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161Tb is an interesting radionuclide for application in the treatment of neuroendocrine neoplasms' small metastases and single cancer cells because of its conversion and Auger-electron emission. Tb has coordination chemistry similar to that of Lu; therefore, like 177Lu, it can stably radiolabel DOTATOC, one of the leading peptides used for the treatment of neuroendocrine neoplasms. However, 161Tb is a recently developed radionuclide that has not yet been specified for clinical use. Therefore, the aim of the current work was to characterize and specify 161Tb and to develop a protocol for the synthesis and quality control of 161Tb-DOTATOC with a fully automated process conforming to good-manufacturing-practice guidelines, in view of its clinical use. Methods:161Tb, produced by neutron irradiation of 160Gd in high-flux reactors followed by radiochemical separation from its target material, was characterized regarding its radionuclidic purity, chemical purity, endotoxin level, and radiochemical purity (RCP) in analogy to what is described in the European Pharmacopoeia for no-carrier-added 177Lu. In addition, 161Tb was introduced into a fully automated cassette-module synthesis to produce 161Tb-DOTATOC, as used for 177Lu-DOTATOC. The quality and stability of the produced radiopharmaceutical in terms of identity, RCP, and ethanol and endotoxin content were assessed by means of high-performance liquid chromatography, gas chromatography, and an endotoxin test, respectively. Results:161Tb produced under the described conditions showed, as the no-carrier-added 177Lu, a pH of 1-2, radionuclidic purity and RCP of more than 99.9%, and an endotoxin level below the permitted range (175 IU/mL), indicating its appropriate quality for clinical use. In addition, an efficient and robust procedure for the automated production and quality control of 161Tb-DOTATOC with clinically applicable specifications and activity levels, that is, 1.0-7.4 GBq in 20 mL, was developed. The radiopharmaceutical's quality control was also developed using chromatographic methods, which confirmed the product's stability (RCP ≥ 95%) over 24 h. Conclusion: The current study demonstrated that 161Tb has appropriate features for clinical use. The developed synthesis protocol guarantees high yields and safe preparation of injectable 161Tb-DOTATOC. The investigated approach could be translated to other DOTA-derivatized peptides; thus, 161Tb could be successfully applied in clinical practice for radionuclide therapy., The Journal of Nuclear Medicine, 64 (7), ISSN:0097-9058, ISSN:0022-3123, ISSN:0161-5505, ISSN:2159-662X, ISSN:1535-5667

This paper proposes a method to infer the future change in the wind-wave climate using reanalysis wind corrected to statistically match data from a regional climate model (RCM). The method is applied to the sea surface wind speed of the reanalysis ERA5 from the European Centre for Medium-Range Weather Forecasts. The correction is determined from a quantile mapping between ERA5 and the RCM at any given point in the geographical space. The issues that need to be addressed to better understand and apply the method are discussed. Corrected ERA5 wind fields are eventually used to force a spectral wave numerical model to simulate the climate of significant wave height. The correction strategy is implemented over the Adriatic Sea (a semi-enclosed basin of the Mediterranean Sea) and includes the present-day period (1981–2010) and the near-future period (2021–2050) under the two IPCC RCP4.5 and RCP8.5 concentration scenarios. Evaluation against observations of wind and waves gives confidence in the reliability of the proposed approach. Results confirm the evolution toward an overall decrease in storm wave severity in the basin, especially under RCP8.5 and in its northern area. It is expected that the methodology may be applied to other reanalyses, RCMs (including multi-model ensembles), or seas with similar characteristics.

This paper highlights the issue of the model consistency for wave hindcasts in enclosed basins, such as lakes and lagoons. For these applications, the wind input mechanism is essential and the differences in the model approaches and available settings make it critical and difficult for the users to comprehensively understand each of the model’s capabilities and limitations. Therefore, three freely accessible regional scale spectral wave models (SWAN, STWAVE, and CMS-Wave), using the Half and Full plane modes where available, are used for wave hindcast purposes in two locations of the Garda Lake (IT). Results achieved with default settings are compared and discussed. Significant differences are found showing that, unfortunately, specific calibration, which is, however, not possible in many practical cases, is essential for applications in enclosed basins.

