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The definition of the tenor as the “primo uomo” emerged gradually beginning in the mid-18th century, and Giuseppe Tibaldi played a crucial role in this process. In the 1750s he embarked on a brilliant career alongside his wife, Rosa Tartaglini. His vocal style inspired the characters of Admeto in Gluck’s Alceste and Aceste in Mozart’s Ascanio in Alba. In addition to being a singer, Tibaldi was a respected composer and served multiple times as principe for the Accademia dei Filarmonici. He had a close friendship with Giambattista Martini, to whom he entrusted the education of his son Ferdinando. Other members of the Tibaldi family also performed on stage, including Pietro, Giuseppe’s brother, and his wife Angela Masi; Giuseppe and Carlo, the tenor’s second and third sons; and Costanza, Carlo’s daughter, who concluded the Tibaldi musical dynasty in the first half of the 19th century. The paper summarizes the Tibaldi family’s history across three generations, highlighting their educational and professional relationships. It presents a 1767 document with which Tibaldi purchased the family palace in Piazza Calderini and discusses the singer’s previously unknown will, accompanied by a detailed inventory of his substantial Bologna residence and rich musical library.

Abstract As seismic events continue to pose significant threats to urban infrastructure, leveraging smartphones equipped with accelerometers for real-time monitoring has gained prominence. To ascertain the reliability and sensitivity of smartphone-based measurements, an in-depth characterization of their response is essential. This article presents a thorough characterization of the performance of typical accelerometers installed on three distinct smartphone models. For this, a novel experimental apparatus has been developed to conduct a comparative study involving three different smartphones against a reference accelerometer. We determine each accelerometer’s transfer functions for Fourier frequencies 0.1–40 Hz, evidencing main differences and demonstrating a higher sensitivity than expected. Possible implementation in future distributed networks of heterogeneous and synchronized sensors, capable of independently generating and validating timely alerts in particular seismic events, are also discussed.

Edge computing brings computation facilities in close proximity to users, hence paving the way to a plethora of applications characterized by stringent requirements. Edge systems are highly dynamic, and clients may have to access their edge services at different locations over time. When this happens, it is fundamental to guarantee seamless service continuity, i.e., letting endpoints reach each other transparently and with no or negligible impact on performance. In this work, we propose a service-continuity solution for edge environments that leverages an ecosystem of distributed edge proxies as its core element. Edge proxies mediate between client applications and edge services and are dynamically reconfigured by a system orchestrator to ensure service continuity when the proxy for a client needs to change. Our proxies exploit HTTP Alternative Services, an extension of the HTTP standard, to inform clients of the new proxy to reach. Our approach is fully transparent to the application logic and does not require any non-standard protocol modification. We implemented a Proof-of-Concept and used it to assess our solution over a small-scale testbed. We considered different experimental scenarios and variants of the proposed strategy, comparing it against alternative approaches, namely one where the edge proxy does not change and one based on DNS resolution. Experimental results show the validity and superior performance of the proposed methodology.

The distribution of entangled qubit pairs to end nodes is the key requirement of a quantum network to enable qubit state transmission through quantum teleportation. Existing protocols for entanglement distribution fix a specific swapping order on the involved quantum repeaters and delegate entanglement purification to upper-layer protocols. This limitation is problematic because entangled states tend to degrade due to quantum noise, and they cannot be purified if their fidelity (i.e., quality) falls below a certain threshold. It is therefore of the utmost importance to co-plan entanglement swapping and purification to achieve a target end-to-end fidelity. In this work, we present the Ranked Entanglement Distribution Protocol (REDiP), which overcomes the aforementioned limits by including the “ranks” mechanism to configure the ordering of both purification and entanglement swapping steps. We show how REDiP can easily be configured to implement custom entanglement swapping and purification strategies, including (but not restricted to) those adopted in two recent works. We also propose an algorithm to estimate the bandwidth to allocate on every link of the REDiP path, and we provide a set of guidelines on how REDiP ranks can be configured depending on user requirements and hardware configuration. Such guidelines are driven by original insights into purification performance. We conduct simulations to verify our results and assess the impact of different REDiP configurations on the performance of a repeater network, in terms of throughput and fidelity.

The Information and Communications Technology subject area is a broad multidisciplinary field of academic research and professional practice covering many topics ranging from electronics to system and network administration, to software development, cyber security, VR, AR, IoT and AI. Due to its nature, it cooperates closely with diverse areas, most notably eLearning and digital education. As contemporary educational institutions undergo a digital transformation, by which its processes are reengineered to take most of the possibilities offered by the emerging technologies, the contribution of the ICT field has become transversal and consequently of critical importance. The term ICT which refers to this wide multidisciplinary field differentiates from IT, which applies specifically to the management and use of computer systems to store, retrieve, transmit, and manipulate data. The continuous expansion of the field to new territories of practice such as education is requiring additional knowledge, skills and wider competences acquisition. In addition, high volatility of the job market creates the need for very adaptable professional profiles. As a result, there is a pressure from the job market for shorter and more job-oriented programmes, but also for competence frameworks which may serve as references for quality higher education and training. In this paper we present the Tuning Quality Reference Framework (QRF) for ICT which was developed as part of the CALOHEE Erasmus+ funded project. A multidisciplinary team with experts from 12 different countries (Portugal, Lithuania, Germany, Italy, Spain, Austria, Belgium, Greece, Turkey, Finland, Ireland and Romania) took part in the task. The QRF is built in a way to flexibly address all the mentioned complexity and continuously emerging new requirements including educational institutions and non-formal education organisations. The approach used also supports innovation in learning, teaching and assessment practices in ICT degrees, fostering open and digital education.

Objective: Pompe disease (PD) is caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to progressive glycogen accumulation and severe myopathy with progressive muscle weakness. In the Infantile-Onset PD (IOPD), death generally occurs

Verification and validation (V&V) are complex processes combining different approaches and incorporating many different methods including many activities. System engineers regularly face the question if their V&V activities lead to better products, and having appropriate criteria at hand for evaluation of safety and cybersecurity of the systems would help to answer such a question. Additionally, when there is a demand to improve the quality of an already managed V&V process, there is a struggle over what criteria to use in order to measure the improvement. This paper presents an extensive set of criteria suitable for safety and cybersecurity evaluation of cyberphysical systems. The evaluation criteria are agreed upon by 60 researchers from 32 academic and industrial organizations jointly working in a large-scale European research project on 13 real-world use cases from the domains of automotive, railway, aerospace, agriculture, healthcare, and industrial robotics.

Two neurodevelopmental conditions, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), have been associated with executive function (EF) impairments but the specificity of their impairments is still controversial. The present meta-analysis aimed to identify the differences in EF profiles of ASD, ADHD, and ASD+ADHD in relation to a control group of individuals with typical development (TD) and to understand whether the EF performance could change depending upon the type of measure used to assess EF (performance tests vs. questionnaires). Results from 36 eligible studies revealed that ADHD and ASD showed more difficulties than the TD group in tests and, particularly, in questionnaires. No significant differences in the EF profile emerged between ASD and ADHD when assessed through neuropsychological tests (d = 0.02), while significant differences emerged when assessed through questionnaires, with ADHD having higher ratings than ASD (d = −0.34). EF questionnaires and neuropsychological tests may catch two different constructs of EF, with the former being more predictive of everyday life EF impairments. The comparison between the double diagnosis group (ADHD+ASD) and the clinical groups pointed out that the former has a more similar EF profile to the ADHD-alone one and that it shows more difficulties than ASD-alone.

