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Global-mean surface temperature rapidly increased 0.29 ± 0.04 K from 2022 to 2023. Such a large interannual global warming spike is not unprecedented in the observational record, with a previous instance occurring in 1976–1977. However, why such large global warming spikes occur is unknown, and the rapid global warming of 2023 has led to concerns that it could have been externally driven. Here we show that climate models that are subject only to internal variability can generate such spikes, but they are an uncommon occurrence (p = 1.6 % ± 0.1 %). However, when a prolonged La Niña immediately precedes an El Niño in the simulations, as occurred in nature in 1976–1977 and 2022–2023, such spikes become much more common (p = 10.3 % ± 0.4 %). Furthermore, we find that nearly all simulated spikes (p = 88.5 % ± 0.3 %) are associated with El Niño occurring that year. Thus, our results underscore the importance of the El Niño–Southern Oscillation in driving the occurrence of global warming spikes such as the one in 2023, without needing to invoke anthropogenic forcing, such as changes in atmospheric concentrations of greenhouse gases or aerosols, as an explanation.

An overview is presented of the progress since 2021 in the construction and scientific programme preparation of the Divertor Tokamak Test (DTT) facility. Licensing for building construction has been granted at the end of 2021. Licensing for Cat. A radiologic source has been also granted in 2022. The construction of the toroidal field magnet system is progressing. The prototype of the 170 GHz gyrotron has been produced and it is now under test on the FALCON facility. The design of the vacuum vessel, the poloidal field coils and the civil infrastructures has been completed. The shape of the first DTT divertor has been agreed with EUROfusion to test different plasma and exhaust scenarios: single null, double null, X-divertor and negative triangularity plasmas. A detailed research plan is being elaborated with the involvement of the EUROfusion laboratories.

The intrinsic poor loading of Ion Cyclotron (IC) plasma-facing antennas makes the use of Tuning and Matching Systems (TMSs) a necessity. The antenna plus TMS is a resonant system; in the TMS and access lines high voltages (tens of kV) must be accounted for in the unavoidable unmatched part of the feeding lines. In this work, we propose and test an innovative type of IC launcher; it is based on achieving resonance of the self-standing antenna, i.e. without the TMS. A mechanical full-metal tuning mechanism is described and demonstrated to allow wide-band operation. A systematic analysis of possible antenna topologies has led to identifying a structure that can allow good impedance matching along with compliance with maximum electric field constraints. Most of the design is carried out using a simplified plasma and a commercial analysis tool and then validated with a realistic plasma using TOPICA code.

This work proposes a low-cost and low-power software-defined radio open-source platform with IEEE 802.11 a/g/p wireless communication capability. A state-of-the-art version of the IEEE 802.11 a/g/p software for GNU Radio (a free and open-source software development framework) is available online, but we show here that its computational complexity prevents operations in low-power general purpose processors, even at throughputs below the standard. We therefore propose an evolution of this software that achieves a faster and lighter IEEE 802.11 a/g/p transmitter and receiver, suitable for low-power general purpose processors, for which GNU Radio provides very limited support; we discuss and describe the software radio processing structuring that is necessary to achieve the goal, providing a review of signal processing techniques. In particular, we emphasize the advanced reduced-instruction set (RISC) machine (ARM) study case, for which we also optimize some of the processing libraries. The presented software will remain open-source.

Climate signals are the results of interactions of multiple timescale media such as the atmosphere and ocean in the coupled earth system. Coupled data assimilation (CDA) pursues balanced and coherent climate analysis and prediction initialization by incorporating observations from multiple media into a coupled model. In practice, an observational time window (OTW) is usually used to collect measured data for an assimilation cycle to increase observational samples that are sequentially assimilated with their original error scales. Given different timescales of characteristic variability in different media, what are the optimal OTWs for the coupled media so that climate signals can be most accurately recovered by CDA? With a simple coupled model that simulates typical scale interactions in the climate system and twin CDA experiments, we address this issue here. Results show that in each coupled medium, an optimal OTW can provide maximal observational information that best fits the characteristic variability of the medium during the data blending process. Maintaining correct scale interactions, the resulting CDA improves the analysis of climate signals greatly. These simple model results provide a guideline for when the real observations are assimilated into a coupled general circulation model for improving climate analysis and prediction initialization by accurately recovering important characteristic variability such as sub-diurnal in the atmosphere and diurnal in the ocean.

Coppa di testa is a traditional cooked pork salami produced in different Italian regions. The main raw material is deboned meat of pork head with the addition of tongue and rind. After a long (3-5 h) high temperature (97°C) cooking, additives and flavourings are added and the salami is prepared. After cooling the salami is often portioned and vacuum- packaged. In this study the growth of naturally occurring contamination of Listeria innocua in three batches of vacuum packaged Coppa di testa, stored at 4°C for 80 days, is described. The average max was 0.24 (days-1) and the average doubling time was 2.87 days. The maximum growth level ranged from 4.90 to 8.17 (log10 cfu/g). These results indicate that Coppa di testa definitely supports the growth of Listeria innocua in the considered storage conditions. Taking into account that at 4°C Listeria monocytogenes strains are associated with higher grow rates than L. innocua, these results emphasize the importance of preventing Listeria monocytogenes contamination in the production stages following cooking.

