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E-grocery is a growing phenomenon that has the potential to rapidly change the way shopping is performed and goods distributed in cities. The impacts of this innovation can vary according to the delivery service performed, thus affecting positively or negatively the overall sustainability of urban freight transport. Understanding the dynamics of demand (i.e. consumers) will be useful to know how supply (i.e. supermarkets) should adapt, and how policy-makers should deal with this phenomenon. This paper presents an agent-based model to simulate different e-grocery scenarios at a neighbourhood scale. Agents are characterized with individual utility functions from a latent class model based on a stated preference survey performed in Rome (Italy). First results of a one-month simulation allow deriving some useful conclusion on the impact different grocery channels can have on travelled distance and consumer shopping time and formulating some policy implications.

In recent years, we have witnessed an ever wider spread of multimedia streaming platforms (e.g., Netflix, Spotify, and Amazon). Hence, it has become more and more essential to provide such systems with advanced recommendation facilities, in order to support users in browsing these massive collections of multimedia data according to their preferences and needs. In this context, the modeling of entities and their complex relationships (e.g., users listening to topic-based songs or authors creating different releases of their lyrics) represents the key challenge to improve the recommendation and maximize the users' satisfaction. To this end, this is the first study to leverage the high representative power of hypergraph data structures in combination with modern graph machine learning techniques in the context of music recommendation. Specifically, we propose hypergraph embeddings for music recommendation (HEMR), a novel framework for song recommendation based on hypergraph embedding. The hypergraph data model allows us to represent seamlessly all the possible and complex interactions between users and songs with the related characteristics; meanwhile, embedding techniques provide a powerful way to infer the user-song similarities by vector mapping. We have experimented the effectiveness and efficiency of our approach with respect to the state-of-the-art most recent music recommender systems, exploiting the Million Song dataset. The results show that HEMR significantly outperforms other state-of-the-art techniques, especially in scenarios where the cold-start problem arises, thus making our system a suitable solution to embed within a music streaming platform.

Nowadays, recruitment processes are increasingly being automated by intelligent systems which provide best candidates for companies’ open positions, and vice versa. However, extracting information from the unstructured documents involved in these processes (e.g. resumes, jobs’ descriptions) still represents an open challenge because of their high heterogeneity (in the form and style) and the lack of pre-defined standards between different companies and/or countries. In this paper, we address the resume information extraction problem, focusing on documents within the Italian Labor Market. Specifically, we propose an effective and efficient end-to-end framework capable of providing a complete candidate overview including his personal information, skills and work experiences. Specifically, after having extracted the raw data from the resume documents, the system segments them into semantically consistent parts using linguistics patterns. Each segment is further processed with a NER algorithm, based on pre-trained language models, to extract relevant information which an HR specialist could consult in order to assess the suitability of a candidate for a job offer. We collected (and labeled) a new Italian resume dataset and our results prove the effectiveness of the proposed method, especially considering the great advantages our segmentation strategy brings to the NER performance with respect to standard line-based segmentation approaches. In addition, our system achieves promising performance when combined with modern NLP models.

Hydroxytyrosol (HT), a peculiar olive and olive oil phenolic antioxidant, plays a significant role in the endothelial and cardiovascular protection associated with olive oil consumption. However, studies examining the effects of HT on the whole-genome expression of endothelial cells, which are prominent targets for vasculo-protective effects of olive oil polyphenols, have been lacking. This study aims to comprehensively evaluate the genomic effects exerted by HT, at the transcriptional level, in endothelial cells under resting or proinflammatory conditions. Human umbilical vein endothelial cells (HUVECs) were treated with 10 µmol/L HT for 1 h and then stimulated with 5 ng/mL interleukin (IL)-1β for 3 h. Total RNA was extracted, and gene expression profile assessed with microarray analysis. Functional enrichment analysis and pathway analysis were performed by Ingenuity Pathways Analysis. Microarray data were validated by qRT-PCR. Fixing a significance threshold at 1.5-fold change, HT affected the expression of 708 and 599 genes, respectively, in HUVECs under resting and IL-1β-stimulated conditions, among these, 190 were common to both conditions. Unfolded protein response (UPR) and endoplasmic reticulum stress resulted from the two top canonical pathways common between HT and HT-IL-1β affected genes. IL-17F/A signaling was found in the top canonical pathways of HT modified genes under resting unstimulated conditions, whereas cardiac hypertrophy signaling was identified among the pathways affected by HT-IL-1β. The transcriptomic analysis allowed pinpointing immunological, inflammatory, proliferative, and metabolic-related pathways as the most affected by HT in endothelial cells. It also revealed previously unsuspected genes and related gene pathways affected by HT, thus broadening our knowledge of its biological properties. The unbiased identification of novel genes regulated by HT improves our understanding of mechanisms by which olive oil prevents or attenuates inflammatory diseases and identifies new genes to be enquired as potential contributors to the inter-individual variation in response to functional food consumption.

