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Matrix-Vector Multiplications (MVMs) represent a heavy workload for both training and inference in Deep Neural Networks (DNNs) applications. Analog In-memory Computing (AIMC) systems based on Phase Change Memory (PCM) has been shown to be a valid competitor to enhance the energy efficiency of DNN accelerators. Although DNNs are quite resilient to computation inaccuracies, PCM non-idealities could strongly affect MVM operations precision, and thus the accuracy of DNNs. In this paper, a combined hardware and software solution to mitigate the impact of PCM non-idealities is presented. The drift of PCM cells conductance is compensated at the circuit level through the introduction of a conductance ratio at the core of the MVM computation. A model of the behaviour of PCM cells is employed to develop a device-aware training for DNNs and the accuracy is estimated in a CIFAR-10 classification task. This work is supported by a PCM-based AIMC prototype, designed in a 90-nm STMicroelectronics technology, and conceived to perform Multiply-and-Accumulate (MAC) computations, which are the kernel of MVMs. Results show that the MAC computation accuracy is around 95% even under the effect of cells drift. The use of a device-aware DNN training makes the networks less sensitive to weight variability, with a 15% increase in classification accuracy over a conventionally-trained Lenet-5 DNN, and a 36% gain when drift compensation is applied.

Huntington's disease (HD) is a fatal neurodegenerative disorder with no effective cure currently available. Over the past few years our research has shown that alterations in sphingolipid metabolism represent a critical determinant in HD pathogenesis. In particular, aberrant metabolism of sphingosine-1-phosphate (S1P) has been reported in multiple disease settings, including human postmortem brains from HD patients. In this study, we investigate the potential therapeutic effect of the inhibition of S1P degradative enzyme SGPL1, by the chronic administration of the 2-acetyl-5-tetrahydroxybutyl imidazole (THI) inhibitor. We show that THI mitigated motor dysfunctions in both mouse and fly models of HD. The compound evoked the activation of pro-survival pathways, normalized levels of brain-derived neurotrophic factor, preserved white matter integrity, and stimulated synaptic functions in HD mice. Metabolically, THI restored normal levels of hexosylceramides and stimulated the autophagic and lysosomal machinery, facilitating the reduction of nuclear inclusions of both wild-type and mutant huntingtin proteins.

A thermoplastic matrix composite flat panel stiffened by induction welded stringers, according to a typical aerospace configuration was tested. A Poly-Ether-Ether-Ketone (PEEK) matrix reinforced by carbon fibers was adopted. The aim of this study was to investigate the shear buckling, a load condition that is very common for the aerospace structures, of the panel obtained using a non-conventional approach for its fabrication, that is, induction welding. A finite element (FE) model capable to describe the buckling and the postbuckling behavior of the stiffened panel was also developed and compared with experimental results. Testing was performed using fixtures suitably designed to transmit a pure shear to the panel, and strain gauges were mounted on the external surfaces to measure the deformations.

Moraxella catarrhalis is an important and common respiratory pathogen that can cause Otitis Media, Community Acquired Pneumonia, and has been associated with an increased risk of exacerbations in chronic obstructive pulmonary disease in adults, leading to morbidity and mortality. Its ubiquitous surface protein A2 (UspA2) has been shown to interact with host structures and extracellular matrix proteins, suggesting a role at an early stage of infection and a contribution to bacterial serum resistance. The UspA proteins are homo-trimeric autotransporters that appear as a lollipop-shaped structure in electron micrographs. They are composed of an N-terminal head with adhesive properties, followed by a stalk, which ends by an amphipathic helix and a C-terminal membrane domain. The three family members UspA1, UspA2 and UspA2H, present different amino acid signatures both at the head and membrane-spanning regions. By combining electron microscopy, hydrogen deuterium exchange mass spectrometry and protein modeling, we identified a shared and repeated epitope recognized by FHUSPA2/10, a potent cross-bactericidal monoclonal antibody raised by UspA2 and deduced key amino acids involved in the binding. The finding strengthens the potential of UspA2 to be incorporated in a vaccine formulation against M. catarrhalis.

Despite receiving appropriate antiseizure medications (ASMs), a relevant percentage of neuropsychiatric patients do not benefit from this approach, and one reason is subtherapeutic ASMs plasma concentration (C(p)) due to improper drug adherence, interindividual pharmacokinetic differences, or metabolic interactions among different drugs. For these reasons, therapeutic drug monitoring (TDM) by measuring ASMs C(p) is an effective tool that improves pharmacological therapies in clinical practice. Based on these premises, in the present real-world study, we analyzed the C(p) of the most used ASMs in diverse medical conditions, which were assayed during the years 2018–2022 at the University Hospital of Pisa, including about 24,000 samples. This population was largely heterogeneous, and our database did not contain clinical information about the patients. The most used ASMs were Valproate (VPA: 54.5%) and Levetiracetam (LEV: 18.6%), followed by Oxcarbazepine (OxCBZ: 8.3%) and Carbamazepine (CBZ: 7.2%), whereas the associations LEV/VPA, Ethosuximide (ESM)/VPA, and CBZ/VPA were the most frequently proposed. In about 2/3 of assays, ASMs C(p) was in range, except for VPA, which was underdosed in almost half of the samples. Importantly, toxic levels of ASMs C(p) were found very rarely. For VPA, there was a decrease of mean C(p) across ages, from adolescents to older patients, while the C(p) of LEV, CBZ, OxCBZ, and Topiramate (TPM) showed a slight tendency to increase. When we compared females and males, we found that for VPA, the average age was higher for females, whereas women taking Lamotrigine (LTG) and OxCBZ were younger than men. Then, comparing ASMs used in neurologic and psychiatric disorders, based on the request form, it emerged that the mean C(p) of CBZ, OxCBZ, and LTG on samples collected in the Psychiatric Unit was lower compared to the Neurology and Child Neuropsychiatry Units. Finally, the ASMs subjected to multiple dosing starting from an initial subtherapeutic C(p) increased their level at different time points within a year, reaching the reference range for some of them. In conclusion, the present study suggests that TDM is widely applied to monitor ASMs C(p), finding many of them within the reference range, as a demonstration of its utility in clinical practice.