This paper investigates the impact of climate change on coastal dynamics along the Adriatic Italian coast, with reference to the period 2021–2050 considering the IPCC RCP 4.5 and 8.5 scenarios. The wave datasets are obtained by forcing a spectral wave model with ERA5 wind fields corrected with a procedure that makes them suitable for the investigated semi-enclosed basin where local meteorological events occur at scales of a few kilometers. The wave climate changes between the historic run (1981–2010) and the future scenarios are studied in terms of mean values, percentile and extreme waves in 120 virtual buoys along the coasts. Moreover, a morphological equivalent wave is computed for all the datasets to highlight the consequences of climate change on coastal sediment transport. Along the Adriatic Italian coast, a small decrease in the significant wave heights is found, both for mean and extreme values, and the sediment transport is reduced. However, significant deviations along the coast are highlighted and the longshore sediment transport even reverses its direction in some locations for the future scenarios.

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BackgroundTerbium-155 [T1/2 = 5.32 d, Eγ = 87 keV (32%) 105 keV (25%)] is an interesting radionuclide suitable for single photon emission computed tomography (SPECT) imaging with potential application in the diagnosis of oncological disease. It shows similar decay characteristics to the clinically established indium-111 and would be a useful substitute for the diagnosis and prospective dosimetry with biomolecules that are afterwards labeled with therapeutic radiolanthanides and pseudo-radiolanthanides, such as lutetium-177 and yttrium-90. Moreover, terbium-155 could form part of the perfect “matched pair” with the therapeutic radionuclide terbium-161, making the concept of true radiotheragnostics a reality. The aim of this study was the investigation of the production of terbium-155 via the155Gd(p,n)155Tb and156Gd(p,2n)155Tb nuclear reactions and its subsequent purification, in order to obtain a final product in quantity and quality sufficient for preclinical application. The156Gd(p,2n)155Tb nuclear reaction was performed with 72 MeV protons (degraded to ~ 23 MeV), while the155Gd(p,n)155Tb reaction was degraded further to ~ 10 MeV, as well as performed at an 18 MeV medical cyclotron, to demonstrate its feasibility of production.ResultThe156Gd(p,2n)155Tb nuclear reaction demonstrated higher production yields of up to 1.7 GBq, however, lower radionuclidic purity when compared to the final product (~ 200 MBq) of the155Gd(p,n)155Tb nuclear reaction. In particular, other radioisotopes of terbium were produced as side products. The radiochemical purification of terbium-155 from the target material was developed to provide up to 1.0 GBq product in a small volume (~ 1 mL 0.05 M HCl), suitable for radiolabeling purposes. The high chemical purity of terbium-155 was proven by radiolabeling experiments at molar activities up to 100 MBq/nmol. SPECT/CT experiments were performed in tumor-bearing mice using [155Tb]Tb-DOTATOC.ConclusionThis study demonstrated two possible production routes for high activities of terbium-155 using a cyclotron, indicating that the radionuclide is more accessible than the exclusive mass-separated method previously demonstrated. The developed radiochemical purification of terbium-155 from the target material yielded [155Tb]TbCl3in high chemical purity. As a result, initial cell uptake investigations, as well as SPECT/CT in vivo studies with [155Tb]Tb-DOTATOC, were successfully performed, indicating that the chemical separation produced a product with suitable quality for preclinical studies.

Executive functions (EF) are a set of higher-order cognitive abilities that enable goal-directed behavior by controlling lower-level operations. In the brain, those functions have been traditionally associated with activity in the Frontoparietal Network, but recent neuroimaging studies have challenged this view in favor of more widespread cortical involvement. In the present study, we aimed to explore whether the network that serves as critical hubs at rest, which we term network reliance, differentiate individuals as a function of their level of EF. Furthermore, we investigated whether such differences are driven by genetic as compared to environmental factors. For this purpose, resting-state functional magnetic resonance imaging data and the behavioral testing of 453 twins from the Colorado Longitudinal Twins Study were analyzed. Separate indices of EF performance were obtained according to a bifactor unity/diversity model, distinguishing between three independent components representing: Common EF, Shifting-specific and Updating-specific abilities. Through an approach of step-wise in silico network lesioning of the individual functional connectome, we show that interindividual differences in EF are associated with different dependencies on neural networks at rest. Furthermore, these patterns show evidence of mild heritability. Such findings add knowledge to the understanding of brain states at rest and their connection with human behavior, and how they might be shaped by genetic influences. Supplementary Information The online version contains supplementary material available at 10.1007/s00429-021-02388-4.