Ensuring compliance with the stringent latency requirements of edge services requires close cooperation between the network and computing components. Within mobile 5G networks, the nomadic behavior of users may impact the performance of edge services, prompting the need for workload migration techniques. These techniques allow services to follow users by moving between edge nodes. This paper introduces an innovative approach for edge service continuity by integrating Segment Routing over IPv6 (SRv6) into the 5G core data plane alongside the ETSI multi-access edge computing (MEC) architecture. Our approach maintains compatibility with non-SRv6 5G network components. We use SRv6 for packet steering and Software-Defined Networking (SDN) for dynamic network configuration. Leveraging the SRv6 Network Programming paradigm, we achieve lossless workload migration by implementing a packet buffer as a virtual network function. Our buffer may be dynamically allocated and configured within the network. We test our proposed solution on a small-scale testbed consisting of an Open Network Operating System (ONOS) SDN controller and a core network made of P4 BMv2 switches, emulated using Mininet. A comparison with a non-SRv6 alternative that uses IPv6 routing shows the higher scalability and flexibility of our approach in terms of the number of rules to be installed and time required for configuration.

The contribution investigates the role of the bird’s eye view in perception and thus in the design of buildings and the city. The development of satellite technologies and their use on a large scale is considered a threshold towards a new way of conceiving architecture. In fact, the web allows virtual trips around the world and, the first interface with the city and its architecture is often the view offered by satellite image software. Their wide use, also as navigation tools, has changed the way of relating to the city. Whereas once the first interface between the building and the visitor was the façade, today the roof is often the first visible element. This change has also had an impact on the design of new buildings. For example, technical rooms are increasingly being hidden by roofs, and replaced by garden roofs, which are more attractive for viewing from above. Similarly, large-scale urban interventions, from the expansion plans of artificial islands in gulf countries to the mammoth buildings erected in deserts, follow geometries that are easily recognizable from above. They often use formal expedients –symmetrical shapes, bright colors, large logos– already in use in airport design, conceived to be seen from the privileged height of an aircraft. The democratization of the processes of viewing from above has led to a rethinking of the processes of communicating architecture, which no longer interfaces with the limited audience of flesh-and-blood visitors, but with the broader audience of people connected to the web.

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism, which is currently treated with life-long low-protein diet that can be challenging to maintain. Here the authors develop an AAV8-directed gene therapy providing sustainable disease rescue in a mouse model of MSUD.

In the current JWST era, rest-frame UV spectra play a crucial role in enhancing our understanding of the interstellar medium (ISM) and stellar properties of the first galaxies in the epoch of reionization ( z > 6). Here, we compare well-known and reliable optical diagrams sensitive to the main ionization source (i.e., star formation, SF; active galactic nuclei, AGN; and shocks) to UV counterparts proposed in the literature—the so-called “UV–BPT diagrams”—using the HST COS Legacy Archive Spectroscopic SurveY (CLASSY), which is the largest high-quality, high-resolution, and broad-wavelength range atlas of far-UV spectra for 45 local star-forming galaxies. In particular, we explore where CLASSY UV line ratios are located in the different UV diagnostic plots, taking into account state-of-the-art photoionization and shock models, and, for the first time, the measured ISM and stellar properties (e.g., gas-phase metallicity, ionization parameter, carbon abundance, and stellar age). We find that the combination of C iii ] λ λ 1907,9 He ii λ 1640 and O iii ] λ 1666 can be a powerful tool to separate between SF, shocks, and AGN at subsolar metallicities. We also confirm that alternative diagrams without O iii ] λ 1666 still allow us to define an SF-locus, with some caveats. Diagrams including C iv λ λ 1548,51 should be taken with caution given the complexity of this doublet profile. Finally, we present a discussion detailing the ISM conditions required to detect UV emission lines, visible only in low gas-phase metallicity (12 + log(O/H) ≲ 8.3) and high ionization parameter (log( U ) ≳ −2.5) environments. Overall, CLASSY and our UV toolkit will be crucial in interpreting the spectra of the earliest galaxies that JWST is currently revealing.

The first JWST spectroscopy of the luminous galaxy GN-z11 simultaneously established its redshift at z = 10.6 and revealed a rest-ultraviolet spectrum dominated by signatures of highly ionized nitrogen, which has so far defied clear interpretation. We present a reappraisal of this spectrum in the context of both detailed nebular modeling and nearby metal-poor reference galaxies. The N iv ] emission enables the first nebular density measurement in an apparently predominantly star-forming galaxy at z > 10, revealing evidence for extremely high densities n _e ≳ 10 ^5 cm ^−3 . With a suite of photoionization models, we establish that regardless of the ionization mechanism and accounting for depletion and this density enhancement, gas substantially enriched in nitrogen ([N/O] = +0.52 assuming the nebular emission is dominated by star formation) is required to reproduce the observed lines. We compare the GN-z11 spectrum to local UV databases and highlight a unique nearby galaxy, Mrk 996, where a high concentration of Wolf–Rayet stars and their CNO-processed ejecta produce a UV spectrum remarkably similar in some respects to that of GN-z11 and the Sunburst Arc. Collating this evidence in the context of Galactic stellar abundances, we suggest that the peculiar nitrogenic features prominent in GN-z11 may be a unique signature of intense and densely clustered star formation in the evolutionary chain of the present-day globular clusters, consistent with in situ early enrichment with nuclear-processed stellar ejecta on a massive scale. Combined with insight from local galaxies, these and future JWST data open a powerful new window into the physical conditions of star formation and chemical enrichment at the highest redshifts.

To study the chemical evolution across cosmic epochs, we investigate Ne, S, Cl, and Ar abundance patterns in the Cosmic Origins Spectrograph Legacy Archive Spectroscopic SurveY (CLASSY). CLASSY comprises local star-forming galaxies (SFGs; 0.02 < z < 0.18) with enhanced star formation rates, making them strong analogues to high- z SFGs. With direct measurements of electron temperature, we derive accurate ionic abundances for all elements and assess ionization correction factors (ICFs) to account for unseen ions and derive total abundances. We find Ne/O, S/O, Cl/O, and Ar/O exhibit constant trends with gas-phase metallicity for 12+log(O/H) < 8.5 but significant correlation for Ne/O and Ar/O with metallicity for 12+log(O/H) > 8.5, likely due to ICFs. Thus, the applicability of the ICFs to integrated spectra of galaxies could bias results, underestimating true abundance ratios. Using CLASSY as a local reference, we assess the evolution of Ne/O, S/O, and Ar/O in galaxies at z > 3, finding no cosmic evolution of Ne/O, while the lack of direct abundance determinations for S/O and Ar/O can bias the interpretation of the evolution of these elements. We determine the fundamental metallicity relationship (FMR) for CLASSY and compare to the high-redshift FMR, finding no evolution. Finally, we perform the first mass–neon relationship analysis across cosmic epochs, finding a slight evolution to high Ne at later epochs. The robust abundance patterns of CLASSY galaxies and their broad range of physical properties provide essential benchmarks for interpreting the chemical enrichment of the early galaxies observed with the JWST.