Following preliminary feasibility studies which started at Legnaro National Laboratories (LNL) in 2011, the Italian National Institute for Nuclear Physics (INFN) research activities are underway aiming at the alternative, accelerator-driven, Mo99/Tc99m production routes. One of the most promising approaches is to use 100Mo-enriched (i.e., >99%) molybdenum metallic targets, bombarded with high-beam-current, high-energy proton cyclotrons. In order to get a comprehensive map of radionuclides expected, a detailed theoretical investigation has been carried out using the TALYS-TENDL 2012 excitation functions extended up to (p,6n), (p,p5n), and (p,2p4n) levels. A series of quality parameters have thus been calculated both at the end of beam (EOB) and at longer times. Results point out that accelerator-99Mo is of limited interest for a possible massive production because of the quite low specific activity with respect to reactor-99Mo. Accelerator-Tc99m quality parameters (i.e., radionuclidic purity (RNP), isotopic purity (IP), and specific activities) calculated are instead quite close to the generator-Tc. Calculations at 15, 20, and 25 MeV have thus been performed to assess the best operative irradiation condition for Tc99m production while minimizing both the short-lived and long-lived Tc contaminant radionuclides. Although present in minimum quantities, Tc contaminants may indeed have an impact either on the pharmaceutical labeling procedures or on contributing to patient radiation dose during the diagnostic procedures.

We demonstrate the coupling of bright and dark surface lattice resonances (SLRs), which are collective Fano resonances in 2D plasmonic crystals. As a result of this coupling, a frequency stop gap in the dispersion relation of SLRs is observed. The different field symmetries of the low- and high-frequency SLR bands lead to pronounced differences in their coupling to free-space radiation. Standing waves of very narrow spectral width compared to localized surface-plasmon resonances are formed at the high-frequency band edge, while subradiant damping onsets at the low-frequency band edge, leading the resonance into darkness. We introduce a coupled-oscillator analog to the plasmonic crystal, which serves to elucidate the physics of the coupled plasmonic resonances and which is used to estimate very high quality factors for SLRs.

Abstract During the second long shutdown period of the CERN accelerator complex (LS2, 2019-2021), several upgrade activities took place at the n_TOF facility. The most important have been the replacement of the spallation target with a next generation nitrogen-cooled lead target. Additionally, a new experimental area, at a very short distance from the target assembly (the NEAR Station) was established. In this paper, the core commissioning actions of the new installations are described. The improvement in the n_TOF infrastructure was accompanied by several detector development projects. All these upgrade actions are discussed, focusing mostly on the future perspectives of the n_TOF facility. Furthermore, some indicative current and future measurements are briefly reported.

Abstract The origin of the Mediterranean Outflow is investigated by deploying six millions virtual Lagrangian parcels at the Strait of Gibraltar, and tracing them backward in time using velocity estimates from an eddy‐permitting reanalysis. The Lagrangian parcels are followed until they intercept one of three sections. The hypothesis is that each section is associated with distinct water masses: the Gulf of Lions, related to Western Mediterranean Deep Water and Western Intermediate Water, carries 86% of the Outflow's transport; the Northern Tyrrhenian, related to Tyrrhenian Deep and Intermediate Waters, carries 1% of the transport; the Strait of Sicily, related to Levantine Intermediate Waters, carries 13% of the transport. The median transit times from the sections to the Strait of Gibraltar range from 5 years (Gulf of Lions) to 8 years (Strait of Sicily).

At the Laboratori Nazionali del Sud of INFN (INFN-LNS) in Catania, the construction of the new Radioactive Ion Beams (RIBs) facility FRAISE (FRAgment In-flight SEparator) has reached its ending phase. The facility uses the in-flight technique based on a primary beam fragmentation impinging on light Be or C targets. FRAISE makes use of light and medium mass primary beams, having power up to ≈ 2–3 kW, leading to RIBs, whose intensities vary in the range of ≈ 103–107 pps, for nuclei far from and close to the stability valley, respectively. FRAISE aims at providing high-intensity and high-quality RIBs for nuclear physics experiments, also serving to interdisciplinary research areas, such as medical physics. Critical aspects for high-quality beams are the tuning and transport, representing time-consuming processes and requiring dedicated diagnostics and tagging devices measuring many features of RIBs. Some of these devices should be capable to operate in radioactively activated environments because of the expected 2 kW beam lost in the dipole after the production target. Due to its peculiar robustness to radioactive damage, Silicon Carbide (SiC) technology has been considered for the detection layer. In this view, an R&D campaign has been started aiming at developing the FRAISE facility, the new diagnostics system, and a new tagging device, the latter of which will be useful for the CHIMERA multidetector beamline. In this paper, we discuss the status and the perspectives of the facility with a focus on the RIBs opportunities.

Olive pomace, a heterogeneous solid waste from olive oil production, is one of the most widespread agro- industrial by-products in Mediterranean area. The amount of organic compounds with high chemical and biological oxygen demands present in olive pomace stresses the related industries to adapt adequate treatments for this by-product. Being rich in bioactive molecules, it could be considered a low-cost and renewable source of high added value compounds, such as polyphenols. Dietary plant polyphenols are the subject of increasing scientific interest because of their possible beneficial effects on human health. Recent studies suggested that action of polyphenols goes beyond the modulation of oxidative stress and can improve several physiopathological conditions. In the present study, we investigated the possible effects of polyphenols extracted from olive pomace (PEOP) and of the main single phenolic compounds present in the extract (tyrosol, apigenin and oleuropein) in protecting hepatocytes against excess fat and oxidative stress. PEOP were extracted using a high pressure- temperature agitated reactor (25 bar, 180 °C for 90 min). A mixture of ethanol:water (50:50 v/v) was used as extraction solvents resulting to total polyphenol concentration of 5.77 mgCaffeic Acid Equivalent/mL. In order to test the biological effects of the extract we used rat hepatoma FaO cells exposed to a mixture of oleate/palmitate (2:1 molar ratio) for 3 h which represent a reliable in vitro model for hepatic steatosis. After lipid-loading, hepatic cells were incubated for 24 h in the absence or in the presence of 10 µg/mL tyrosol, 13 µg/mL apigenin or 50 µg/mL oleuropein. Content of intra- and extra-cellular triglycerides (TGs), and oxidative stress-related parameters were evaluated. The preliminary results showed that PEOP ameliorated lipid accumulation and lipid-dependent oxidative unbalance showing their potential applications as therapeutic agents.