Over the last decades, the evaluation of hazards and risks associated with coastal flooding has become increasingly more important in order to protect population and assets. The general purpose of this research was to assess reliable coastal flooding hazard maps due to overflow and wave overtopping. This paper addresses the problem of defining credible joint statistics of significant wave heights Hs and water levels ζ, focusing on the selection of the sample pair that characterizes each sea storm, to evaluate the occurrence probability of extreme events. The pair is selected maximizing a spatial structure variable, i.e., a linear combination of Hs and Relaix, F., Zammit, P.S. Satellite cells are essential for skeletal muscle, specific to each point of the area at risk. The structure variable is defined by the sensitivity of the flooding process to Hs and ζ, as found by analyzing a set of inundation maps produced through a Simplified Shallow-Water numerical model (SSW). The proposed methodology is applied to a coastal stretch in the Venetian littoral (Italy), by means of a 30 year-long time series recorded at the “Acqua Alta” oceanographic research tower, located in the Northern Adriatic Sea in front of the Venetian lagoon. The critical combination of Hs and ζ forming the structure variable is presented in a map, and it can be related to the topography and the presence of mitigation measures. The return period associated with the two recent large storms that occurred in this area in 2018 and 2019 is also investigated. The proposed procedure gives credible occurrence probabilities for these events, whereas other approaches would consider them extremely unlikely.

Neurological deficits following stroke are traditionally described as syndromes related to damage of a specific area or vascular territory. Recent studies indicate that, at the population level, post-stroke neurological impairments cluster in three sets of correlated deficits across different behavioural domains. To examine the reproducibility and specificity of this structure, we prospectively studied first-time stroke patients (n = 237) using a bedside, clinically applicable, neuropsychological assessment and compared the behavioural and anatomical results with those obtained from a different prospective cohort studied with an extensive neuropsychological battery. The behavioural assessment at 1-week post-stroke included the Oxford Cognitive Screen and the National Institutes of Health Stroke Scale. A principal component analysis was used to reduce variables and describe behavioural variance across patients. Lesions were manually segmented on structural scans. The relationship between anatomy and behaviour was analysed using multivariate regression models. Three principal components explained ≈50% of the behavioural variance across subjects. PC1 loaded on language, calculation, praxis, right side neglect and memory deficits; PC2 loaded on left motor, visual and spatial neglect deficits; PC3 loaded on right motor deficits. These components matched those obtained with a more extensive battery. The underlying lesion anatomy was also similar. Neurological deficits following stroke are correlated in a low-dimensional structure of impairment, related neither to the damage of a specific area or vascular territory. Rather they reflect widespread network impairment caused by focal lesions. These factors showed consistency across different populations, neurobehavioural batteries and, most importantly, can be described using a combination of clinically applicable batteries (National Institutes of Health Stroke Scale and Oxford Cognitive Screen). They represent robust behavioural biomarkers for future stroke population studies., Neurological deficits following stroke are traditionally described as syndromes related to damage of a specific area or vascular territory. Bisogno et al. show that post-stroke neurological impairment can be described by robust, reproducible components of correlated deficits across functional domains with a bedside, clinically suitable, neurobehavioural assessment., Graphical Abstract Graphical Abstract

A family of three picolinate pyclen-based ligands, previously investigated for the complexation of Y3+ and some lanthanide ions (Gd3+, Eu3+), was studied with 161Tb and 177Lu in view of potential radiotherapeutic applications. The set of six Tb3+ and Lu3+ complexes was synthesized and fully characterized. The coordination properties in the solid state and in solution were thoroughly studied. Potentiometric titrations, supported by density functional theory (DFT) calculations, showed the very high stability constants of the Tb3+ and Lu3+ complexes, associated with remarkable kinetic inertness for up to 30 days in 1 M HCl. A complete radiolabeling study performed with both 161Tb and 177Lu radionuclides, including experiments with regard to the stability with and without scavengers and kinetic inertness using challenging agents, proved that the ligands could reasonably compete with the DOTA analogue. To conclude, the potential of using the same ligand for both radiotherapy and optical imaging was highlighted for the first time.