We present JWST/NIRSpec prism spectroscopy of MACS0647−JD, a triply lensed z ∼ 11 candidate discovered in Hubble Space Telescope imaging and spatially resolved by JWST imaging into two components, A and B. Spectroscopy of component A yields a spectroscopic redshift z = 10.17 based on seven detected emission lines: C iii ] λ λ 1907, 1909, [O ii ] λ 3727, [Ne iii ] λ 3869, [Ne iii ] λ 3968, H δ λ 4101, H γ λ 4340, and [O iii ] λ 4363. These are the second-most distant detections of these emission lines to date, in a galaxy observed just 460 million years after the Big Bang. Based on observed and extrapolated line flux ratios we derive a gas-phase metallicity 12 + log(O/H) ∼ 7.5–8.0, or Z ∼ (0.06–0.2) Z _⊙ , ionization parameter $\mathrm{log}(U)$ = −1.9 ± 0.2, and an ionizing photon production efficiency $\mathrm{log}({\xi }_{\mathrm{ion}})=25.2\pm 0.2\,$ erg ^−1 Hz. The spectrum has a softened Ly α break, evidence for a strong Ly α damping wing. The Ly α damping wing also suppresses the F150W photometry, explaining the slightly overestimated photometric redshift z = 10.6 ± 0.3. MACS0647−JD has a stellar mass log( M / M _⊙ ) = 8.1 ± 0.3, including ∼6 × 10 ^7 M _⊙ in component A, most of which formed recently (within ∼20 Myr) with a star formation rate ∼ 2 ± 1 M _⊙ yr ^−1 , all within an effective radius 70 ± 24 pc. Spectroscopy of a fainter companion galaxy C separated by a distance of ∼ 3 kpc reveals a Lyman break consistent with z ∼ 10.17. MACS0647−JD is likely the most distant galaxy merger known.

JWST spectroscopy has revolutionized our understanding of galaxies in the early Universe. Covering wavelengths up to 5.3 μ m, NIRSpec can detect rest-frame optical H α emission lines out to z = 7 and [O iii ] to z = 9.5. Observing these lines in more distant galaxies requires longer wavelength spectroscopy with MIRI. Here we present MIRI Medium Resolution Spectrograph integral field unit observations of the lensed galaxy merger MACS0647–JD at z = 10.165. With exposure times of 4.2 hr in each of two bands (SHORT and LONG), we detect H α at 9 σ , [O iii ] λ 5008 at 11 σ , and [O iii ] λ 4960 at 3 σ . Combined with previously reported NIRSpec spectroscopy that yielded seven emission lines including the auroral line [O iii ] λ 4363, we present the first direct metallicity measurement of a z > 10 galaxy: $12+\mathrm{log}({\rm{O}}/{\rm{H}})=7.79\pm 0.09$ , or ${0.13}_{-0.03}^{+0.02}\,{Z}_{\odot }$ . This is similar to galaxies at z ∼ 4–9 with direct metallicity measurements, though higher than expected given the high specific star formation rate log(sSFR/yr ^−1 ) = −7.4 ± 0.3. We further constrain the ionization parameter $\mathrm{log}(U)$ = −1.9 ± 0.1, ionizing photon production efficiency log( ξ _ion ) = 25.3 ± 0.1, and SFR = 5.0 ± 0.6 M _⊙ yr ^−1 within the past 10 Myr. These observations demonstrate the combined power of JWST NIRSpec and MIRI for studying galaxies in the first 500 million years.

We present JWST/NIRSpec high-resolution G395H/F290LP spectroscopy of MACS0647−JD, a gravitationally lensed galaxy merger at z = 10.167. The new spectroscopy, which is acquired for the two lensed images (JD1 and JD2), detects and resolves emission lines in the rest-frame ultraviolet and blue optical, including the resolved [O ii ] λ λ 3726, 3729 doublet, [Ne iii ] λ 3870, He i λ 3890, H δ , H γ , and [O iii ] λ 4363. This is the first observation of the resolved [O ii ] λ λ 3726, 3729 doublet for a galaxy at z > 8. We measure a line flux ratio [O ii ] λ 3729/ λ 3726 = 0.9 ± 0.3, which corresponds to an estimated electron density of $\mathrm{log}({n}_{e}/{\mathrm{cm}}^{-3})=2.9\pm 0.5$ . This is significantly higher than the electron densities of local galaxies reported in the literature. We compile measurements from the literature and further analyze the redshift evolution of n _e . We find that the redshift evolution follows the power-law form of n _e = A × (1 + z ) ^p with $A={54}_{-23}^{+31}$ cm ^−3 and $p={1.2}_{-0.4}^{+0.4}$ . This power-law form may be explained by a combination of metallicity and morphological evolution of galaxies, which become, on average, more metal poor and more compact with increasing redshift.

We present a pioneering, spatially resolved, multiphase gas abundance study on the blue compact dwarf galaxy NGC 5253, targeting 10 star-forming (SF) clusters inside six far-UV (FUV) Hubble Space Telescope/Cosmic Origins Spectrograph (COS) pointings with cospatial optical Very Large Telescope/MUSE observations throughout the galaxy. The SF regions span a wide range of ages (1–15 Myr) and are distributed at different radii (50–230 pc). We performed a robust absorption-line profile fitting on the COS spectra, covering 1065–1430 Å in the FUV, allowing an accurate computation of neutral-gas abundances for 13 different ions sampling eight elements. These values were then compared with the ionized-gas abundances, measured using the direct method on MUSE integrated spectra inside analog COS apertures. Our multiphase, spatially resolved comparisons find abundances, which are lower in the neutral gas than the ionized gas by 0.22, 0.80, and 0.58 dex for log(O/H), log(N/H), and log(N/O), respectively. We modeled the chemical abundance distributions and evaluated correlations as a function of the radius and age. It was found that, while N, O, and N/O abundances decrease as a function of age in the ionized gas, they increase with age in the neutral gas. No strong correlations for N, O, or N/O were observed as a function of the radius. The N/O and N/H offsets between the phases were found to decrease with age, providing evidence that chemical enrichment happens differentially, first in the ionized-gas phase around 2–5 Myrs (due to N-rich Wolf–Rayet stars) and then mixing out into the cold neutral gas on longer timescales of 10–15 Myr.

Feedback-driven massive outflows play a crucial role in galaxy evolution by regulating star formation and influencing the dynamics of surrounding media. Extracting outflow properties from spectral lines is a notoriously difficult process for a number of reasons, including the possibility that a substantial fraction of the outflow is carried by dense gas in a very narrow range in velocity. This gas can hide in spectra with insufficient resolution. Empirically motivated analysis based on the apparent optical depth method, commonly used in the literature, neglects the contribution of this gas, and may therefore underestimate the true gas column density. More complex semianalytical line transfer (e.g., SALT) models, on the other hand, allow for the presence of this gas by modeling the radial density and velocity of the outflows as power laws. Here we compare the two approaches to quantify the uncertainties in the inferences of outflow properties based on 1D “down-the-barrel” spectra, using the UV spectra of the CLASSY galaxy sample. We find that empirical modeling may significantly underestimate the column densities relative to SALT analysis, particularly in the optically thick regime. We use simulations to show that the main reason for this discrepancy is the presence of a large amount of dense material at low velocities, which can be hidden by the finite spectral resolution of the data. The SALT models in turn could overestimate the column densities if the assumed power laws of the density profiles are not a property of actual outflows.