The main objective was to study the appropriateness of membrane bioreactor (MBR) technology in treating petrochemical wastewater under the variable conditions of the petrochemical industry. Five experimental periods were carried out; in the first period the operating conditions of the full scale MBR were examined, and then changes were introduced, such as the addition of more external carbon source, the decrease of the anoxic compartment volume, alternations in configuration and an increase of the influent load. Laboratory batch experiments were conducted in order to assess the impact of spent caustic soda on nitrification. Finally, the impact of fouling and clogging layers on the removal of trace metals/metalloids was studied during the long-term operation of the MBR. The results showed that the composition of petrochemical wastewater affected the biological processes. Specifically, in the pre-denitrification configuration ammonification was not effective, while ammonium oxidation was high. The addition of higher concentration of acetic acid compared to the one added to the full scale plant increased the denitrification rate and the organic carbon oxidation. The decrease in the volume of the anoxic compartment and the abolition of internal recycling reduced the rate of denitrification. Doubling the influent wastewater flow did not significantly affect the quality of the treated effluent. The unwanted biofilm layer was more effective than activated sludge in the uptake of certain metals/metalloids.

Not available.

The Bahía Blanca estuary (Argentina) has a morphological configuration resulting from hydrological and sedimentary processes related to Late Quaternary sea level changes. This estuarine system occupies a large coastal plain with a dense net of tidal channels, low-altitude islands and large intertidal flats. Little is known about the sedimentary units of the marine subbottom. Therefore, a stratigraphical analysis of the northern coast of Bahía Blanca estuary was carried out using high resolution seismic (3.5 kHz) in order to: i) define Quaternary sequences, ii) describe sedimentary structures, and iii) determine the paleoenvironmental conditions of sedimentation. The seismic stratigraphic data collected and their correlation with drilling lithological data show five seismic sequences (S1, S2, S3, S4 and S5), of which S1-S2 were found to be associated with a continental paleoenvironment of Miocene-Pleistocene age. Sequences S3 and S4, whose lithology and seismic facies (paleochannel structures and prograding reflection configurations), were defined on these materials, to evidence the development of an ancient deltaic environment which was part of a large Pleistocene drainage system. The S5 sequence was formed during the Holocene transgressive-regressive process and complete the seismostratigraphic column defined in the present study.

The aim of the article is to provide a summary of the work carried out in the framework of a research project funded by the Italian Ministry of Research. The main goal of the activity was to introduce multiple tools for reliable, affordable, and high-performance microwave hyperthermia for cancer therapy. The proposed methodologies and approaches target microwave diagnostics, accurate in vivo electromagnetic parameters estimation, and improvement in treatment planning using a single device. This article provides an overview of the proposed and tested techniques and shows their complementarity and interconnection. To highlight the approach, we also present a novel combination of specific absorption rate optimization via convex programming with a temperature-based refinement method implemented to mitigate the effect of thermal boundary conditions on the final temperature map. To this purpose, numerical tests were carried out for both simple and anatomically detailed 3D scenarios for the head and neck region. These preliminary results show the potential of the combined technique and improvements in the temperature coverage of the tumor target with respect to the case wherein no refinement is adopted.

Background: Unsupervised clustering of biomarkers derived from noninvasive samples such as nasal fluid is less evaluated as a tool for describing asthma endotypes., Objective: We sought to evaluate whether protein expression in nasal fluid would identify distinct clusters of patients with asthma with specific lower airway molecular phenotypes., Methods: Unsupervised clustering of 168 nasal inflammatory and immune proteins and Shapley values was used to stratify 43 patients with severe asthma (endotype of noneosinophilic asthma) using a 2 "modeling blocks" machine learning approach. This algorithm was also applied to nasal brushings transcriptomics from U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes). Feature reduction and functional gene analysis were used to compare proteomic and transcriptomic clusters. Gene set variation analysis provided enrichment scores of the endotype of noneosinophilic asthma protein signature within U-BIOPRED sputum and blood., Results: The nasal protein machine learning model identified 2 severe asthma endotypes, which were replicated in U-BIOPRED nasal transcriptomics. Cluster 1 patients had significant airway obstruction, small airways disease, air trapping, decreased diffusing capacity, and increased oxidative stress, although only 4 of 18 were current smokers. Shapley identified 20 cluster-defining proteins. Forty-one proteins were significantly higher in cluster 1. Pathways associated with proteomic and transcriptomic clusters were linked to T H 1, T H 2, neutrophil, Janus kinase-signal transducer and activator of transcription, TLR, and infection activation. Gene set variation analysis of the nasal protein and gene signatures were enriched in subjects with sputum neutrophilic/mixed granulocytic asthma and in subjects with a molecular phenotype found in sputum neutrophil-high subjects., Conclusions: Protein or gene analysis may indicate molecular phenotypes within the asthmatic lower airway and provide a simple, noninvasive test for non-type 2 immune response asthma that is currently unavailable., (Copyright © 2022. Published by Elsevier Inc.)