The SH-SY5Y neuroblastoma cell line is often used as an in vitro model of neuronal function and is widely applied to study the molecular events leading to Alzheimer’s disease (AD). Indeed, recently, basic research on SH-SY5Y cells has provided interesting insights for the discovery of new drugs and biomarkers for improved AD treatment and diagnosis. At the same time, untargeted NMR metabolomics is widely applied to metabolic profile analysis and screening for differential metabolites, to discover new biomarkers. In this paper, a compression technique based on convolutional autoencoders is proposed, which can perform a high dimensionality reduction in the spectral signal (up to more than 300 times), maintaining informative features (guaranteed by a reconstruction error always smaller than 5%). Moreover, before compression, an ad hoc preprocessing method was devised to remedy the scarcity of available data. The compressed spectral data were then used to train some SVM classifiers to distinguish diseased from healthy cells, achieving an accuracy close to 78%, a significantly better performance with respect to using standard PCA-compressed data.

Aim: Concerns have been raised about possible neuropsychiatric sequelae of COVID-19. The objective of this study was to examine the plausibility of long-term mental health consequences of COVID-19 by assessing a sample of children after the resolution of the acute SARS-CoV-2 infection. Method: As part of a systematic follow-up assessment of pediatric patients with COVID-19 conducted at two university children’s hospitals, 50 children (56% males) aged 8 to 17 years (median 11.5), 26% with previous multisystem inflammatory syndrome in children (MIS-C), without a prior history of neuropsychiatric disorders, received a battery of clinical neuropsychiatric and neuropsychological rating scales that included the Pediatric Migraine Disability Assessment (PedMIDAS), Sleep Disturbance Scale for Children (SDSC), Multidimensional Anxiety Scale for Children (MASC-2), Child Depression Inventory (CDI-2), Child Behavior Checklist (CBCL), and the NEPSY II (Neuropsychological Assessment, Second Edition). The assessments were conducted between 1 and 18 months (median 8 months) after the acute infection. Results: The CBCL internalizing symptoms score was in the clinical range for 40% of the participants (vs. a population expected rate of about 10%, p < 0.001). A sleep disturbance was detected in 28%, clinically significant anxiety in 48%, and depressive symptoms in 16%. The NEPSY II scores showed impairment in attention and other executive functions in 52%, and memory deficits in 40% of the children. Conclusions: These data from direct assessment of a sample of children who had SARS-CoV-2 infection show higher than expected rates of neuropsychiatric symptoms, thus supporting the possibility that COVID-19 may have mental health sequelae long after the resolution of the acute infection.

The Burkholderia cepacia complex comprises environmental and clinical Gram-negative bacteria that infect particularly debilitated people, such as those with cystic fibrosis. Their high level of antibiotic resistance makes empirical treatments often ineffective, increasing the risk of worst outcomes and the diffusion of multi-drug resistance. However, the discovery of new antibiotics is not trivial, so an alternative can be the use of vaccination. Here, the reverse vaccinology approach has been used to identify antigen candidates, obtaining a short-list of 24 proteins. The localization and different aspects of virulence were investigated for three of them—BCAL1524, BCAM0949, and BCAS0335. The three antigens were localized in the outer membrane vesicles confirming that they are surface exposed. We showed that BCAL1524, a collagen-like protein, promotes bacteria auto-aggregation and plays an important role in virulence, in the Galleria mellonella model. BCAM0949, an extracellular lipase, mediates piperacillin resistance, biofilm formation in Luria Bertani and artificial sputum medium, rhamnolipid production, and swimming motility; its predicted lipolytic activity was also experimentally confirmed. BCAS0335, a trimeric adhesin, promotes minocycline resistance, biofilm organization in LB, and virulence in G. mellonella. Their important role in virulence necessitates further investigations to shed light on the usefulness of these proteins as antigen candidates.

In Italy, the National Register on Occupational Exposure to Carcinogens (SIREP) is established pursuant to article 243 of Legislative Decree 81/2008 and is aimed to collect information on the exposure of workers to carcinogens transmitted by employers. The aim of this study is to assess its level of implementation comparing prevailing carcinogens reported in SIREP with the monitoring of risks in the workplace evidenced by the International Agency for Research on Cancer (IARC). The data reported in the SIREP have been integrated with IARC and the database on carcinogenic risk in the workplace named MATline in order to build a matrix containing the carcinogens classified according to the IARC (Group 1 and 2A agents) and to a semi-quantitative indicator of risk level (High or Low) calculated upon the number of exposures reported in SIREP. The matrix contains the following data: carcinogens, economic sector (NACE Rev2 coding) and cancer sites. The comparison between SIREP and IARC evidence allowed us to highlight situations with a high risk of carcinogenicity and to address appropriate actions of prevention to contain the risks of exposure to carcinogenic substances.