Background: The presence of actionable alterations in advanced biliary tract cancer patients opened new therapeutic possibilities for second-line treatments. However, for around 60% of the patients, chemotherapy remains the only therapeutic option. The aim of our study was to evaluate outcomes and prognostic parameters in patients with intrahepatic cholangiocarcinomas treated with second-line chemotherapy. Methods: A total of 255 consecutive metastatic intrahepatic cholangiocarcinoma (ICC) patients were retrospectively reviewed and clinicopathologic and survival data were collected. Results: Fourty-four percent of ICC patients underwent second-line chemotherapy. In particular, younger ICC patients with better ECOG PS status, and with disease control after first-line chemotherapy were those who were treated with second-line treatments. Median progression-free survival in the patients treated with second-line chemotherapy was 3 months. Finally, the patients affected by intrahepatic cholangiocarcinoma with better ECOG PS, with prior surgical resection of the primary tumor, who responded to first-line chemotherapy, and had better progression-free survival with second-line chemotherapy, were associated with better outcomes in multivariate analysis. Conclusions: Not all patients seem to benefit from second-line chemotherapy. To improve therapeutic decisions, performance status and disease control with first-line chemotherapy should lead to the decision on the usefulness of second-line treatments in advanced ICC patients.

Super-resolution image acquisition has turned photo-activated far-infrared thermal imaging into a promising tool for the characterization of biological tissues. By the sub-diffraction localization of sparse temperature increments primed by the sample absorption of modulated focused laser light, the distribution of (endogenous or exogenous) photo-thermal biomarkers can be reconstructed at tunable ∼10−50 μm resolution. We focus here on the theoretical modeling of laser-primed temperature variations and provide the guidelines to convert super-resolved temperature-based images into quantitative maps of the absolute molar concentration of photo-thermal probes. We start from camera-based temperature detection via Stefan–Boltzmann’s law, and elucidate the interplay of the camera point-spread-function and pixelated sensor size with the excitation beam waist in defining the amplitude of the measured temperature variations. This can be accomplished by the numerical solution of the three-dimensional heat equation in the presence of modulated laser illumination on the sample, which is characterized in terms of thermal diffusivity, conductivity, thickness, and concentration of photo-thermal species. We apply our data-analysis protocol to murine B16 melanoma biopsies, where melanin is mapped and quantified in label-free configuration at sub-diffraction 40 µm resolution. Our results, validated by an unsupervised machine-learning analysis of hematoxylin-and-eosin images of the same sections, suggest potential impact of super-resolved thermography in complementing standard histopathological analyses of melanocytic lesions.

The Internet of Things (IoT) brings Internet connectivity to devices and everyday objects. This huge volume of connected devices has to be managed taking into account the severe energy, memory, processing, and communication constraints of IoT devices and networks. In this context, the OMA LightweightM2M (LWM2M) protocol is designed for remote management of constrained devices, and related service enablement, through a management server usually deployed in a distant cloud data center. Following the Edge Computing paradigm, we propose in this work the introduction of a LWM2M Proxy that is deployed at the network edge, in between IoT devices and management servers. On one hand, the LWM2M Proxy improves various LWM2M management procedures whereas, on the other hand, it enables the support of QoS-aware services provided by IoT devices by allowing the implementation of advanced policies to efficiently use network, computing, and storage (i.e., cache) resources at the edge, thus providing benefits in terms of reduced and more predictable end-to-end latency. We evaluate the proposed solution both by simulation and experimentally, showing that it can strongly improve the LWM2M performance and the QoS of the system.

In an article published in 2009, Brun et al. proved that in the presence of a “Deutschian” closed timelike curve, one can map $K$ distinct nonorthogonal states (hereafter, input set) to the standard orthonormal basis of a $K$-dimensional state space. To implement this result, the authors proposed a quantum circuit that includes, among SWAP gates, a fixed set of controlled operators (boxes) and an algorithm for determining the unitary transformations carried out by such boxes. To our knowledge, what is still missing to complete the picture is an analysis evaluating the performance of the aforementioned circuit from an engineering perspective. The objective of this article is, therefore, to address this gap through an in-depth simulation analysis, which exploits the approach proposed by Brun et al. in 2017. This approach relies on multiple copies of an input state, multiple iterations of the circuit until a fixed point is (almost) reached. The performance analysis led us to a number of findings. First, the number of iterations is significantly high even if the number of states to be discriminated against is small, such as 2 or 3. Second, we envision that such a number may be shortened as there is plenty of room to improve the unitary transformation acting in the aforementioned controlled boxes. Third, we also revealed a relationship between the number of iterations required to get close to the fixed point and the Chernoff limit of the input set used: the higher the Chernoff bound, the smaller the number of iterations. A comparison, although partial, with another quantum circuit discriminating the nonorthogonal states, proposed by Nareddula et al. in 2018, is carried out and differences are highlighted.

Abstract Background Rare diseases (RDs) encompass many difficult-to-treat conditions with different characteristics often associated with end-stage renal disease (ESRD). However, data about transplant outcomes in adult patients are still lacking and limited to case reports/case series without differentiation between immunological/non-immunological RDs. Methods Retrospective analysis among all adult kidney transplanted patients (KTs) with RDs (RDsKT group) performed in our high-volume transplantation center between 2005 and 2016. RDs were classified according to the Orphanet code system differentiating between immunological and non-immunological diseases, also comparing clinical outcomes and temporal trends to a control population without RDs (nRDsKT). Results Among 1381 KTs, 350 patients (25.3%) were affected by RDs (RDsKTs). During a f/up > 5 years [median 7.9 years (4.8–11.1)], kidney function and graft/patient survival did not differ from nRDsKTs. Considering all post-transplant complications, RDsKTs (including, by definition, patients with primary glomerulopathy except on IgA nephropathy) have more recurrent and de-novo glomerulonephritis (14.6% vs. 9.6% in nRDsKTs; p = 0.05), similar rates of de-novo cancers, post-transplant diabetes, dysmetabolism, hematologic disorders, urologic/vascular problems, and lower infectious episodes than nRDsKTs (63.7% vs 72.7%; p = 0.013). Additional stratification for immunological and non-immunological RDsKTs or transplantation periods (before/after 2010) showed no differences or temporal trends between groups. Conclusions Kidney transplant centers are deeply involved in RDs management. Despite their high-complex profile, both immunological and non-immunological RDsKTs experienced favorable patients’ and graft survival.

Pompe disease is currently treated with enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (GAA). Here, the authors show hepatic-directed gene therapy with AAV vectors enhances GAA bioavailability compared with ERT, resulting in improved rescue of the disease phenotype in mice and broad enzyme distribution in mice and non-human primates.