Most medical and health science schools adopt innovative tools to implement the teaching of anatomy to their undergraduate students. The increase in technological resources for educational purposes allows the use of virtual systems in the field of medicine, which can be considered decisive for improving anatomical knowledge, a requisite for safe and competent medical practice. Among these virtual tools, the Anatomage Table 7.0 represents, to date, a pivotal anatomical device for student education and training medical professionals. This review focuses attention on the potential of the Anatomage Table in the anatomical learning process and clinical practice by discussing these topics based on recent publication findings and describing their trends during the COVID-19 pandemic period. The reports documented a great interest in and a positive impact of the use of this technological table by medical students for teaching gross anatomy. Anatomage allows to describe, with accuracy and at high resolution, organ structure, vascularization, and innervation, as well as enables to familiarize with radiological images of real patients by improving knowledge in the radiological and surgical fields. Furthermore, its use can be considered strategic in a pandemic period, since it ensures, through an online platform, the continuation of anatomical and surgical training on dissecting cadavers.

Crowdsourced delivery services (crowdshipping) represent a shipping alternative to traditional delivery systems, particularly suitable for e-commerce. Although some benefits in terms of reduced pollution and congestion could be obtained by replacing dedicated freight trips, the impacts of crowdshipping are unclear and depend on several factors such as the transport mode used, the match between supply and demand, length of detours, and possible induced demand. For example, private drivers could modify their existing routes or engage in new trips to pick up and drop off packages; similarly, public transport users could carry along packages on their trips and drop them off at lockers installed around the stations. In this paper, we analyze by means of a simulation-based approach the potential impacts of alternative implementation frameworks. In order to account more realistically for last-mile delivery operations, a hybrid dynamic traffic simulation is adopted such that the macroscopic features of traffic (triggering of congestion, queue spillbacks and interactions with traffic signals) are reproduced in combination with the microscopic features of delivery operations (delivery vehicles are tracked along their routes). The effects on traffic and emissions are investigated for the adoption of crowdshipping by carriers delivering parcels in the city center of Rome, Italy. Results show that not only is the mode employed by crowdshippers crucial for the sustainability of such a measure, but also operational aspects involving the length of detour, parking behavior, and daily traffic variations. Crowdsourced deliveries by car have generally higher negative impacts than corresponding deliveries by public transit. However, limiting the deviations of crowdshippers from the original trips, providing adequate parking options, and incentivizing off-peak deliveries, could significantly reduce crowdshipping externalities.