Parkinson's disease is a common, incurable neurodegenerative disorder that is clinically heterogeneous: it is likely that different cellular mechanisms drive the pathology in different individuals. So far it has not been possible to define the cellular mechanism underlying the neurodegenerative disease in life. We generated a machine learning-based model that can simultaneously predict the presence of disease and its primary mechanistic subtype in human neurons. We used stem cell technology to derive control or patient-derived neurons, and generated different disease subtypes through chemical induction or the presence of mutation. Multidimensional fluorescent labelling of organelles was performed in healthy control neurons and in four different disease subtypes, and both the quantitative single-cell fluorescence features and the images were used to independently train a series of classifiers to build deep neural networks. Quantitative cellular profile-based classifiers achieve an accuracy of 82%, whereas image-based deep neural networks predict control and four distinct disease subtypes with an accuracy of 95%. The machine learning-trained classifiers achieve their accuracy across all subtypes, using the organellar features of the mitochondria with the additional contribution of the lysosomes, confirming the biological importance of these pathways in Parkinson's. Altogether, we show that machine learning approaches applied to patient-derived cells are highly accurate at predicting disease subtypes, providing proof of concept that this approach may enable mechanistic stratification and precision medicine approaches in the future., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)

Purpose: The aim of this study was to investigate the performance and the reversibility of different classes of Hyaluronic Acid (HA) dermal fillers. We analysed 4 HA based fillers, belonging to 3 different chemical classes of products, commonly used in the field of wrinkles correction: linear HA 8 mg/mL (Viscoderm 0.8), thermically stabilized hybrid complexes of high and low molecular weight HA molecules at a concentration of 32 mg/mL and 45 mg/mL respectively (Profhilo and Profhilo Structura) and cross-linked HA 25 mg/mL (Aliaxin GP)., Methods: The products were tested by a well-established animal model. The generated implants were analyzed through High-Frequency Ultrasound technology. Then, reversibility of the treatment was evaluated by enzymatic degradation kinetics studies, characterised by a combined approach of Carbazole assay and HP-SEC/TDA method., Results: Implants generated by linear HA 8 mg/mL remained detectable by ultrasound acquisition for 4 weeks, whereas those generated by injection of HA hybrid complex 32 mg/mL were detectable for 10 weeks. HA hybrid complex 45 mg/mL and cross-linked HA 25 mg/mL were detectable for 29 and at least 33 weeks, respectively. Enzymatic degradation kinetics studies demonstrated that the HA content in HA hybrid complex 45 mg/mL was almost completely depolymerized and homogeneous after 3 h of treatment. For cross-linked HA 25 mg/mL, 24 h of incubation are needed to obtain the same degree of depolymerization., Conclusion: The study confirmed the ability of the experimental model to predict the behaviour of HA based dermal fillers in vivo and showed the innovative aspects of HA hybrid complex 45 mg/mL, that combines the high-safety profile, in terms of reversibility of the treatment, of the linear HA-based products with the durability of a high degree cross-linked gels, paving the way to the chance to be used for a wide range of applications in the field of aesthetic medicine., Competing Interests: Mario Scrima, Filomena Merola, Nicoletta Vito, Daniele Pacchioni, Gabriele Vecchi, Carmela Melito, Antonio Iorio, Andrea Maria Giori and Angela Ferravante are employees of IBSA Farmaceutici Italia, a pharmaceutical company based in Lodi, Italy. Andrea Maria Giori reports personal fees from IBSA Farmaceutici Italia, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2022 Scrima et al.)

Tropical cyclone rapid intensification events often cause destructive hurricane landfalls because they are associated with the strongest storms and forecasts with the highest errors. Multi-decade observational datasets of tropical cyclone behavior have recently enabled documentation of upward trends in tropical cyclone rapid intensification in several basins. However, a robust anthropogenic signal in global intensification trends and the physical drivers of intensification trends have yet to be identified. To address these knowledge gaps, here we compare the observed trends in intensification and tropical cyclone environmental parameters to simulated natural variability in a high-resolution global climate model. In multiple basins and the global dataset, we detect a significant increase in intensification rates with a positive contribution from anthropogenic forcing. Furthermore, thermodynamic environments around tropical cyclones have become more favorable for intensification, and climate models show anthropogenic warming has significantly increased the probability of these changes., (© 2022. The Author(s).)

The large-scale moistening of the atmosphere in response to increasing greenhouse gases amplifies the existing patterns of precipitation minus evaporation (P-E) which, in turn, amplifies the spatial contrast in sea surface salinity (SSS). Through a series of transient CO 2 doubling experiments, we demonstrate that surface salinification driven by the amplified dry conditions (P-E < 0), primarily in the subtropical ocean, accelerates ocean heat uptake. The salinification also drives the sequestration of upper-level heat into the deeper ocean, reducing the thermal stratification and increasing the heat uptake through a positive feedback. The change in Atlantic Meridional Overturning Circulation due to salinification plays a secondary role in heat uptake. Consistent with the heat uptake changes, the transient climate response would increase by approximately 0.4 K without this process. Observed multi-decadal changes in subsurface temperature and salinity resembles those simulated, indicating that anthropogenically-forced changes in salinity are likely enhancing the ocean heat uptake., Competing Interests: Competing interests The authors declare no competing interests.