Summary: Calcineurin (CN) inhibitors currently used to avoid transplant rejection block the activation of adaptive immune responses but also prevent the development of tolerance toward the graft, by directly inhibiting T cells. CN, through the transcription factors of the NFAT family, plays an important role also in the differentiation dendritic cells (DCs), the main cells responsible for the activation of T lymphocytes. Therefore, we hypothesized that the inhibition of CN only in DCs and not in T cells could be sufficient to prevent T cell responses, while allowing for the development of tolerance. Here, we show that inhibition of CN/NFAT pathway in innate myeloid cells, using a new nanoconjugate capable of selectively targeting phagocytes in vivo, protects against graft rejection and induces a longer graft acceptance compared to common CN inhibitors. We propose a new generation of nanoparticles-based selective immune suppressive agents for a better control of transplant acceptance.

AAV gene transfer is a promising treatment for many patients with life-threatening genetic diseases. However, host immune response to the vector poses a significant challenge for the durability and safety of AAV-mediated gene therapy. Here, we characterize the innate immune response to AAV in human whole blood. We identified neutrophils, monocyte-related dendritic cells, and monocytes as the most prevalent cell subsets able to internalize AAV particles, while conventional dendritic cells were the most activated in terms of the CD86 co-stimulatory molecule upregulation. Although low titers (≤1:10) of AAV neutralizing antibodies (NAb) in blood did not have profound effects on the innate immune response to AAV, higher NAb titers (≥1:100) significantly increased pro-inflammatory cytokine/chemokine secretion, vector uptake by antigen presenting cells (APCs) and complement activation. Interestingly, both full and empty viral particles were equally potent in inducing complement activation and cytokine secretion. By using a compstatin-based C3 and C3b inhibitor, APL-9, we demonstrated that complement pathway inhibition lowered CD86 levels on APCs, AAV uptake, and cytokine/chemokine secretion in response to AAV. Together these results suggest that the pre-existing humoral immunity to AAV may contribute to trigger adverse immune responses observed in AAV-based gene therapy, and that blockade of complement pathway may warrant further investigation as a potential strategy for decreasing immunogenicity of AAV-based therapeutics.

BIM (building information modelling) has led to substantial improvements in all design steps. Applied mainly as an information management system in the digital design of structures and buildings, only in recent years has the use of BIM also extended to the construction of road infrastructure. The so-called I-BIM (infrastructure building information modelling) methodology supports the designer in the phases of construction and execution of the design considering all aspects related to the project, including sustainability. Through the software “Roads” of “SierraSoft S.r.l.”, in this article, the I-BIM approach has been used to design a 35 km cycle path as sustainable as possible. From an operational point of view, the design of a cycle path section begins with the modelling of the infrastructure in all its aspects: a study of the route, analysis of interference, modelling of the infrastructure (floor plan, profile and sections) and an intersection study. Creating an infrastructure that increases soft mobility vehicles through a comprehensive design, attracting as many users as possible, is the real innovative challenge.

A clinical trial using adeno-associated virus serotype 8 (AAV8)-human uridine diphosphate glucuronosyltransferase 1A1 (hUGT1A1) to treat inherited severe unconjugated hyperbilirubinemia (Crigler-Najjar syndrome) is ongoing, but preclinical data suggest that long-term efficacy in children is impaired due to loss of transgene expression upon hepatocyte proliferation in a growing liver. This study aims to determine at what age long-term efficacy can be obtained in the relevant animal model and whether immune modulation allows re-treatment using the same AAV vector. Neonatal, suckling, and juvenile Ugt1a1-deficient rats received a clinically relevant dose of AAV8-hUGT1A1, and serum bilirubin levels and anti-AAV8 neutralizing antibodies (NAbs) in serum were monitored. The possibility of preventing the immune response toward the vector was investigated using a rapamycin-based regimen with daily intraperitoneal (i.p.) injections starting 2 days before and ending 21 days after vector administration. In rats treated at postnatal day 1 (P1) or P14, the correction was (partially) lost after 12 weeks, whereas the correction was stable in rats injected at P28. Combining initial vector administration with the immune-suppressive regimen prevented induction of NAbs in female rats, allowing at least partially effective re-administration. Induction of NAbs upon re-injection could not be prevented, suggesting that this strategy will be ineffective in patients with low levels of preexisting anti-AAV NAbs.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked liver disorder caused by partial or total loss of OTC enzyme activity. It is characterized by elevated plasma ammonia, leading to neurological impairments, coma, and death in the most severe cases. OTCD is managed by combining dietary restrictions, essential amino acids, and ammonia scavengers. However, to date, liver transplantation provides the best therapeutic outcome. AAV-mediated gene-replacement therapy represents a promising curative strategy. Here, we generated an AAV2/8 vector expressing a codon-optimized human OTC cDNA by the α1-AAT liver-specific promoter. Unlike standard codon-optimization approaches, we performed multiple codon-optimization rounds via common algorithms and ortholog sequence analysis that significantly improved mRNA translatability and therapeutic efficacy. AAV8-hOTC-CO (codon optimized) vector injection into adult OTCSpf-Ash mice (5.0E11 vg/kg) mediated long-term complete correction of the phenotype. Adeno-Associated viral (AAV) vector treatment restored the physiological ammonia detoxification liver function, as indicated by urinary orotic acid normalization and by conferring full protection against an ammonia challenge. Removal of liver-specific transcription factor binding sites from the AAV backbone did not affect gene expression levels, with a potential improvement in safety. These results demonstrate that AAV8-hOTC-CO gene transfer is safe and results in sustained correction of OTCD in mice, supporting the translation of this approach to the clinic.

Extra‐pair paternity (EPP) has been broadly reported in socially monogamous bird species and it has been hypothesized that females engage in extra‐pair copulations to increase the genetic variability of the offspring and to reduce the risk of inbreeding and genetic incompatibilities. This hypothesis makes two predictions: within populations, females should engage with more dissimilar/heterozygous males and, among populations, females should pursue more frequently EPP in populations characterized by a lower genetic variability and a higher homozygosity. However, support is still unclear throughout literature, and usually involves the study of a single population. We compared a peripheral population of rock sparrow Petronia petronia living at the marginal distribution of the species and characterized by a high EPP level (> 50%) (Italian Alps) with a population located in the centre of the species' distribution (central Spain), to understand if variations in EPP could be linked to differences in mean heterozygosity and genetic similarity both between and within populations. EPP in the Spanish population was 18.1%, three times lower than that observed in the Alpine one (51.2%), and this difference remained fairly constant across different years. Supporting the between populations prediction, we found lower heterozygosity and reduced allelic richness in the Alpine population compared to the Spanish one. In contrast, social and extra‐pair males, as well as within and extra‐pair offspring, did not significantly differ in terms of genetic similarity and heterozygosity within brood in either population. Social and extra‐pair males did not differ in tarsus size, body weight or yellow badge size, suggesting that females were not choosing extra‐pair partners based on heterozygosity, genetic similarity or phenotypic quality. Although based on a limited sample in the within population analysis, our results indicate that EPP may evolve in response to a low level of genetic variability in the population.