Alzheimer’s Disease (AD) affects the quality of life of millions of people worldwide and represents one of the biggest challenges for the whole society. The SH-SY5Y neuroblastoma cell line is often used as an in vitro model of neuronal function and is widely applied to study the molecular events leading to AD. In the last few years, basic research on SH-SY5Y cells has provided interesting insights for the discovery of new drugs and biomarkers for improved AD treatment and diagnosis. At the same time, untargeted NMR metabolomics is widely applied on biological fluids for (i) metabolic profile analysis, (ii) screening for differential metabolites, (iii) analysis of metabolic pathways, and (iv) the discovery of new biomarkers. Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA) have proved to be powerful methods for processing NMR data, being useful in signal quantization, even if more sophisticated --- typically non--linear --- techniques are needed to obtain compact yet information--rich embeddings for complex spectra. In this paper, a compression technique based on convolutional autoencoders is proposed, which can perform a high dimensionality reduction of the spectral signal (up to more than 300 times), maintaining informative features (guaranteed by a reconstruction error always smaller than 5%). Moreover, before compression, an ad hoc preprocessing method was devised to remedy the scarcity of available data. The compressed spectral data were then used to train some SVM classifiers to distinguish diseased from healthy cells, achieving an accuracy close to 78%, a significantly better performance with respect to using PCA--compressed data.

Hinterland basins are low-lying and often heavily populated areas at the back of orogenic belts which have significant economic and infrastructural importance. The tectonic-stratigraphic and regional characterisation of hinterland basins is fundamental for evaluating their subsurface utilisation and potential geohazards.This study focuses on the origin and development of the Tuscan hinterland basins of the Northern Apennines. These basins have been associated with a compressional regime lasting until the Late Pliocene-Pleistocene during which out-of-sequence thrusts and back-thrusts in the inner portion of the chain accommodated the compressive stress accumulated in the frontal zones. An alternative interpretation considers the evolution of these basins in an extensional regime as an effect of large-scale back-arc processes or gravitational collapse of thickened crust following the Apennine orogeny since the Early Miocene. In this tectonic regime, the basins have been interpreted as graben, half-graben or bowl-shaped basins evolving into graben.Our work aims to determine the tectonic-sedimentary evolution of the Valdera-Volterra Basin through the analysis of ~271.8 km of 2D seismic reflection profiles and wireline logs from two exploration wells. The Valdera-Volterra Basin basin is an NW–SE oriented depocenter ~60 km long ~30 km wide filled with a clastic succession of Miocene-Pleistocene fluvial-lacustrine to marine deposits up to ~2 km thick.The analysis has revealed a polyphased tectonic history of the basin with a Messinian-Zanclean compressional phase deforming the basin-infill as indicated by seismic imaging of synformal geometries and strongly tilted unconformities. Such deformation is tentatively associated with E/NE vergent blind thrusts and SW vergent blind back-thrusts. During the Piacenzian, the activity of normal border faults and the presence in their hanging wall of associated sedimentary wedges thickening towards NE suggest an extensional phase following the earlier Messinian-Zanclean compression. Broad folding of the shallow Piacenzian units in the hangingwall of the normal faults suggests the occurrence of mild positive inversion at the end of the Piacenzian/Lowermost Pleistocene?.This tectonic history has been associated with crustal shortening in the Northern Apennines hinterland, accommodated by thrusting, that occurred discontinuously until the end of the Pliocene/Lowermost Pleistocene?. The formation of the border faults during the Piacenzian has been related to a prolongated phase of tectonic quiescence that led to the collapse of the sedimentary pile and the Pre-Neogene substrate. In this setting, the positive inversion occurred at the end of the Piacenzian/Lowermost Pleistocene? represents the last compressive event related to crustal shortening.

IntroductionVirus vectored genetic vaccines (Vvgv) represent a promising approach for eliciting immune protection against infectious diseases and cancer. However, at variance with classical vaccines to date, no adjuvant has been combined with clinically approved genetic vaccines, possibly due to the detrimental effect of the adjuvant-induced innate response on the expression driven by the genetic vaccine vector. We reasoned that a potential novel approach to develop adjuvants for genetic vaccines would be to “synchronize” in time and space the activity of the adjuvant with that of the vaccine.MethodsTo this aim, we generated an Adenovirus vector encoding a murine anti-CTLA-4 monoclonal antibody (Ad-9D9) as a genetic adjuvant for Adenovirus based vaccines.ResultsThe co-delivery of Ad-9D9 with an Adeno-based COVID-19 vaccine encoding the Spike protein resulted in stronger cellular and humoral immune responses. In contrast, only a modest adjuvant effect was achieved when combining the vaccine with the same anti-CTLA-4 in its proteinaceous form. Importantly, the administration of the adjuvant vector at different sites of the vaccine vector abrogates the immunostimulatory effect. We showed that the adjuvant activity of Ad-α-CTLA-4 is independent from the vaccine antigen as it improved the immune response and efficacy of an Adenovirus based polyepitope vaccine encoding tumor neoantigens.DiscussionOur study demonstrated that the combination of Adenovirus Encoded Adjuvant (AdEnA) with an Adeno-encoded antigen vaccine enhances immune responses to viral and tumor antigens, representing a potent approach to develop more effective genetic vaccines.