Alzheimer's disease, which is the most common form of dementia, is characterized by the aggregation of the amyloid β peptide (Aβ) and by an impairment of calcium homeostasis caused by excessive activation of glutamatergic receptors (excitotoxicity). Here, we studied the effects on calcium homeostasis caused by the formation of Aβ oligomeric assemblies. We found that Aβ oligomers cause a rapid influx of calcium ions (Ca 2+ ) across the cell membrane by rapidly activating extrasynaptic N -methyl-d-aspartate (NMDA) receptors and, to a lower extent, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. We also observed, however, that misfolded oligomers do not interact directly with these receptors. Further experiments with lysophosphatidylcholine and arachidonic acid, which cause membrane compression and stretch, respectively, indicated that these receptors are activated through a change in membrane tension induced by the oligomers and transmitted mechanically to the receptors via the lipid bilayer. Indeed, lysophosphatidylcholine is able to neutralize the oligomer-induced activation of the NMDA receptors, whereas arachidonic acid activates the receptors similarly to the oligomers with no additive effects. An increased rotational freedom observed for a fluorescent probe embedded within the membrane in the presence of the oligomers also indicates a membrane stretch. These results reveal a mechanism of toxicity of Aβ oligomers in Alzheimer's disease through the perturbation of the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors.

Purpose: The primary aim of this study was to evaluate the performance of the study product, in terms of volumizing activity as well as the duration of the effect, in women with age-related midfacial volume defects. In addition, the study allowed the evaluation of the tolerability of the product by both volunteers and investigators., Patients and Methods: Twenty-two female volunteers, aged 42-60 years, participated in this study, which was performed under dermatological control in a single center. After an initial visit at baseline to verify adherence to the protocol criteria, volunteers received an injection of Aliaxin ® SV (IBSA Farmaceutici Italia Srl), followed 3-4 weeks later by a second touch-up treatment to treat eventual asymmetries. Four subsequent visits, the last performed 9 months from the first injection, were performed to evaluate clinically and instrumentally the efficacy of the treatment., Results: Clinical and statistically significant improvement in cheek volume was recorded after the first postinjection visit, and the effect was maintained until the end of the study period. A clinically measurable amelioration of wrinkle severity was also observed. By 3D picture recording and subsequent quantitative analysis, it was possible to determine the efficacy in terms of increased facial volume, which was already appreciable at the first visit, was further increased at the second and third visits and was maintained at the fourth and last visits. The injections were very well tolerated by the volunteers, as determined by their self-evaluation questionnaires., Conclusion: The results of the study confirm the esthetic performance of the study product on age-related midfacial volume defects. The very strong high-volumizing activity of the study product was not only properly determined by the investigators but also confirmed by self-evaluation by the volunteers. These effects were obtained with no appreciable undesired effects., Competing Interests: AMG, GV and GB are employees of IBSA Farmaceutici Italia. AS, BT and LLP are employees of DERMING S.r.l. Professor Chiara Schiraldi reports grants from Bioteknet, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Sparavigna et al.)

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42-77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.

The aim of the present work was the development of a novel glycosaminoglycan (GAG)-based injectable formulation intended for intra-articular administration that should best mimic the healthy synovial fluid. Hyaluronic acid (HA) was chosen among GAG polymers, since it is the most abundant component of the synovial fluid. A DoE (Design of Experiment) approach was used for the development of a formulation containing two HA (very high (VHMW) and low (LMW) molecular weight) grades. The rationale for this choice is that so far, no commercial product based on a single HA grade or even on binary HA mixture possesses optimal viscoelastic properties in comparison with healthy synovial fluid. A full factorial design was chosen to investigate the influence of concentration and relative fraction of the two polymer grades (retained as factors of the model) on formulation functional (viscosity and viscoelastic) properties, which are considered response variables. Thanks to the DoE approach, the composition of the optimized HA formulation was found. The addition to such formulation of an injectable grade fat-free soy phospholipid, which was rich in phosphatidylcholine (PC), resulted in improved lubrication properties. The final HA + PC formulation, packaged in pre-filled sterile syringes, was stable in long-term and accelerated ICH (International Council for Harmonisation) storage conditions. The overall results pointed out the formulation suitability for further steps of pharmaceutical developments, namely for the passage to pilot scale.

In this paper, we present a fully automated procedure for the direct design of a novel class of single-feed flat antennas with patterning of a conductive surface. We introduce a convenient surface discretization, based on hexagonal cells, and define an appropriate objective function, including both gain and input matching requirements. The reference geometry is constituted by a very thin, single feed-point square panel. It features a backing metal plate ("ground") and a top conductive layer, which is automatically patterned to achieve the desired radiation and input matching properties. The process employs an evolutionary algorithm combined with a boundary element electromagnetic solver. By applying this method, we designed an antenna tailored to the 2.4 GHz ISM frequency band, with a size of [Formula: see text], i.e., [Formula: see text] wavelengths and an height of 4 mm, or 0.03 wavelengths. Measured data confirmed the expected high gain (13 dBi), with a remarkable aperture efficiency (higher than 50%, including losses), thus validating the proposed approach.