Simple Summary The onco-immunotherapeutic viruses, among which stand the onco-immunotherapeutic herpes simplex viruses, have gained renewed interest due to their ability to unlock the potential of checkpoint inhibitors in preclinical and clinical settings. In prior decades, safety concerns led to the generation of overall safe, partially or highly attenuated oncolytic viruses. Current focus is on more efficacious onco-immunotherapeutic viruses with limited ability to cause off-tumor and off-target infections and the capability to subvert the tumor microenvironment immunosuppression—hence to potentiate checkpoint inhibitors. These viruses might serve as potential partners of T-cell therapies. Abstract Our laboratory has pursued the generation of cancer-specific oncolytic herpes simplex viruses (oHSVs) which ensure high efficacy while maintaining a high safety profile. Their blueprint included retargeting to a Tumor-Associated Antigen, e.g., HER2, coupled to detargeting from natural receptors to avoid off-target and off-tumor infections and preservation of the full complement of unmodified viral genes. These oHSVs are “fully virulent in their target cancer cells”. The 3rd generation retargeted oHSVs carry two distinct retargeting moieties, which enable infection of a producer cell line and of the target cancer cells, respectively. They can be propagated in an ad hoc Vero cell derivative at about tenfold higher yields than 1st generation recombinants, and more effectively replicate in human cancer cell lines. The R-335 and R-337 prototypes were armed with murine IL-12. Intratumorally-administered R-337 conferred almost complete protection from LLC-1-HER2 primary tumors, unleashed the tumor microenvironment immunosuppression, synergized with the checkpoint blockade and conferred long-term vaccination against distant challenge tumors. In summary, the problem intrinsic to the propagation of retargeted oHSVs—which strictly require cells positive for targeted receptors—was solved in 3rd generation viruses. They are effective as immunotherapeutic agents against primary tumors and as antigen-agnostic vaccines.

With the recent COVID-19 outbreak, we have assisted to the development of new epidemic models or the application of existing methodologies to predict the virus spread and to analyze how the different lock-down strategies can effectively influence the epidemic diffusion. In this paper, we propose a novel machine learning based framework able to estimate the parameters of any epidemiological model, such as contact rates and recovery rates, based on static and dynamic features of places. In particular, we model mobility data through a graph series whose spatial and temporal features are investigated by combining Graph Convolutional Neural Networks (GCNs) and Long short-term memories (LSTMs) in order to infer the parameters of SIR and SIRD models. We evaluate the proposed approach using data related to the COVID-19 dynamics in Italy and we compare the forecasts of the trained model with available data about the epidemic spread.

This paper investigates tourists' preferences in Rome (Italy) with respect to their “last mile” transport walking experience. Stated preference experiments and discrete choice models are used to estimate tourists' preferences for alternative walking paths configurations, taking into account path characteristics and conditions (e.g. public services presence, interference with other modes of transport and thermal comfort). We estimate Multinomial logit (MNL) models on the base of 365 choice experiments. The most important attribute is cleanliness, followed by green spaces. The paper estimates both time elasticity and the “willingness to walk” with respect to different path attributes. Segmenting the sample and estimating different MNL models allows considering preference heterogeneity. Results show there are some differences within the sample. In fact, those who usually walk are willing to walk more than others given some improvements in the path. Besides, we also propose, on the base of the last walking path followed, a “tourist walking satisfaction index” linked to utility. This sheds light on tourists' walking experience in different zones of the study area. In particular, adding restrooms along the paths increases tourist walking satisfaction the most. The paper provides useful information for policy-makers on how to plan, design and manage walking networks.

E-grocery is the fastest growing e-commerce segment, while still a niche market. Notwithstanding the channel choice when buying groceries might have relevant transport and environmental implications, little attention is paid to demand analysis. The paper fills this research gap, by using stated preferences to estimate market shares for e-grocery, distinguishing between home deliveries and click&pick, using the in-store option as a reference, and by considering a case study in Norway. It investigates the role of various purchase characteristics (i.e. product price, service cost, lead-time, time window, travel time and product range) when choosing which purchase channel to use. Results suggest that the most important characteristics for consumers are related to price, in particular product price, but there is also significant heterogeneity in preferences within the sample. Scenario simulations allow estimating transport and environmental impacts deriving from channel market share changes. This information can be useful for developing both managerial strategies to increase e-grocery market share and public policy interventions to minimize negative externalities.