Notwithstanding the ban in 1992, asbestos exposure for workers in the construction sector in Italy remains a concern. The purpose of this study is to describe the characteristics of malignant mesothelioma (MM) cases recorded by the Italian registry (ReNaM) among construction workers. Incident mesothelioma cases with a definite asbestos exposure have been analyzed. Characteristics of cases and territorial clusters of crude rates of MM in construction workers have been described, as well as the relation between asbestos use before the ban and the historical trend of workforce in the construction sector in Italy. ReNaM has collected 31,572 incident MM cases in the period from 1993 to 2018 and asbestos exposure has been assessed for 24,864 (78.2%) cases. An occupational exposure has been reported for 17,191 MM cases (69.1% of subjects with a definite asbestos exposure). Among them, 3574 had worked in the construction sector, with an increasing trend from 15.8% in the 1993–98 period to 23.9% in 2014–2018 and a ubiquitous territorial distribution. The large use of asbestos in construction sector before the ban makes probability of exposure for workers a real concern still today, particularly for those working in maintenance and removal of old buildings. There is a clear need to assess, inform, and prevent asbestos exposure in this sector.

Experimental fatigue tests performed on riveted carbon fiber laminates showed that the specimens, after some thousands of cycles, heated up, reaching around the rivet holes high temperatures. These temperatures if not properly controlled could be detrimental for the joint health. In order to understand the relative importance of all the mechanical and geometric parameters involved in the joint manufacturing, a numerical model of the joined carbon fiber laminates was developed using a commercial finite elements code. A simplified analytical model of heat transfer was then used to simulate the rivets thermal behavior under the assigned operating conditions: this model allowed comparisons with finite elements and can be used for simple thermal simulations. The numerical and analytical results were found in a good agreement with the available experimental results. The present research conclusions can be used for drawing better design rules in the definition of riveted carbon fiber laminates.

Smart devices for structural health monitoring provide edge computing capabilities to reduce wireless transmission and, thus, power consumption. Although effective algorithms have been proposed in the last few decades, traditional microcontrollers require heavy data flow between the memory and the central processing unit that involves a considerable fraction of the total energy consumption. Phase change memory has recently emerged as an attractive solution in the field of resistive non-volatile memory for analog in-memory computing, which is a valid approach to avoid data being conveyed among distinct elaboration units. However, it has never been envisaged in structural health monitoring applications. As this technology is still in an embryonic state, several challenges related to nonlinearities and nonidealities of the memory elements and the energy expenditure related to the memory reprogramming process may undermine its usage. In this paper, the application of a novel identification approach for civil infrastructures is investigated using phase change memories. The main computational core of the presented algorithm, consisting of 1-dimensional convolutions, is particularly suitable for implementations involving analog in-memory computing, thus showing the great potential of this technology for structural health monitoring applications. The test unit is an embedded phase change memory provided by STMicroelectronics and designed in 90-nm smart power bipolar complementary metal-oxide-semiconductor (CMOS)-double-diffused metal-oxide-semiconductor (DMOS) technology with a Ge-rich Ge-Sb-Te alloy for automotive applications. Experimental results obtained for a viaduct of an Italian motorway support the efficacy of the method. Moreover, the influence of nonidealities on the outcomes of damage identification based on both dynamic and quasi-static structural parameters is examined.

Chronic pain is sustained by a maladaptive form of neuronal plasticity occurring in all stations of the pain neuraxis, including cortical regions of the pain matrix. We report that chronic inflammatory pain induced by unilateral injection of complete Freund's adjuvant (CFA) in the hindpaw of male mice was associated with a progressive build-up of perineuronal nets (PNNs) in the contralateral somatosensory cortex (SSC), medial prefrontal cortex (mPFC), and reticular thalamic nucleus. In the SSC, the density of PNNs labeled by Wisteria floribunda agglutinin (WFA) was increased at both 3 and 7 d following CFA injection, but only after 7 d in the mPFC. The number of parvalbumin (PV)-positive interneurons enwrapped by WFA+/PNNs was also increased in all three brain regions of mice injected with CFA. Remarkably, PNN degradation induced by intracortical infusion of chondroitinase-ABC significantly reduced mechanical and thermal pain, and also reversed the increased frequency of IPSCs recorded in layer 5 pyramidal neurons of the contralateral SSC in CFA-injected mice. These findings suggest a possible relationship between cortical PNNs and nociceptive sensitization, and support the hypothesis that PNNs maintain their plasticity in the adult life and regulate cortical responses to sensory inputs.SIGNIFICANCE STATEMENTThe brain extracellular matrix not only provides structural support, but also regulates synapse formation and function, and modulates neuronal excitability. We found that chronic inflammatory pain in mice enhances the density of perineuronal nets (PNNs) in the somatosensory cortex and medial prefrontal cortex. Remarkably, enzymatic degradation of PNNs in the somatosensory cortex caused analgesia and reversed alterations of inhibitory synaptic transmission associated with chronic pain. These findings disclose a novel mechanism of nociceptive sensitization and support a role for PNNs in mechanisms of neuronal plasticity in the adult brain.