Potency assessment of clinical-grade vector lots is crucial to support adeno-associated virus (AAV) vector release and is required for future marketing authorization. We have developed and validated a cell-based, quantitative potency assay that detects both transgenic expression and activity of an AAV8-hUGT1A1 vector, which is currently under clinical evaluation for the treatment of Crigler-Najjar syndrome. Potency of AAV8-hUGT1A1 was evaluated in vitro. After transduction of human hepatoma 7 (Huh7) cells, transgene-positive cells were quantified using flow cytometry and transgenic activity by a bilirubin conjugation assay. The in vitro potency of various AAV8-hUGT1A1 batches was compared with their potency in vivo. After AAV8-hUGT1A1 transduction, quantification of UGT1A1-expressing cells shows a linear dose-response relation (R2 = 0.98) with adequate intra-assay and inter-day reproducibility (coefficient of variation [CV] = 11.0% and 22.6%, respectively). In accordance, bilirubin conjugation shows a linear dose-response relation (R2 = 0.99) with adequate intra- and inter-day reproducibility in the low dose range (CV = 15.7% and 19.7%, respectively). Both in vitro potency assays reliably translate to in vivo efficacy of AAV8-hUGT1A1 vector lots. The described cell-based potency assay for AAV8-hUGT1A1 adequately determines transgenic UGT1A1 expression and activity, which is consistent with in vivo efficacy. This novel approach is suited for the determination of vector lot potency to support clinical-grade vector release.

Abstract The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12‐15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists. Presenters are asked to create Illustrated Capsules of their talks, which are concise illustrations with minimal explanatory text. Capsules cover major themes of the presentation, and these undergo formal peer review for inclusion in this article. Owing to the shift to a virtual congress this year, organizers reduced the program size. There were 39 SOA lectures virtually presented, and 29 capsules (9 from talks omitted from the virtual congress) were both submitted and successful in peer review, and are included in this article. Topics include the roles of the hemostatic system in inflammation, infection, immunity, and cancer, platelet function and signaling, platelet function disorders, megakaryocyte biology, hemophilia including gene therapy, phenotype tests in hemostasis, von Willebrand factor, anticoagulant factor V, computational driven discovery, endothelium, clinical and basic aspects of thrombotic microangiopathies, fibrinolysis and thrombolysis, antithrombotics in pediatrics, direct oral anticoagulant management, and thrombosis and hemostasis in pregnancy. Capsule authors invite virtual congress attendees to refer to these capsules during the live presentations and participate on Twitter in discussion. Research and Practice in Haemostasis and Thrombosis will release 2 tweets from @RPTHJournal during each presentation, using #IllustratedReview, #CoagCapsule and #ISTH2020. Readers are also welcome to utilize capsules for teaching and ongoing education.

Abstract Novel therapies for hemophilia, including non‐factor replacement and in vivo gene therapy, are showing promising results in the clinic, including for patients having a history of inhibitor development. Here, we propose a novel therapeutic approach for hemophilia based on llama‐derived single‐domain antibody fragments (sdAbs) able to restore hemostasis by inhibiting the antithrombin (AT) anticoagulant pathway. We demonstrated that sdAbs engineered in multivalent conformations were able to block efficiently AT activity in vitro, restoring the thrombin generation potential in FVIII‐deficient plasma. When delivered as a protein to hemophilia A mice, a selected bi‐paratopic sdAb significantly reduced the blood loss in a model of acute bleeding injury. We then packaged this sdAb in a hepatotropic AAV8 vector and tested its safety and efficacy profile in hemophilic mouse models. We show that the long‐term expression of the bi‐paratopic sdAb in the liver is safe and poorly immunogenic, and results in sustained correction of the bleeding phenotype in hemophilia A and B mice, even in the presence of inhibitory antibodies to the therapeutic clotting factor.

Many inborn errors of metabolism require life-long treatments and, in severe conditions involving the liver, organ transplantation remains the only curative treatment. Non-integrative AAV-mediated gene therapy has shown efficacy in adult patients. However, treatment in pediatric or juvenile settings, or in conditions associated with hepatocyte proliferation, may result in rapid loss of episomal viral DNA and thus therapeutic efficacy. Re-administration of the therapeutic vector later in time may not be possible due to the presence of anti-AAV neutralizing antibodies. We have previously shown the permanent rescue of the neonatal lethality of a Crigler-Najjar mouse model by applying an integrative gene-therapy based approach. Here, we targeted the human coagulation factor IX (hFIX) cDNA into a hemophilia B mouse model. Two AAV8 vectors were used: a promoterless vector with two arms of homology for the albumin locus, and a vector carrying the CRISPR/SaCas9 and the sgRNA. Treatment of neonatal P2 wild-type mice resulted in supraphysiological levels of hFIX being stable 10 months after dosing. A single injection of the AAV vectors into neonatal FIX KO mice also resulted in the stable expression of above-normal levels of hFIX, reaching up to 150% of the human levels. Mice subjected to tail clip analysis showed a clotting capacity comparable to wild-type animals, thus demonstrating the rescue of the disease phenotype. Immunohistological analysis revealed clusters of hFIX-positive hepatocytes. When we tested the approach in adult FIX KO mice, we detected hFIX in plasma by ELISA and in the liver by western blot. However, the hFIX levels were not sufficient to significantly ameliorate the bleeding phenotype upon tail clip assay. Experiments conducted using a AAV donor vectors containing the eGFP or the hFIX cDNAs showed a higher recombination rate in P2 mice compared to adult animals. With this study, we demonstrate an alternative gene targeting strategy exploiting the use of the CRISPR/SaCas9 platform that can be potentially applied in the treatment of pediatric patients suffering from hemophilia, also supporting its application to other liver monogenic diseases. For the treatment of adult patients, further studies for the improvement of targeting efficiency are still required.

This paper provides the fourth edition of the checklist of birds recorded in northwestern Italy (the Piedmont and Aosta Valley regions) and covers more than 300 years of ornithological data, including subspecies. This work updates the previous works published in 1981, 2003, and 2009, with the revision of the AERC codes and the addition of special annotations for several species. We also provide some new settings to make the bird checklist a more useful tool for all users, particularly scholars and professionals interested in biodiversity assessment and conservation reports. To this end, (a) new coding concerning population estimates and trends, as well as risk categories (Red List), is introduced; (b) bird lists are structured for analysis at two temporal levels: the General Checklist (GCL), covering the period from 1685 to 2022, and the Operational Checklist (OCL), covering the decade 2010–2019, providing periods of reference for comparison and analysis; and (c) an electronic spreadsheet is provided as part of the online Supplementary Materials to allow for further data analysis by readers, if necessary. The list presently contains 408 species and 444 taxonomic units, which consist of both subspecies and monotypic species. Each of them has been allocated to one of the AERC categories A, B, C, or D, while category E has been excluded. Since the publication of the previous list (2009), 19 species have been added. The avifauna currently breeding in the Piedmont and Aosta Valley regions comprises 197 species, with an additional 9 species that were once breeders but are now considered regionally extinct.

Galaxy formation and evolution are regulated by the feedback from galactic winds. Absorption lines provide the most widely available probe of winds. However, since most data only provide information integrated along the line of sight, they do not directly constrain the radial structure of the outflows. In this paper, we present a method to directly measure the gas electron density in outflows ( n _e ), which in turn yields estimates of outflow cloud properties (e.g., density, volume filling factor, and sizes/masses). We also estimate the distance ( r _n ) from the starburst at which the observed densities are found. We focus on 22 local star-forming galaxies primarily from the COS Legacy Archive Spectroscopic SurveY (CLASSY). In half of them, we detect absorption lines from fine-structure excited transitions of Si ii (i.e., Si ii *). We determine n _e from relative column densities of Si ii and Si ii *, given Si ii * originates from collisional excitation by free electrons. We find that the derived n _e correlates well with the galaxy’s star formation rate per unit area. From photoionization models or assuming the outflow is in pressure equilibrium with the wind fluid, we get r _n ∼ 1–2 r _* or ∼5 r _* , respectively, where r _* is the starburst radius. Based on comparisons to theoretical models of multiphase outflows, nearly all of the outflows have cloud sizes large enough for the clouds to survive their interaction with the hot wind fluid. Most of these measurements are the first ever for galactic winds detected in absorption lines and, thus, will provide important constraints for future models of galactic winds.