The Sustainable Urban Mobility Plan (SUMP) has been identified as the privileged tool for addressing economic, social, and environmental issues in transport policy at the urban scale from a long-term strategic perspective. Indeed, urban policymakers intend adopting measures to cope with the negative externalities generated by transport. The focus is on reducing traffic flows (number and length) of motorized-trips and minimize their related impact. Among these measures, together with electric vehicles promotion, active travel (AT) – including walking and cycling – represents an interesting strategy. This is especially true as local public transport (LPT) is progressively less attractive, also due to overcrowding and lower service quality, since the outbreak of Covid-19 pandemic. AT, moreover, creates the preconditions for a healthier life. Within this context, it is interesting to investigate to what extent SUMPs promote AT as a solution for achieving sustainable mobility (SM) at the urban scale. The paper analyses, by looking at SUMPs adopted in major Italian cities, the AT measures undertaken. The Italian case is of particular interest since its motorization rate is second only to Luxembourg in the whole European Union. Specifically, the paper exploits a multiple case-study comparative approach allowing to identify the correlation between main SUMP characteristics and AT-related initiatives. The main findings of the paper show that infrastructural AT projects play the lion role thus casting a shadow on the likely effectiveness of AT promotion. In fact, a comprehensive package approach (e.g. citizens engagement, land-use planning, gamification, data collection, etc.) for AT promotion is still lacking.

Several commentaries have suggested that the overconsumption of animal foods exerts several detrimental effects on human and environmental health. However, no studies have accurately estimated the impact of a reduction in animal food consumption on mortality due to the direct effects on metabolic health (i.e. animal protein and saturated fat intake as modulators of pathways leading to cardiovascular disease, cancer and accelerated ageing), and indirect effects on health due to excessive exposure to pollutants (i.e. PM10 concentrations originated by livestock ammonia emissions). The proposed modelling approach is innovative since it integrates social acceptability, environmental and health impacts. It is adopted to investigate different scenarios at a regional scale presenting the Lombardy region case study. The work focuses on the impact on the human and environmental health of diets characterized by three different animal protein intake levels. Our integrated assessment modelling approach faces the issue from two points of view. On one side, it estimates the mortality due to the population exposure to PM10 concentrations including the inorganic fraction originated by livestock ammonia emissions, on the other, it evaluates the mortality (i.e. total, cardiovascular and cancer) due to high dietary animal protein and/or saturated fat intake. The impacts of the mentioned animal protein intake levels of diets are also estimated through the people willingness to change their eating behaviour. The importance of putting in place end-of-pipe and energy measures in order to reduce ammonia and methane emissions from the breeding activities, going further the current EU legislation on air quality and climate, is emphasized.

Poor logistics efficiency, due to low load factors caused by high demand fragmentation, will have relevant negative consequences for cities in terms of pollution, congestion and overall city liveability. Policy-makers should equip themselves with appropriate tools to perform reliable, comprehensive and timely analyses of urban logistics scenarios, also considering upcoming (i) technological changes, (ii) business model evolutions and (iii) spatial-temporal changes these innovations will produce. This paper discusses the Digital Twin (DT) concept, illustrating the role it might play and clarifying how to properly conceive it with respect to urban freight transport policy-making and planning. The main message is that without a sound theory and knowledge with respect to the relationships linking contextual reality and choice/behaviour, it is not possible to make sense of what happens in the real world. Therefore, the joint use of behavioural and simulation models should characterise a DT within a Living Lab approach so to stimulate effective, well-informed and participated planning processes, but also to forecast both behaviour and reactions to structural changes and policy measures implementations.

This paper presents a modelling framework to investigate the potential acceptability of digitalized services connected to groceries, i.e. e-grocery, via a discrete choice agent-based approach. A preliminary investigation of consumers’ preferences for buying groceries on-line has been performed via a stated preference survey. Besides, a new agent-based model is presented with the aim to test different e-grocery scenarios and the potential spreading of this solution, characterizing agents with the results of the survey. This will allow evaluating stakeholders’ acceptability and making a first assessment of the potential of e-grocery to improve the efficiency of urban freight transport.

Despite the huge growth in online purchases, e-grocery (i.e. ordering grocery online) was still limited in scope in Italy so far. More recently, its growth has been substantial and 2020 witnessed a huge increase due to COVID-19-related mobility restrictions. In principle, e-grocery could reduce the number of shopping trips, yet an exponential increase in shipping and deliveries could have a negative impact on the environment. In order to explore the willingness to e-grocery, and delivery preferences (self-delivery, home delivered grocery or collected in a specific place) - and estimate their market shares - a stated preference survey was carried in Rome and Milan. Respondents were asked about their grocery shopping habits and to choose among different shopping and delivery options. Discrete choice modelling allows investigating preference heterogeneity and estimating willingness to pay measures. Main results indicate that respondents, characterised by distinct socio-economic, attitudinal, and geographical elements, react differently to attribute variations for alternative grocery shopping channels. Scenario simulations can help in defining successful business-strategies and possible solutions to external costs. Under this respect, results suggest that the best strategy to increase e-grocery shares in the two cities should be non-monetary, but rather aimed at expanding the product range available online.