Background The aim of the study is to determine that Glycopirrolate is safe and effective in decreasing drooling in children with medical complexity under 3 years of age. Medical treatment is based on anticholinergic drugs as transdermal scopolamine, benzotropine and GLY. GLY (Glycopyrronium bromide) is a synthetic quaternary ammonium anticholinergic agent with poor blood–brain barrier penetration and consequently has limited central effects. Actually, the oral GLY formulation was approved by the United States Food and Drug Administration (FDA) to treat drooling in children aged 3–16 years. Five studies reported on GLY use for the treatment of drooling in children with cerebral palsy and other conditions with neurological impairment; four are prospective studies while one a retrospective review. Methods this is a case report of eighteen children (sex ratio 11/8, median age 17 months, range 2–36 months) under three years of age, followed by a multidisciplinary team at the Bambino Gesù Children Hospital. The median follow-up was of 31.5 months (range 1–69 months). Response to treatment was assessed according to the Drooling Impact Scale administered at time 0 and after 1 month. All patients have an important neurological impairment: nine patients have a cerebral palsy (Gross Motor Function Classification System class V) and nine a genetic/malformative syndrome. Twelve patients have a tracheostomy and two need mechanical ventilation. Gastrostomy is present in 16 out of 18 patients. All patients received Glycopirrolate. The median starting daily dose was 0.065 mg/kg/die (range 0.02–0.21 mg/kg/die) three times a day. The drooling impact scale was administered at time O and after 1 month. Results Four out 18 patients stopped treatment for adverse event, lack of efficacy or parental decision. The mean Drooling Impact Scale at time 0 was 89 (range 81–100) and after 1 month 61(range 43–78); the difference was statistically significant (P Conclusions This is the first study to determine the safety and effectiveness of Glycopyrrolate in decreasing drooling in a specific subset of patients. No major side effects were observed. Further comparative studies are needed to confirm our results.

Tumors with microsatellite instability (MSI) are caused by a defective DNA mismatch repair system that leads to the accumulation of mutations within microsatellite regions. Indels in microsatellites of coding genes can result in the synthesis of frameshift peptides (FSP). FSPs are tumor-specific neoantigens shared across patients with MSI. In this study, we developed a neoantigen-based vaccine for the treatment of MSI tumors. Genetic sequences from 320 MSI tumor biopsies and matched healthy tissues in The Cancer Genome Atlas database were analyzed to select shared FSPs. Two hundred nine FSPs were selected and cloned into nonhuman Great Ape Adenoviral and Modified Vaccinia Ankara vectors to generate a viral-vectored vaccine, referred to as Nous-209. Sequencing tumor biopsies of 20 independent patients with MSI colorectal cancer revealed that a median number of 31 FSPs out of the 209 encoded by the vaccine was detected both in DNA and mRNA extracted from each tumor biopsy. A relevant number of peptides encoded by the vaccine were predicted to bind patient HLA haplotypes. Vaccine immunogenicity was demonstrated in mice with potent and broad induction of FSP-specific CD8 and CD4 T-cell responses. Moreover, a vaccine-encoded FSP was processed in vitro by human antigen-presenting cells and was subsequently able to activate human CD8 T cells. Nous-209 is an “off-the-shelf” cancer vaccine encoding many neoantigens shared across sporadic and hereditary MSI tumors. These results indicate that Nous-209 can induce the optimal breadth of immune responses that might achieve clinical benefit to treat and prevent MSI tumors.Significance:These findings demonstrate the feasibility of an “off-the-shelf” vaccine for treatment and prevention of tumors harboring frameshift mutations and neoantigenic peptides as a result of microsatellite instability.

List of 1087 FSPs suitable for the inclusion in NOUS-209 vaccine.

Top Nous-209-derived peptides predicted to bind to HLA-A*02:01.

The development of effective antitumor immune responses is normally constrained by low-avidity, tumor-specific CTLs that are unable to eradicate the tumor. Strategies to rescue antitumor activity of low-avidity melanoma-specific CTLs in vivo may improve immunotherapy efficacy. To boost the in vivo effectiveness of low-avidity CTLs, we immunized mice bearing lung melanoma metastases with artificial antigen-presenting cells (aAPC), made by covalently coupling pepMHC-Ig dimers and B7.1-Ig molecules to magnetic beads. aAPC treatment induced significant tumor reduction in a mouse telomerase antigen system, and complete tumor eradication in a mouse TRP-2 antigen system, when low-avidity CTLs specific for these antigens were adoptively transferred. In addition, in an in vivo treatment model of subcutaneous melanoma, aAPC injection also augmented the activity of adoptively transferred CTLs and significantly delayed tumor growth. In vivo tumor clearance due to aAPC administration correlated with in situ proliferation of the transferred CTL. In vitro studies showed that aAPC effectively stimulated cytokine release, enhanced CTL-mediated lysis, and TCR downregulation in low-avidity CTLs. Therefore, in vivo aAPC administration represents a potentially novel approach to improve cancer immunotherapy. [Cancer Res 2009;69(24):9376–84]

Supplementary Figure 3 from In vivo Administration of Artificial Antigen-Presenting Cells Activates Low-Avidity T Cells for Treatment of Cancer

Supplementary Figure 1 from In vivo Administration of Artificial Antigen-Presenting Cells Activates Low-Avidity T Cells for Treatment of Cancer

Supplementary Figure 4 from In vivo Administration of Artificial Antigen-Presenting Cells Activates Low-Avidity T Cells for Treatment of Cancer

Supplementary Figures 1-4 from In vivo Administration of Artificial Antigen-Presenting Cells Activates Low-Avidity T Cells for Treatment of Cancer

The presentation of viral antigens on nanoparticles in multivalent arrays has emerged as a valuable technology for vaccines. On the nanoparticle surface, highly ordered, repetitive arrays of antigens can mimic their geometric arrangement on virion surfaces and elicit stronger humoral responses than soluble viral antigens. More recently, bacterial antigens have been presented on self-assembling protein nanoparticles and have elicited protective antibody and effective T-helper responses, further supporting the nanoparticle platform as a universal approach for stimulating potent immunogenicity. Here, we present the rational design, structural analysis, and immunogenicity of self-assembling ferritin nanoparticles displaying eight copies of the Neisseria meningitidis trimeric adhesin NadA. We engineered constructs consisting of two different NadA fragments, head only and head with stalk, that we fused to ferritin and expressed in Escherichia coli. Both fusion constructs self-assembled into the expected nanoparticles as determined by Cryo electron microscopy. In mice, the two nanoparticles elicited comparable NadA antibody levels that were 10- to 100-fold higher than those elicited by the corresponding NadA trimer subunits. Further, the NadAferritin nanoparticles potently induced complement-mediated serum bactericidal activity. These findings confirm the value of self-assembling nanoparticles for optimizing the immunogenicity of bacterial antigens and support the broad applicability of the approach to vaccine programs, especially for the presentation of trimeric antigens.

