature and/or inferred from volcanic deposits and morphological features observed remotely and in the field. To illustrate the effects of considering the expected eruption style in the construction of vent opening maps, we focus on the analysis of small-scale pyroclastic density currents derived from phreatomagmatic activity or from low-intensity magmatic volcanism. For the numerical simulation of these phenomena we adopted the recently developed branching energy cone model by using the program ECMapProb. Our results show that the implementation of thematic vent opening maps can produce significantly different hazard levels from those estimated with traditional, non-thematic maps.
TLQP-21 is a multifunctional neuropeptide and a promising new medicinal target for cardiometabolic and neurological diseases. However, to date its clearance kinetics and plasma stability have not ...been studied. The presence of four arginine residues led us to hypothesize that its half-life is relatively short. Conversely, its biological activities led us to hypothesize that the peptide is still taken up by adipose tissues effectively. 125ITLQP-21 was i.v. administered in rats followed by chasing the plasma radioactivity and assessing tissue uptake. Plasma stability was measured using LC-MS. In vivo lipolysis was assessed by the palmitate rate of appearance. Results: A small single i.v. dose of 125ITLQP-21 had a terminal half-life of 110 min with a terminal clearance rate constant, kt, of 0.0063/min, and an initial half-life of 0.97 min with an initial clearance rate constant, ki, of 0.71/min. The total net uptake by adipose tissue accounts for 4.4% of the entire dose equivalent while the liver, pancreas and adrenal gland showed higher uptake. Uptake by the brain was negligible, suggesting that i.v.-injected peptide does not cross the blood-brain-barrier. TLQP-21 sustained isoproterenol-stimulated lipolysis in vivo. Finally, TLQP-21 was rapidly degraded producing several N-terminal and central sequence fragments after 10 and 60 min in plasma in vitro. This study investigated the clearance and stability of TLQP-21 peptide for the first time. While its pro-lipolytic effect supports and extends previous findings, its short half-life and sequential cleavage in the plasma suggest strategies for chemical modifications in order to enhance its stability and therapeutic efficacy.
•i.v.-injected 125ITLQP-21 had an initial half-life of 0.97 min and a terminal half-life of 110 min.•The total net uptake by adipose tissue was 4.4% of the entire i.v.-injected dose equivalent.•Upon i.v.-injection, liver, pancreas and adrenal gland showed higher uptake, while uptake by the brain was negligible.•TLQP-21 sustained isoproterenol-stimulated lipolysis in vivo.•TLQP-21 was rapidly degraded to several N-terminal and central sequence fragments after 10 and 60 min in plasma in vitro.
Cardiac contraction and relaxation are regulated by conformational transitions of protein complexes that are responsible for calcium trafficking through cell membranes. Central to the muscle ...relaxation phase is a dynamic membrane protein complex formed by Ca2+-ATPase (SERCA) and phospholamban (PLN), which in humans is responsible for ∼70% of the calcium re-uptake in the sarcoplasmic reticulum. Dysfunction in this regulatory mechanism causes severe pathophysiologies. In this report, we used a combination of nuclear magnetic resonance, electron paramagnetic resonance, and coupled enzyme assays to investigate how single mutations at position 21 of PLN affects its structural dynamics and, in turn, its interaction with SERCA. We found that it is possible to control the activity of SERCA by tuning PLN structural dynamics. Both increased rigidity and mobility of the PLN backbone cause a reduction of SERCA inhibition, affecting calcium transport. Although the more rigid, loss-of-function (LOF) mutants have lower binding affinities for SERCA, the more dynamic LOF mutants have binding affinities similar to that of PLN. Here, we demonstrate that it is possible to harness this knowledge to design new LOF mutants with activity similar to S16E (a mutant already used in gene therapy) for possible application in recombinant gene therapy. As proof of concept, we show a new mutant of PLN, P21G, with improved LOF characteristics in vitro.
Purpose
The aim of this study was to evaluate the safety and compliance with the enhanced recovery after surgery (ERAS) protocol in octogenarian patients undergoing colorectal surgery in 12 Italian ...high-volume centers.
Methods
A retrospective analysis was conducted in a consecutive series of patients who underwent elective colorectal surgery between 2016 and 2018. Patients were grouped by age (≥ 80 years vs < 80 years), propensity score matching (PSM) analysis was performed, and the groups were compared regarding clinical outcomes and the mean number of ERAS items applied.
Results
Out of 1646 patients identified, 310 were octogenarians. PSM identified 2 cohorts of 125 patients for the comparison of postoperative outcomes and ERAS compliance. The 2 groups were homogeneous regarding the clinical variables and mean number of ERAS items applied (11.3 vs 11.9,
p
-ns); however, the application of intraoperative items was greater in nonelderly patients (
p
0.004). The functional recovery was similar between the two groups, as were the rates of postoperative severe complications and 30-day mortality rate. Elderly patients had more overall complications. Furthermore, the mean hospital stay was higher in the elderly group (
p
0.027). Multivariable analyses documented that postoperative stay was inversely correlated with the number of ERAS items applied (
p
< 0.0001), whereas age ≥ 80 years significantly correlated with the overall complication rate (
p
0.0419).
Conclusion
The ERAS protocol is safe in octogenarian patients, with similar levels of compliance and surgical outcomes. However, octogenarian patients have a higher rate of overall complications and a longer hospital stay than do younger patients.
A general methodology of pyroclastic fall hazard assessment is proposed on the basis of integrated results of field studies and numerical simulations. These approaches result in two different methods ...of assessing hazard: (1) the “field frequency,” based on the thickness and distribution of past deposits and (2) the “simulated probability,” based on the numerical modeling of tephra transport and fallout. The proposed methodology mostly applies to volcanoes that, by showing a clear correlation between the repose time and the magnitude of the following eruptions, allows the definition of a reference “maximum expected event” (MEE). The application to Vesuvius is shown in detail. Using the field frequency method, stratigraphic data of 24 explosive events in the 3–6 volcanic explosivity index range in the last 18,000 years of activity are extrapolated to a regular grid in order to obtain the frequency of exceedance in the past of a certain threshold value of mass loading (100, 200, 300, and 400 kg/m2). Using the simulated probability method, the mass loading related to the MEE is calculated based on the expected erupted mass (5 × 1011 kg), the wind velocity profiles recorded during 14 years, and various column heights and grain‐size populations. The role of these factors was parametrically studied performing ∼160,000 simulations, and the probability that mass loading exceeded the chosen threshold at each node was evaluated. As a general rule, the field frequency method results are more reliable in proximal regions, provided that an accurate database of field measurements is available. On the other hand, the simulated probability method better describes events in middle distal areas, provided that the MEE magnitude can be reliably assumed. In the Vesuvius case, the integration of the two methods results in a new fallout hazard map, here presented for a mass loading value of 200 kg/m2.
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