The largest ever Sri Lankan dengue outbreak of 2017 provides an opportunity for investigating the relative contributions of climatological, epidemiological and sociological drivers on the epidemic patterns of this clinically important vector-borne disease. To do so, we develop a climatologically driven disease transmission framework for dengue virus using spatially resolved temperature and precipitation data as well as the time-series susceptible-infected-recovered (SIR) model. From this framework, we first demonstrate that the distinct climatological patterns encountered across the island play an important role in establishing the typical yearly temporal dynamics of dengue, but alone are unable to account for the epidemic case numbers observed in Sri Lanka during 2017. Using a simplified two-strain SIR model, we demonstrate that the re-introduction of a dengue virus serotype that had been largely absent from the island in previous years may have played an important role in driving the epidemic, and provide a discussion of the possible roles for extreme weather events and human mobility patterns on the outbreak dynamics. Lastly, we provide estimates for the future burden of dengue across Sri Lanka using the Coupled Model Intercomparison Phase 5 climate projections. Critically, we demonstrate that climatological and serological factors can act synergistically to yield greater projected case numbers than would be expected from the presence of a single driver alone. Altogether, this work provides a holistic framework for teasing apart and analysing the various complex drivers of vector-borne disease outbreak dynamics.

The accumulation of protein deposits in neurodegenerative diseases has been hypothesized to depend on a metastable subproteome vulnerable to aggregation. To investigate this phenomenon and the mechanisms that regulate it, we measured the solubility of the proteome in the mouse Neuro2a cell line under six different protein homeostasis stresses: 1) Huntington's disease proteotoxicity, 2) Hsp70, 3) Hsp90, 4) proteasome, 5) endoplasmic reticulum (ER)-mediated folding inhibition, and 6) oxidative stress. Overall, we found that about one-fifth of the proteome changed solubility with almost all of the increases in insolubility were counteracted by increases in solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodeling of protein complexes involved in adaptation to perturbation, most notably, stress granule (SG) proteins, which responded differently to different stresses. These results indicate that the protein homeostasis system is organized in a modular manner and aggregation patterns were not correlated with protein folding stability (Δ G ). Instead, distinct cellular mechanisms regulate assembly patterns of multiple classes of protein complexes under different stress conditions., Competing Interests: The authors declare no competing interest.

To function effectively proteins must avoid aberrant aggregation, and hence they are expected to be expressed at concentrations safely below their solubility limits. By analyzing proteome-wide mass spectrometry data of Caenorhabditis elegans , however, we show that the levels of about three-quarters of the nearly 4,000 proteins analyzed in adult animals are close to their intrinsic solubility limits, indeed exceeding them by about 10% on average. We next asked how aging and functional self-assembly influence these solubility limits. We found that despite the fact that the total quantity of proteins within the cellular environment remains approximately constant during aging, protein aggregation sharply increases between days 6 and 12 of adulthood, after the worms have reproduced, as individual proteins lose their stoichiometric balances and the cellular machinery that maintains solubility undergoes functional decline. These findings reveal that these proteins are highly prone to undergoing concentration-dependent phase separation, which on aging is rationalized in a decrease of their effective solubilities, in particular for proteins associated with translation, growth, reproduction, and the chaperone system., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

The formation of misfolded protein oligomers during early stages of amyloid aggregation and the activation of neuroinflammatory responses are two key events associated with neurodegenerative diseases. Although it has been established that misfolded oligomers are involved in the neuroinflammatory process, the links between their structural features and their functional effects on the immune response remain unknown. To explore such links, we took advantage of two structurally distinct soluble oligomers (type A and B) of protein HypF-N and compared the elicited microglial inflammatory responses. By using confocal microscopy, protein pull-down, and high-throughput mass spectrometry, we found that, even though both types bound to a common pool of microglial proteins, type B oligomers-with a lower solvent-exposed hydrophobicity-showed enhanced protein binding, correlating with the observed inflammatory response. Furthermore, the interactome associated with inflammatory-mediated neurodegeneration revealed previously unidentified receptors and signaling molecules likely to be involved in the oligomer-elicited innate immune response.

Stress-inducible molecular chaperones have essential roles in maintaining protein homeostasis, but the extent to which they affect overall proteome stability remains unclear. Here, we analyze the effects of the DnaK (Hsp70) system on protein stability in Escherichia coli using pulse proteolysis combined with quantitative proteomics. We quantify ∼1,500 soluble proteins and find ∼500 of these to be protease sensitive under normal growth conditions, indicating a high prevalence of conformationally dynamic proteins, forming a metastable subproteome. Acute heat stress results in the unfolding of an additional ∼200 proteins, reflected in the exposure of otherwise buried hydrophobic regions. Overexpression of the DnaK chaperone system markedly stabilizes numerous thermo-sensitive proteins, including multiple ribosomal proteins and large, hetero-oligomeric proteins containing the evolutionarily ancient c.37 fold (P loop nucleoside triphosphate hydrolases). Thus, the Hsp70 system, in addition to its known chaperone functions, has a remarkable capacity to stabilize proteins in their folded states under denaturing stress conditions., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: The nematode worm C. elegans is a model organism widely used for studies of genetics and of human disease. The health and fitness of the worms can be quantified in different ways, such as by measuring their bending frequency, speed or lifespan. Manual assays, however, are time consuming and limited in their scope providing a strong motivation for automation., New Method: We describe the development and application of an advanced machine vision system for characterising the behaviour of C. elegans, the Wide Field-of-View Nematode Tracking Platform (WF-NTP), which enables massively parallel data acquisition and automated multi-parameter behavioural profiling of thousands of worms simultaneously., Results: We screened more than a million worms from several established models of neurodegenerative disorders and characterised the effects of potential therapeutic molecules for Alzheimer's and Parkinson's diseases. By using very large numbers of animals we show that the sensitivity and reproducibility of behavioural assays is very greatly increased. The results reveal the ability of this platform to detect even subtle phenotypes., Comparison With Existing Methods: The WF-NTP method has substantially greater capacity compared to current automated platforms that typically either focus on characterising single worms at high resolution or tracking the properties of populations of less than 50 animals., Conclusions: The WF-NTP extends significantly the power of existing automated platforms by combining enhanced optical imaging techniques with an advanced software platform. We anticipate that this approach will further extend the scope and utility of C. elegans as a model organism., (Copyright © 2018. Published by Elsevier B.V.)