As stated in the European Green Deal: "to tackle climate and environmental-related challenges is this generation defining task". Young generations represent a juncture between understanding the potential hazardous impact of climate change on society and local communities. In this frame, STEAM education in school proved its ability to nurture students' curiosity and cognitive resources, provide them with the right tools to understand the world's complexity and face the challenges that the current times are posing, like climate change, among many others. However, STEAM subjects are not always part of educational curricula: according to the OECD Programme for International Student Assessment (PISA) report 2018, more than 20% of pupils in the European Union has insufficient proficiency in reading, mathematics, or science. Such a lack of diversity in the offer may decrease pupils' motivation to pursue STEAM academic paths, often perceived as highly theoretical and complex. The improvement of STEAM education in secondary schools is the core objective of the Erasmus+ funded project "GIS4Schools", which aims at promoting a new innovative approach to foster the teaching of STEAM subjects in secondary schools across four different European countries: Italy, Portugal, Romania, and Spain. The project intends to introduce the education of GIS and satellite technologies for Earth Observation- rarely adopted in secondary schools- and applying them to the thematic area of Climate Change. GIS4Schools combines Inquiry-Based Science Education (IBSE) with Problem Based Learning (PBL) approaches to an interdisciplinary contextualisation of the science topic. Pupils actively contributes to the co-creation of new knowledge by assessing with GIS tools the impacts of specific climate challenges affecting their local community thanks to Copernicus products, Sentinels' satellite-derived information, and other ancillary data. The paper illustrates the genesis of the project, and more specifically, the process leading to the development of training packages for secondary schools' teachers and pupils. Furthermore, the paper explores which methodology and pedagogic approach must be adopted to transfer new knowledge from teachers to pupils. The paper also describes how the teaching of GIS and satellite technologies for Earth observation in secondary school can impact pupils' perception of STEAM subjects and how this can impact their future academic careers. Specific attention is also dedicated to the description of the innovative tools developed and applied for monitoring and evaluation.

Graph Neural Networks (GNNs) have become the leading paradigm for learning on (static) graph-structured data. However, many real-world systems are dynamic in nature, since the graph and node/edge attributes change over time. In recent years, GNN-based models for temporal graphs have emerged as a promising area of research to extend the capabilities of GNNs. In this work, we provide the first comprehensive overview of the current state-of-the-art of temporal GNN, introducing a rigorous formalization of learning settings and tasks and a novel taxonomy categorizing existing approaches in terms of how the temporal aspect is represented and processed. We conclude the survey with a discussion of the most relevant open challenges for the field, from both research and application perspectives.

In the last years, epitaxial graphene (epi-Gr) demonstrated to be an excellent substrate for the epitaxial or intercalated synthesis of two dimensional (2D) materials. Among 2D materials, silicene has been for a long time a dream for the scientific community, for its importance both from fundamental and application point of view. Despite the theoretical prediction of silicene energetic viability, experimentally it is not so simple to induce silicon to hybridize in sp2 configuration. In this respect, the substrate proved to play a fundamental role in the Si atom absorption process, leading in case of metal substrates to a mixed phase formation. For van der Waals chemical inert substrates, instead, like highly oriented pyrolytic graphite and MoS2, Si atom intercalation even at room temperature has been reported and associated to non-ideality of their surfaces. Interestingly, very recently it has been shown that hundreds of nanometer area quasi-free standing silicene can be grown on top an almost ideal epi-Gr layer synthesized on 6H-SiC substrate. In the present paper, using scanning tunneling microscopy and spectroscopy and Raman analysis, we demonstrate that a non-ideal (slightly defected) epi-Gr network obtained by thermal decomposition of Si-terminated 4H-SiC(0001) enables the Si atoms penetration forming intercalated silicene nanosheets at RT, thus opening a path toward controlling intercalated silicene nanosheet formation through pristine graphene defect concentration managing and silicene application in nanotechnology.

There is a lot of evidence in the literature showing that early-onset depression determines an emotional and cognitive vulnerability for psychiatric disorders in subsequent years. AIMS: The first aim of this outcome research was to analyze the impact of parental support treatment in a sample of depressed preschool children divided into two groups of comparison (under-reactive and over-reactive) through evolution in the Clinical Global Impression (CGI). The second aim was to analyze the correlation between the presence of parental psychopathology and the severity of children’s disorders. METHODS: Our clinical sample consisted of 32 preschool-age children with a final diagnosis of MDD. The children’s assessment included a psychiatric assessment to establish a diagnosis of MDD, confirmed by means of a semi-structured interview, which was administered again one month after the end of parental treatment. All the parents began a six-month parent training treatment conducted by experienced child psychiatrists, whereas children were not treated. During this period, the Clinical Global Impression Scale (CGI) was filled out monthly in order to observe the evolution of the children’s disorders. Results: Post-hoc tests showed a significant difference from before the treatment to after the treatment only in the over-reactive group (p = 0.00). Regarding parental psychiatric disorders, in the over-reactive group, only 3 children had no parents with psychopathology. In the under-reactive group, no child lacked a parent with psychopathology. Conclusion: Parent training treatment seems to be a valid intervention to improve preschool depression, especially in over-reactive groups, and to prevent dysfunctional parental styles connected to parental psychopathology.