A family of three picolinate pyclen based ligands, previously investigated for the complexation of Y3+ and some lanthanide ions (Gd3+, Eu3+), was studied with 161Tb and 177Lu in view of potential radiotherapeutic applications. The set of six Tb3+ and Lu3+ complexes was synthesized and fully characterized. The coordination properties in the solid state and in solution were thoroughly studied. Potentiometric titrations, corroborated by DFT calculations, showed the very high stability constants of the Tb3+ and Lu3+ complexes, which are associated to remarkable kinetic inertness. A complete radiolabeling study performed with both 161Tb and 177Lu radionuclides, including experiments with regard to the stability with and without scavengers and kinetic inertness using challenging agents, proved that the ligands could reasonably compete with the DOTA analogue. To conclude, the potential of using the same ligand for both radiotherapy and optical imaging was highlighted for the first time.

A broad class of natural and man-made systems exhibits rich patterns of cluster synchronization in healthy and diseased states, where different groups of interconnected oscillators converge to cohesive yet distinct behaviors. To provide a rigorous characterization of cluster synchronization, we study networks of heterogeneous Kuramoto oscillators and we quantify how the intrinsic features of the oscillators and their interconnection parameters affect the formation and the stability of clustered configurations. Our analysis shows that cluster synchronization depends on a graded combination of strong intra-cluster and weak inter-cluster connections, similarity of the natural frequencies of the oscillators within each cluster, and heterogeneity of the natural frequencies of coupled oscillators belonging to different groups. The analysis leverages linear and nonlinear control theoretic tools, and it is numerically validated.

This paper aims at evaluating the wave overtopping discharge over the pavement of &ldquo, Piazza S. Marco&rdquo, (Venice) in order to select the best option to mitigate the risk of flooding of the Piazza and to protect the monuments and historic buildings, e.g., the &ldquo, Basilica S. Marco&rdquo, In fact, the MO.S.E. (MOdulo Sperimentale Elettromeccanico) system is designed to keep the water level below a certain value, for the safety of the lagoon, but it does not guarantee the defence of the Piazza, where flooding is still possible, being its pavement locally much lower than the maximum expected water level. To completely defend the Piazza, specific additional works are planned to prevent the back-flow through the natural drainage system (now the primary pathway) or by filtration or by overtopping. This paper investigates on the overtopping mechanism, under conditions compatible with a fully operational MO.S.E. system, through 2-D experiments. The pavement of the Piazza is gently sloping towards the masonry quay which, in some parts is formed by 5 descending steps, and in some other parts, is just a vertical wall. Close to the &ldquo, Marciana&rdquo, Library, a critical part is present, with a slightly lower crest freeboard. In total, three cross-sections were examined in the 36 m long wave flume of the Padova University. The test programme includes 10 irregular wave attacks and three different water levels. The test results differ considerably from the results of the available formulas, since the investigated cross-sections by far exceed their range of applicability. The presence of the steps affects only the reflection coefficient rather than the overtopping discharges. In general, if the waves incident to the Piazza are higher than 40 cm, which is a possible scenario, some other adaptation works must be considered, such as the pavement rise, temporary barriers or the reduction of the waves impacting the quay through, for instance, floating breakwaters.

While numerous studies have suggested that large natural, biological, social, and technological networks are fragile, convincing theories are still lacking to explain why natural evolution and human design have failed to optimize networks and avoid fragility. In this paper we provide analytical and numerical evidence that a tradeoff exists in networks with linear dynamics, according to which general measures of robustness and performance are in fact competitive features that cannot be simultaneously optimized. Our findings show that large networks can either be robust to variations of their weights and parameters, or efficient in responding to external stimuli, processing noise, or transmitting information across long distances. As illustrated in our numerical studies, this performance tradeoff seems agnostic to the specific application domain, and in fact it applies to simplified models of ecological, neuronal, and traffic networks.