In Alzheimer's disease, aggregates of Aβ and tau in amyloid plaques and neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying a tissue-specific vulnerability to the disease. We report a transcriptional analysis of healthy brains and identify an expression signature that predicts-at ages well before the typical onset-the tissue-specific progression of the disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the expression patterns of the proteins that coaggregate in amyloid plaques and neurofibrillary tangles, together with those of the protein homeostasis components that regulate Aβ and tau. Because this expression signature is evident in healthy brains, our analysis provides an explanatory link between a tissue-specific environmental risk of protein aggregation and a corresponding vulnerability to Alzheimer's disease.

Background: The aim of this study was to assess in-hospital and long-term results of the novo unprotected left main (UPLM) percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) or stable coronary artery disease (CAD), in an unselected population admitted to a single high- volume cath-lab without on-site cardiac surgery., Methods: From 2008 to 2011, among 317 PCI performed in patients with the novo UPLM stenosis, 49 patients presented ST-elevation myocardial infarction (STEMI), 152 non ST-elevation MI/unstable angina (NSTEMI/UA), 116 stable CAD., Results: In-hospital mortality was 20% in STEMI, 5.3% in NSTEMI/UA and 1.7% in stable CAD patients (P<0.001). Two-year total mortality was 24.5%, 25.6% and 6% in the 3 groups, and cardiac death was 20%, 13.8% and 3.4% (P=0.002). Left main target lesion revascularization (TLR) was similar in the 3 groups, as the clinically-driven TLR (10% vs. 11% vs. 7.7%, P=0.642), with neither definite nor probable stent thrombosis. Multivariate analysis showed the following independent predictors of 2-year mortality: bare-metal stent use (OR 4.53, P<0.001), Syntax Score >32 (OR 3.53, P=0.012), ACS as the indication (OR 3.24, P=0.012), peripheral artery disease (OR 2.20, P=0.042), and age >75 years (OR 2.09, P=0.05)., Conclusions: Our experience showed acceptable results of UPLM PCI in STEMI patients, where short-term prognosis was related to hemodynamic conditions, good results in NSTEMI/UA patients where mortality increased in the follow-up due to comorbidities, and very good results in patients with stable CAD.

Objectives: to assess in-hospital and long-term results of the novo unprotected left main (UPLM) percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) or stable coronary artery disease (CAD), in an unselected population admitted to a single high- volume cathlab without on-site cardiac surgery., Methods: from 2008 to 2011, among 317 PCI performed in patients with the novo UPLM stenosis, 49 patients presented ST-elevation myocardial infarction (STEMI), 152 non ST-elevation MI/unstable angina (NSTEMI/UA), 116 stable CAD., Results: in-hospital mortality was 20% in STEMI, 5.3% in NSTEMI/UA and 1.7% in stable CAD patients (p<0.001). Two-year total mortality was 24.5%, 25.6% and 6% in the 3 groups, and cardiac death was 20%, 13.8% and 3.4% (p=0.002). Left main target lesion revascularization (TLR) was similar in the 3 groups, as the clinically- driven TLR (10% vs 11% vs 7.7% , p= 0.642), with neither definite nor probable stent thrombosis. Multivariate analysis showed the following independent predictors of 2-year mortality: bare-metal stent use (OR 4.53, p<0.001), Syntax score >32 (OR 3.53, p=0.012), ACS as the indication (OR 3.24, p=0.012), peripheral artery disease (OR 2.20, p=0.042), and age > 75 years (OR 2.09, p=0.05)., Conclusions: our experience showed acceptable results of UPLM PCI in STEMI patients, where short-term prognosis was related to hemodynamic conditions, good results in NSTEMI/UA patients where mortality increased in the follow-up due to comorbidities, and very good results in patients with stable CAD.

Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. These changes are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant. While ribosomal proteins decline and lose normal stoichiometry, proteasome complexes increase. Proteome imbalance is accompanied by widespread protein aggregation, with abundant proteins that exceed solubility contributing most to aggregate load. Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed. We suggest that sequestering proteins into chaperone-enriched aggregates is a protective strategy to slow proteostasis decline during nematode aging., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Acute ST-elevation myocardial infarction (STEMI) usually results from coronary atherosclerotic plaque disruption with superimposed thrombus formation. Detection of coronary thrombi is a poor prognostic indicator, which is mostly proportional to their size and composition. Particularly, intracoronary thrombi impair both epicardial blood flow and myocardial perfusion, by occluding major coronary arteries and causing distal embolization, respectively. Thus, although primary percutaneous coronary intervention is the preferred treatement strategy in STEMI setting, the associated use of adjunctive antithrombotic drugs and/or percutaneous thrombectomy is crucial to optimize therapy of STEMI patients, by improving either angiographical and clinical outcomes. This review article will focus on the prognostic significance of intracoronary thrombi and on current antithrombotic pharmacological and interventional strategies used in the setting of STEMI to manage thrombotic lesions.