Graph Neural Networks (GNNs) are a large class of relational models for graph processing. Recent theoretical studies on the expressive power of GNNs have focused on two issues. On the one hand, it has been proven that GNNs are as powerful as the Weisfeiler-Lehman test (1-WL) in their ability to distinguish graphs. Moreover, it has been shown that the equivalence enforced by 1-WL equals unfolding equivalence. On the other hand, GNNs turned out to be universal approximators on graphs modulo the constraints enforced by 1-WL/unfolding equivalence. However, these results only apply to Static Undirected Homogeneous Graphs with node attributes. In contrast, real-life applications often involve a variety of graph properties, such as, e.g., dynamics or node and edge attributes. In this paper, we conduct a theoretical analysis of the expressive power of GNNs for these two graph types that are particularly of interest. Dynamic graphs are widely used in modern applications, and its theoretical analysis requires new approaches. The attributed type acts as a standard form for all graph types since it has been shown that all graph types can be transformed without loss to Static Undirected Homogeneous Graphs with attributes on nodes and edges (SAUHG). The study considers generic GNN models and proposes appropriate 1-WL tests for those domains. Then, the results on the expressive power of GNNs are extended by proving that GNNs have the same capability as the 1-WL test in distinguishing dynamic and attributed graphs, the 1-WL equivalence equals unfolding equivalence and that GNNs are universal approximators modulo 1-WL/unfolding equivalence. Moreover, the proof of the approximation capability holds for SAUHGs, which include most of those used in practical applications, and it is constructive in nature allowing to deduce hints on the architecture of GNNs that can achieve the desired accuracy.

A finite difference algorithm that evaluates the health conditions of a bonded joint is presented and discussed. The mathematical formulation of the problem is developed, paying particular attention to the singularity around the corners of the joint and implementing an original discretisation method of the partial differential equations governing the propagation of the elastic waves. The equations are solved under the only hypothesis of a bidimensional field. The algorithm is sensible to defects in the bonded joint and can be used as an effective structural health monitoring tool, as proven by the experiments that show close agreement with the numerical simulations.

Pancreatic islet transplantation is a therapeutic option for achieving physiologic regulation of plasma glucose in Type 1 diabetic patients. At the same time, mesenchymal stem cells (MSCs) have demonstrated their potential in controlling graft rejection, the most fearsome complication in organ/tissue transplantation. MSCs can interact with innate and adaptive immune system cells either through direct cell-cell contact or through their secretome including exosomes. In this review, we discuss current findings regarding the graft microenvironment of pancreatic islet recipient patients and the crucial role of MSCs operation as cell managers able to control the immune system to prevent rejection and promote endogenous repair. We also discuss how challenging stressors, such as oxidative stress and impaired vasculogenesis, may jeopardize graft outcomes. In order to face these adverse conditions, we consider either hypoxia-exposure preconditioning of MSCs or human stem cells with angiogenic potential in organoids to overcome islets’ lack of vasculature. Along with the shepherding of carbon nanotubes-loaded MSCs to the transplantation site by a magnetic field, these studies look forward to exploiting MSCs stemness and their immunomodulatory properties in pancreatic islet transplantation.

Abstract: Bipolar disorders (BDs) are a heterogeneous group of severe affective disorders generally described by the alternation of (hypo)manic, depressive, and mixed phases, with euthymic intervals of variable duration. BDs are burdened with high psychiatric and physical comorbidity, increased suicide risk and reduced life expectancy. In addition, BDs can progress into complicated forms (e.g., mixed states, rapid/irregular cycling), which are more difficult to treat and often require personalized pharmacological combinations. Mood stabilizers, particularly Lithium and Valproic acid (VPA), still represent the cornerstones of both acute and chronic pharmacotherapies of BDs. Lithium is the gold standard in BD-I and BDII with typical features, while VPA seems more effective for atypical forms (e.g., mixed-prevalence and rapid-cycling). However, despite appropriate mood stabilization, many patients show residual symptoms, and more than a half recur within 1-2 years, highlighting the need of additional strategies. Among these, the association of atypical antipsychotics (AAPs) with mood stabilizers is recurrent in the treatment of acute phases, but it is also being growingly explored in the maintenance pharmacotherapy. These combinations are clinically more aggressive and often needed in the acute phases, whereas simplifying pharmacotherapies to mood stabilizers only is preferable in the long-term, whenever possible. When mood stabilizers are not enough for maintenance treatment, Quetiapine and, less consistently, Aripiprazole have been proposed as the most advisable adjunctive strategies, for their safety and tolerability profiles. However, in view of the increased risk of serious adverse effects, a careful patient-centered balance between costs and benefits is mandatory.