Star-forming, H α -emitting clumps are found embedded in the gaseous tails of galaxies undergoing intense ram pressure stripping in galaxy clusters, so-called jellyfish galaxies. These clumps offer a unique opportunity to study star formation under extreme conditions, in the absence of an underlying disk and embedded within the hot intracluster medium. Yet, a comprehensive, high-spatial-resolution study of these systems is missing. We obtained UVIS/Hubble Space Telescope (HST) data to observe the first statistical sample of clumps in the tails and disks of six jellyfish galaxies from the GASP survey; we used a combination of broadband (UV to I) filters and a narrowband H α filter. HST observations are needed to study the sizes, stellar masses, and ages of the clumps and their clustering hierarchy. These observations will be used to study the clump scaling relations and the universality of the star formation process, and to verify whether a disk is irrelevant, as hinted at by results from jellyfish galaxies. This paper presents the observations, data reduction strategy, and some general results based on the preliminary data analysis. The high spatial resolution of UVIS gives an unprecedentedly sharp view of the complex structure of the inner regions of the galaxies and of the substructures in the galaxy disks. We found clear signatures of stripping in regions very close in projection to the galactic disk. The star-forming regions in the stripped tails are extremely bright and compact and we did not detect a significant number of star-forming clumps in regions where MUSE did not detect any. The paper finally presents the development plan for the project.

Cluster galaxies are subject to the ram pressure exerted by the intracluster medium, which can perturb or even strip away their gas while leaving the stars undisturbed. We model the distribution and kinematics of the stars and the molecular gas in four late-type cluster galaxies (JO201, JO204, JO206, and JW100), which show tails of atomic and ionized gas indicative of ongoing ram pressure stripping. We analyze MUSE@VLT data and CO data from the Atacama Large Millimeter Array searching for signatures of radial gas flows, ram pressure stripping, and other perturbations. We find that all galaxies, with the possible exception of JW100, host stellar bars. Signatures of ram pressure are found in JO201 and JO206, which also shows clear indications of ongoing stripping in the molecular disk outskirts. The stripping affects the whole molecular gas disk of JW100. The molecular gas kinematics in JO204 is instead dominated by rotation rather than ram pressure. We also find indications of enhanced turbulence of the molecular gas compared to field galaxies. Large-scale radial flows of molecular gas are present in JO204 and JW100, but more uncertain in JO201 and JO206. We show that our sample follows the molecular gas mass–size relation, confirming that it is essentially independent of environment even for the most extreme cases of stripping. Our findings are consistent with the molecular gas being affected by the ram pressure on different timescales and less severely than the atomic and ionized gas phases, likely because the molecular gas is denser and more gravitationally bound to the galaxy.

We present a first look at the MRS observations of the nucleus of the nearby galaxy M83, taken with MIRI on board JWST. The observations show a rich set of emission features from the ionized gas, warm molecular gas, and dust. To begin dissecting the complex processes in this part of the galaxy, we divide the observations into four different regions. We find that the strength of the emission features varies strongly from region to region, with the southeast region displaying the weakest features tracing the dust continuum and interstellar medium (ISM) properties. Comparison between the cold molecular gas traced by the ^12 CO (1–0) transition with the Atacama Large Millimeter/submillimeter Array and the H _2 S(1) transition shows a similar spatial distribution. This is in contrast to the distribution of the much warmer H _2 emission from the S(7) transition found to be concentrated around the optical nucleus. We use the rotational emission lines and model the H _2 excitation to estimate a total molecular gas mass accounting for the warm H _2 component of M (>50 K) ${}_{{{\rm{H}}}_{2}}$ = 67.90 (±5.43) × 10 ^6 M _⊙ . We compare this value to the total gas mass inferred by probing the cold H _2 gas through the ^12 CO (1–0) emission, M (CO) ${}_{{{\rm{H}}}_{2}}$ = 17.15 × 10 ^6 M _⊙ . We estimate that ∼75% of the total molecular gas mass is contained in the warm H _2 component. We also identify [O iv ] 25.89 μ m and [Fe ii ] 25.99 μ m emission. We propose that the diffuse [Fe ii ] 25.99 μ m emission might be tracing shocks created during the interactions between the hot wind produced by the starburst and the much cooler ISM above the galactic plane. More detailed studies are needed to confirm such a scenario.

Ly α line profiles are a powerful probe of interstellar medium (ISM) structure, outflow speed, and Lyman-continuum escape fraction. In this paper, we present the Ly α line profiles of the Cosmic Origins Spectrograph (COS) Legacy Archive Spectroscopic SurveY, a sample rich in spectroscopic analogs of reionization-era galaxies. A large fraction of the spectra show a complex profile, consisting of a double-peaked Ly α emission profile in the bottom of a damped, Ly α absorption trough. Such profiles reveal an inhomogeneous ISM. We successfully fit the damped Ly α absorption and the Ly α emission profiles separately, but with complementary covering factors, a surprising result because this approach requires no Ly α exchange between high- N _H _i and low- N _H _i paths. The combined distribution of column densities is qualitatively similar to the bimodal distributions observed in numerical simulations. We find an inverse relation between Ly α peak separation and the [O iii ]/[O ii ] flux ratio, confirming that the covering fraction of Lyman-continuum-thin sightlines increases as the Ly α peak separation decreases. We combine measurements of Ly α peak separation and Ly α red peak asymmetry in a diagnostic diagram, which identifies six Lyman-continuum leakers in the COS Legacy Archive Spectrocopy SurveY (CLASSY) sample. We find a strong correlation between the Ly α trough velocity and the outflow velocity measured from interstellar absorption lines. We argue that greater vignetting of the blueshifted Ly α peak, relative to the redshifted peak, is the source of the well-known discrepancy between shell-model parameters and directly measured outflow properties. The CLASSY sample illustrates how scattering of Ly α photons outside the spectroscopic aperture reshapes Ly α profiles because the distances to these compact starbursts span a large range.

In recent decades, the utility of cognitive tele-assessment has increasingly been highlighted, both in adults and in children. The present study aimed to present TeleFE, a new tool for the tele-assessment of EF in children aged 6–13. TeleFE consists of a web platform including four tasks based on robust neuropsychological paradigms to evaluate inhibition, interference suppression, working memory, cognitive flexibility, and planning. It also includes questionnaires on EF for teachers and parents, to obtain information on the everyday functioning of the children. As TeleFE allows the assessment of EF both remotely and in-person, a comparison of the two modalities was conducted by administering TeleFE to 1288 Italian primary school children. A series of ANOVA was conducted, showing no significant effect of assessment modality (p > 0.05 for all the measures). In addition, significant differences by class emerged for all the measures (p < 0.001 for all the measures except p = 0.008 for planning). Finally, a significant sex effect emerged for inhibition (p < 0.001) and for the reaction times in both interference control (p = 0.013) and cognitive flexibility (p < 0.001), with boys showing a lower inhibition and faster reaction times. The implications of these results along with the indications for the choice of remote assessment are discussed.