In recent years, marine flooding and its impacts have become a question of growing interest, since coastal areas are the most heavily populated and developed land zones in the world. This paper presents a rapid tool for mapping at regional scale the hazard associated with coastal flooding due to overflow. The tool merges a recently developed numerical model that solves a simplified form of the Shallow-Water Equations and is suited for Graphic Processing Unit (GPU) acceleration, with a Level II reliability method that allows producing hazard maps of inland flooding propagation. The procedure was applied to two stretches of the Venetian littoral, i.e., Valle Vecchia and Caorle, located in the northern Adriatic Sea. The application includes the site descriptions and the resulting hazard maps that show the probability of failure in each point of the coast for a given inland inundation level.

Mathematical theories and empirical evidence suggest that several complex natural and man-made systems are fragile: as their size increases, arbitrarily small and localized alterations of the system parameters may trigger system-wide failures. Examples are abundant, from perturbation of the population densities leading to extinction of species in ecological networks [1], to structural changes in metabolic networks preventing reactions [2], cascading failures in power networks [3], and the onset of epileptic seizures following alterations of structural connectivity among populations of neurons [4]. While fragility of these systems has long been recognized [5], convincing theories of why natural evolution or technological advance has failed, or avoided, to enhance robustness in complex systems are still lacking. In this paper we propose a mechanistic explanation of this phenomenon. We show that a fundamental tradeoff exists between fragility of a complex network and its controllability degree, that is, the control energy needed to drive the network state to a desirable state. We provide analytical and numerical evidence that easily controllable networks are fragile, suggesting that natural and man-made systems can either be resilient to parameters perturbation or efficient to adapt their state in response to external excitations and controls.

Synchronization is crucial for the correct functionality of many natural and man-made complex systems. In this work we characterize the formation of synchronization patterns in networks of Kuramoto oscillators. Specifically, we reveal conditions on the network weights and structure and on the oscillators' natural frequencies that allow the phases of a group of oscillators to evolve cohesively, yet independently from the phases of oscillators in different clusters. Our conditions are applicable to general directed and weighted networks of heterogeneous oscillators. Surprisingly, although the oscillators exhibit nonlinear dynamics, our approach relies entirely on tools from linear algebra and graph theory. Further, we develop a control mechanism to determine the smallest (as measured by the Frobenius norm) network perturbation to ensure the formation of a desired synchronization pattern. Our procedure allows us to constrain the set of edges that can be modified, thus enforcing the sparsity structure of the network perturbation. The results are validated through a set of numerical examples.

This paper discusses the key aspects of the recent Coastal Plan of the Veneto Region (IT). Its aim is to propose a single mitigation strategy for coastal erosion that is valid for the whole Veneto Region, and possibly elsewhere, as well as a method to assign a priority level to any action. The suggested mitigation action against erosion depends on urbanization level, beach width, as well as cross-shore and long-shore sediment transport. The criterion used to give a priority level to mitigation actions is based on a vulnerability index that takes into account erosive tendency, existing coastal flooding hazards, coast value, environmental relevance, tourist pressure, urbanization level, the presence of production activities, and cultural heritage. A sample case featuring the littoral of Rosolina is also provided and includes a site description, the sediment budget, critical issues and possible mitigation measures.

The problem of emergent synchronization patterns in a complex network of coupled oscillators has caught scientists' interest in a lot of different disciplines. In particular, from a biological point of view, considerable attention has been recently devoted to the study of the human brain as a network of different cortical regions that show coherent activity during resting-state. In literature, there can be found different large-scale models of resting-state dynamics in health and disease. In this context, the Kuramoto model, a classical model apt to describe oscillators' dynamics, has been extended to capture the spatial displacement and the communication conditions in such brain network. Starting from a previous work in this field [1], we analyze this modified model and compare it with other existing large-scale models. In doing so, our aim is to promote a set of mathematical tools useful to better understand real experimental data in neuroscience and estimate brain dynamics.

Over the past decade, considerable attention has been devoted to the problem of emergence of synchronization patterns in a network of coupled oscillators, which can be observed in a variety of disciplines, from the biological to the engineering fields. In this context, the Kuramoto model is a classical model for describing synchronization phenomena that arise in large-scale systems that exploit local information and interactions. In this work, an extension of such a model is presented, that considers the spatial distances among the oscillator nodes. In detail, coupling strength and spatial conditions are derived, needed to reach phase cohesiveness and frequency synchronization, both in the scenario when a single population of agents is present and when two different populations interact. These theoretical findings are confirmed by extensive numerical Monte Carlo simulations and statistical analysis.