Background Timely recognition of malignant melanoma (MM) is challenging for dermatologists worldwide and represents the main determinant for mortality. Dermoscopic examination is influenced by dermatologists’ experience and fails to achieve adequate accuracy and reproducibility in discriminating atypical nevi (AN) from early melanomas (EM). Objective We aimed to develop a Deep Convolutional Neural Network (DCNN) model able to support dermatologists in the classification and management of atypical melanocytic skin lesions (aMSL). Methods A training set (630 images), a validation set (135) and a testing set (214) were derived from the idScore dataset of 979 challenging aMSL cases in which the dermoscopic image is integrated with clinical data (age, sex, body site and diameter) and associated with histological data. A DCNN_aMSL architecture was designed and then trained on both dermoscopic images of aMSL and the clinical/anamnestic data, resulting in the integrated “iDCNN_aMSL” model. Responses of 111 dermatologists with different experience levels on both aMSL classification (intuitive diagnosis) and management decisions (no/long follow-up; short follow-up; excision/preventive excision) were compared with the DCNNs models. Results In the lesion classification study, the iDCNN_aMSL achieved the best accuracy, reaching an AUC = 90.3 %, SE = 86.5 % and SP = 73.6 %, compared to DCNN_aMSL (SE = 89.2 %, SP = 65.7 %) and intuitive diagnosis of dermatologists (SE = 77.0 %; SP = 61.4 %). Conclusions The iDCNN_aMSL proved to be the best support tool for management decisions reducing the ratio of inappropriate excision. The proposed iDCNN_aMSL model can represent a valid support for dermatologists in discriminating AN from EM with high accuracy and for medical decision making by reducing their rates of inappropriate excisions.

The present work is concerned with adhesive bonding of thermoplastic composites used in general aerospace applications, including polyphenylene sulfide (PPS), polyetherimide (PEI) and polyetheretherketone (PEEK) carbon fibre composites. Three different surface treatments have been applied to the PEEK, PPS and PEI-based composites in order to enhance the adhesion: atmospheric plasma, ultraviolet radiation (UV) and isopropanol wiping as a control. Water contact angles and free surface energies were measured following the standard experimental procedure based on the employment of three different liquid droplets. Infrared spectroscopy and X-ray photoelectron spectroscopy (XPS) were subsequently performed to characterize the surface chemistry of the samples after treatment. The single lap joints were manufactured and bonded by an Aerospace grade epoxy-based film adhesive originally developed for use on metals but with the ability to bond treated thermoplastics to good strength (supplied by Henkel Ireland). Quasi-static (QS) tests were conducted. The lap shear strength was evaluated, and the failure mechanisms of the different joints were examined for the range of surface treatments considered. It was found that the performances of the PEEK and PPS joints were considerably improved by the plasma and UV treatments resulting in cohesive and delamination failures, while PEI was unaffected by the plasma and UV treatments and performed very well throughout.

In the last years, bistable composite structures are finding interest in several aeronautical applications such as power harvesting devices or morphing applications on very small aircraft/drones, not needing servo-activated control systems. Residual stresses, developed upon cooling after curing, leads to warped the composite laminates. Several batches of unsymmetrical and unbalanced [0°/90°] laminates were cured in an autoclave according to a standard temperature cycle, following the pre-preg supplier suggested curing cycle. In order to increase the thermal stresses (and hence the bistability phenomenon), these laminates were removed from the autoclave immediately after the curing reaction and rapidly cooled down at room temperature not applying the indicated cool rate between 2 and 5 °C min−1. During storage at room temperature, thermal stresses changed over time, indicating that asymptotic stress relaxation occurs. The first part of this work looks at residual stress characterization of bistable composite plates measuring the changes of shape observed during room temperature annealing. Rectangular plates were produced and the bistable geometric shapes were accurately assessed using a laser scanner system over several days, in order to monitor the curvature changes due to stress relaxation. Then phenomenological viscoelastic predicting models were proposed for a quick estimate for the strain/stress relaxation phenomenon. The loss of bistability was demonstrated with the help of numerical simulation and experimental testing. The final goal was to gain a better knowledge of the relation between processing and final shape of bistable laminates, in order to make them suitable for application on small air vehicles.

Composite materials, in addition to the high specific mechanical properties, have properties enabling their applications in high-pressure, high-temperature (HPHT) and corrosive environment as occurs in deep water. Their use for manufacturing pipelines and offshore risers can provide relevant performance advantages over steel such as lower weight, improved fatigue capacity, corrosion resistance and higher strain limits. However, composite materials are more complex to use in design than metallic materials due to their anisotropic properties and lack of accurate failure prediction models. Thus, a continuous in-situ and in real-time Structural Health Monitoring (SHM) of composite components would be necessary and useful to promote their use in a wider range of operational conditions. In this work, an FRP pipe sample was instrumented with Piezoelectric Wafer Active Sensors (PWAS) used either as passive receivers or as transmitters of guided waves for active health monitoring in pitch-catch configuration. The propagation properties of guided waves in glass fibres reinforced composites were studied by developing MATLAB scripts, running FE simulation and experiments. The numerical and experimental signals were post-processed in MATLAB by Short Time Fourier Transform (STFT) in order to evaluate their frequency and time-frequency content. Furthermore, the guided waves were used to detect artificial defects imposed on the structure identifying their location. Several testcases were studied to find out the limitations and the most suitable conditions of using guided waves for defects monitoring in a composite pipe. The work proposes effective methods for pipe structural health evaluation by non-destructive techniques and ultrasonic guided waves.

Purpose Asbestos is a human carcinogen and can cause some types of cancer, including mesothelioma. A relevant number of workers are still engaged in asbestos removal and disposal activities, whose actual risk of asbestos-related diseases is still scarcely recognized. The main objective of this study is to assess the cause-specific mortality among workers involved in asbestos removal and disposal after the ban in Italy. Methods Data from the Italian national registry on occupational exposure to carcinogens (SIREP) in the period 1996–2018 were selected. Proportionate mortality ratios (PMRs) by cause of death were calculated linking exposure occupational information to national mortality statistics (2005–2018), assuming a Poisson distribution of the data. Results A total of 142 deaths were identified among 13,715 asbestos removal and disposal workers. A significant excess (p