Growing evidence in support of a connection between active galactic nuclei (AGN) activity and the ram pressure stripping (RPS) phenomenon has been found both observationally and theoretically in the past decades. In this work, we further explore the impact of RPS on the AGN activity by estimating the gas-phase metallicity of nuclear regions and the mass–metallicity relation of galaxies at z ≤ 0.07 and with stellar masses $\mathrm{log}{M}_{* }/{M}_{\odot }\geqslant 9.0$ , either experiencing RPS or not. To measure oxygen abundances, we exploit Integral Field Spectroscopy data from the GASP and MaNGA surveys, photoionization models generated with the code Cloudy and the code Nebulabayes to compare models and observations. In particular, we build Cloudy models to reproduce line ratios induced by photoionization from stars, AGN, or a contribution of both. We find that the distributions of metallicity and [O iii ] λ 5007 luminosity of galaxies undergoing RPS are similar to the ones of undisturbed galaxies. Independently of the RPS, we do not find a correlation between stellar mass and AGN metallicity in the mass range $\mathrm{log}{M}_{* }/{M}_{\odot }\geqslant 10.4$ , while for the star-forming galaxies we observe the well-known mass–metallicity relation between $9.0\leqslant \mathrm{log}\ {M}_{* }/{M}_{\odot }\leqslant 10.8$ with a scatter mainly driven by the star formation rate and a plateau around $\mathrm{log}{M}_{* }/{M}_{\odot }\sim 10.5$ . The gas-phase metallicity in the nuclei of AGN hosts is enhanced with respect to those of star-forming galaxies by a factor of ∼ 0.05 dex regardless of the RPS.

Thermal characterization of biological tissues can traditionally provide either large fields of view or high resolution. By the development of super-resolution infrared photo-thermal imaging, the authors reconstruct temperature-based maps of absorptive centers in millimeter-sized biological samples.

The main topic of the history didactics project hereby presented was the history of Bologna’s canals, an essential component of its urban and territorial heritage. The objective of this project was to initiate students to a research that would allow them to recognize and explore the legacy of the city’s hydraulic network, in order to make them aware of the value of creations that provided the local community with essential resources for its prosperity. In this way, students gained awareness and responsibility toward this element of the urban heritage, and they then concretely contributed to its protection and valorization. One can say, then, that starting from the knowledge of the heritage, students have reached awareness and responsibility for it, formulating new suggestions for its safeguard, to finding new ways to add value and transmit that same knowledge they gained to the entire community.

The pro-tolerogenic environment of the liver makes this tissue an ideal target for gene replacement strategies. In other peripheral tissues such as the skeletal muscle, anti-transgene immune response can result in partial or complete clearance of the transduced fibers. Here, we characterized liver-induced transgene tolerance after simultaneous transduction of liver and muscle. A clinically relevant transgene, α-sarcoglycan, mutated in limb-girdle muscular dystrophy type 2D, was fused with the SIINFEKL epitope (hSGCA-SIIN) and expressed with adeno-associated virus vectors (AAV-hSGCA-SIIN). Intramuscular delivery of AAV-hSGCA-SIIN resulted in a strong inflammatory response, which could be prevented and reversed by concomitant liver expression of the same antigen. Regulatory T cells and upregulation of checkpoint inhibitor receptors were required to establish and maintain liver-mediated peripheral tolerance. This study identifies the fundamental role of the synergy between Tregs and upregulation of checkpoint inhibitor receptors in the liver-mediated control of anti-transgene immunity triggered by muscle-directed gene transfer. Keywords: AAV, gene transfer, liver, peripheral tolerance, checkpoint inhibitors, Tregs, PD-1, LAG3

Abstract Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.

Adeno-associated viruses (AAVs) are among the most efficient vectors for liver gene therapy. Results obtained in the first hemophilia clinical trials demonstrated the long-term efficacy of this approach in humans, showing efficient targeting of hepatocytes with both self-complementary (sc) and single-stranded (ss) AAV vectors. However, to support clinical development of AAV-based gene therapies, efficient and scalable production processes are needed. In an effort to translate to the clinic an approach of AAV-mediated liver gene transfer to treat Crigler-Najjar (CN) syndrome, we developed an (ss)AAV8 vector carrying the human UDP-glucuronosyltransferase family 1-member A1 (hUGT1A1) transgene under the control of a liver-specific promoter. We compared our construct with similar (sc)AAV8 vectors expressing hUGT1A1, showing comparable potency in vitro and in vivo. Conversely, (ss)AAV8-hUGT1A1 vectors showed superior yields and product homogeneity compared with their (sc) counterpart. We then focused our efforts in the scale-up of a manufacturing process of the clinical product (ss)AAV8-hUGT1A1 based on the triple transfection of HEK293 cells grown in suspension. Large-scale production of this vector had characteristics identical to those of small-scale vectors produced in adherent cells. Preclinical studies in animal models of the disease and a good laboratory practice (GLP) toxicology-biodistribution study were also conducted using large-scale preparations of vectors. These studies demonstrated long-term safety and efficacy of gene transfer with (ss)AAV8-hUGT1A1 in relevant animal models of the disease, thus supporting the clinical translation of this gene therapy approach for the treatment of CN syndrome. Keywords: AAV vector, Crigler-Najjar syndrome, UGT1A1, liver gene transfer, long-term safety

Hepatocyte-restricted, AAV-mediated gene transfer is being used to provide sustained, tolerogenic transgene expression in gene therapy. However, given the episomal status of the AAV genome, this approach cannot be applied to pediatric disorders when hepatocyte proliferation may result in significant loss of therapeutic efficacy over time. In addition, many multi-systemic diseases require widespread expression of the therapeutic transgene that, when provided with ubiquitous or tissue-specific non-hepatic promoters, often results in anti-transgene immunity. Here we have developed tandem promoter monocistronic expression cassettes that, packaged in a single AAV, provide combined hepatic and extra-hepatic tissue-specific transgene expression and prevent anti-transgene immunity. We validated our approach in infantile Pompe disease, a prototype disease caused by lack of the ubiquitous enzyme acid-alpha-glucosidase (GAA), presenting multi-systemic manifestations and detrimental anti-GAA immunity. We showed that the use of efficient tandem promoters prevents immune responses to GAA following systemic AAV gene transfer in immunocompetent Gaa−/− mice. Then we demonstrated that neonatal gene therapy with either AAV8 or AAV9 in Gaa−/− mice resulted in persistent therapeutic efficacy when using a tandem liver-muscle promoter (LiMP) that provided high and persistent transgene expression in non-dividing extra-hepatic tissues. In conclusion, the tandem promoter design overcomes important limitations of AAV-mediated gene transfer and can be beneficial when treating pediatric conditions requiring persistent multi-systemic transgene expression and prevention of anti-transgene immunity. Keywords: tandem promoters, transgene immunity, transgene persistence, AAV, gene therapy