Percutaneous mechanical thrombectomy (PMT) for treatment of clinically significant pulmonary embolism (PE) has been shown to be technically feasible and effective, aiming at thrombus resolution without increase in major bleeding. Despite its success, use of PMT in clinical practise has not become widespread, because it is challenging. Among several devices proposed, AngioJet rheolytic thrombectomy (ART) appears as the most effective and easy-to-use. We present the case of a 69-year-old woman who developed acute intermediate-risk PE, with right ventricular dysfunction and major myocardial necrosis, who was successfully treated by ART. The peculiarities of the case, toghether with the principles, tecnique and tips and tricks of ART, its effectiveness and potential complications are discussed.

Spontaneous coronary artery dissection is a rare cause of acute ischemic coronary events and sudden cardiac death. It usually occurs in young women not experiencing traditional risk factors for coronary artery disease during pregnancy or postpartum period. The pathophysiology of spontaneous arterial dissection remains uncertain and the management may be challenging. Herein, we report a case of a 41-year woman with no apparent cardiovascular risk factors, who underwent a successfull in vitro fertilization and embryo transfer with a subsequent at term cesarean section of a twin pregnancy. Six days after delivery, she presented with anterior ST-segment elevation myocardial infarction. Coronary angiography revealed dissection of all three coronary arteries with involvement of left main stem, which was successfully treated with percutaneous coronary intervention and drug-eluting stents implantation. The peculiarities of the case, toghether with the treatment strategy and the clinical and angiographic six-month follow-up are discussed.

Background: Despite the well-known prognostic impact of systolic dysfunction in unselected patients undergoing percutaneous coronary intervention (PCI), limited data are available on its current predictive role after PCI for unprotected left main disease (ULM). We thus appraised the prognostic role of left ventricular ejection fraction (LVEF) in patients undergoing PCI for ULM with drug-eluting stents (DES)., Methods: Consecutive eligible subjects were retrospectively enrolled in a national registry. Patients were divided into three groups: LVEF < 30%, LVEF 30-45%, and LVEF > 45%. Relevant baseline and outcome data were compared with bivariate and multivariable tests., Results: A total of 975 subjects was included (LVEF < 30%: 46, LVEF 30-45%: 208, LVEF > 45%: 721). Patients with LVEF < 30% had several other unfavorable clinical features, including older age and higher EuroSCORE. Adverse event rates were different already at 7 days (p = 0.012 for all-cause death and p = 0.015 for major adverse cardiac events [MACE]), with even more significant trends up to 30 days and at long-term (p < 0.001 for death, and p < 0.001 for MACE). After a median of 18 months, risk of death totaled 39 versus 13 versus 8% (p < 0.001) and risk of MACE 44 versus 24 versus 22% (p = 0.003). Multivariable analyses showed however that reduced LVEF was not an independent predictor of adverse events at any time-point., Conclusions: Whereas reduced LVEF is apparently a significant predictor of adverse events after PCI with DES for ULM, its prognostic impact is mostly due to clustering with other adverse features.

We demonstrate the coupling of multipolar surface plasmons with photonic modes in periodic arrays of metallic nanoantennas. This coupling leads to sharp resonances known as lattice surface modes. In spite of the weak interaction of multipolar surface plasmons with light, lattice surface modes provide an efficient radiative decay channel for emitters in the proximity of the array. We observe a tenfold emission enhancement of dyes coupled to lattice resonances. Lattice surface modes light up multipolar plasmonic resonances, opening new possibilities for fluorescence spectroscopies.

Aims: Percutaneous coronary intervention (PCI) is increasingly being used for unprotected left main (ULM) disease. Limited data are available on sex-related differences in this setting. We investigated gender-associated differences in patients undergoing stent-based PCI for ULM., Methods and Results: We analysed baseline, procedural and long-term data of patients with ULM undergoing stent-based PCI at participating centres. The primary end-point was the long-term rate of major cardiovascular events rate (MACE, i.e., the composite of death, myocardial infarction, or target lesion revascularisation). The study population included 1,452 cases, with 27.8% females and 72.2% males. Women were older, more frequently diabetic, hypertensive or presenting with an acute coronary syndrome, and thus with a higher EuroSCORE, but were less commonly treated with drug-eluting stents (DES), in comparison to men (all p<0.01). After a median follow-up of 18 months, women showed an unadjusted higher risk of death (p=0.040), cardiac death (p=0.033), and the death/myocardial infarction (p=0.012). However, after multivariable adjustment, gender was no longer an independent predictor of death (hazard ratio=1.119 [0.804-1.558]), cardiac death (hazard ratio=1.045 [0.697-1.567]), or death/myocardial infarction (hazard ratio=0.531 [0.192-1.465]), given the predominant role of age, diabetes and EuroSCORE as independent predictors and confounders of the gender-based comparison., Conclusions: Women undergoing PCI for ULM present more often with an acute coronary syndrome, are treated less frequently with DES, and have more adverse events, but these gender biases are not confirmed after adjusting for confounders. Thus, stent-based PCI for ULM offers similarly favourable clinical results in women as well as in men.