The paper considers random utility models that use a single common vector of random utilities for the computation of best, worst and best–worst choice probabilities, i.e. consistent models. Choice probabilities are derived for two distributions of the random terms: i.i.d. extreme value, i.e. Logit, and multivariate normal, i.e. Probit. We prove strict log-concavity of the likelihood, with respect to the coefficients of the systematic utilities, for best, worst and best–worst choice probabilities in Logit, and for best and worst choice probabilities in Probit, under a mild necessary and sufficient condition of absence of perfect multicollinearity in the matrix of alternative and individual characteristics. This condition parallels that in ordinary least squares linear regression models. The hypothesis of equality of the utility coefficients of best choice models and of worst choice models is tested with data on mode choice, collected for the assessment of user responses to urban congestion charging policies. The numerical results show, in both Logit and Probit, statistically significant differences between utility coefficients of best and worst models. The estimations based on worst choice data exhibit coefficient attenuation and higher mean values of travel time savings with larger standard errors.

Many cities of different size and in different areas of the world have successfully tested the introduction of off-hour deliveries (OHD) on a voluntary basis, reporting positive effects, both on freight distribution efficiency and sustainability. However, those initiatives have not been implemented so far at a large scale. This paper investigates OHD potential in Rome, focusing on one of the most important barriers to its adoption, i.e. stakeholder acceptability. The study investigates stakeholders' preferences for different OHD configurations using both a qualitative approach, based on in-depth interviews, and a quantitative analysis, based on an interactive multi-actor multi-criteria analysis. Results show that stakeholders prefer a solution where OHD are jointly implemented together with one or more urban consolidation centres. This preliminary analysis paves the way for further technical/economic evaluations needed for OHD implementation in Rome. Stakeholders’ involvement is of outmost importance to understand their heterogeneous preferences and increase their awareness of urban freight transport problems, with the overall aim to foster behaviour change.

The European Commission has recently developed a growing awareness with respect to the challenges urban freight transport (UFT) poses to cities and, consequently, has started defining specific policies and promoting dedicated tools to address them. Transport is a shared responsibility between the European Union and the Member States, where the subsidiarity principle applies. Accordingly, the former provides European local authorities with support in different areas, including research and innovation funding. This paper aims to assess the linkage and consistency between European policy priorities for UFT and the corresponding calls of the Horizon 2020 (H2020) Research Programme, created to foster research and innovation. The paper identifies and extrapolates in a comparable format ten UFT priority solutions and estimates their degree of correspondence with the H2020 Work Programmes using the amount of research funds allocated to each of them as a proxy. Findings show that, generally, the European Commission addresses UFT through a systematic and coherent approach. Moreover, all the identified solutions are covered by at least one H2020 call, although the extent of the coverage is heterogeneous. Four of the UFT solutions present an overall consistency when it comes to comparing the extent of the scope of the solution and the number of policy documents addressing it, on the one hand, and the number of calls considering it and the budget (potentially) available, on the other.

The oncolytic herpes simplex virus (HSV) that has been approved for clinical practice and those HSVs in clinical trials are attenuated viruses, often with the neurovirulence gene γ 1 34.5 and additional genes deleted. One strategy to engineer nonattenuated oncolytic HSVs consists of retargeting the viral tropism to a cancer-specific receptor of choice, exemplified by HER2 (human epidermal growth factor receptor 2), which is present in breast, ovary, and other cancers, and in detargeting from the natural receptors. Because the HER2-retargeted HSVs strictly depend on this receptor for infection, the viruses employed in preclinical studies were cultivated in HER2-positive cancer cells. The production of clinical-grade viruses destined for humans should avoid the use of cancer cells. Here, we engineered the R-213 recombinant, by insertion of a 20-amino-acid (aa) short peptide (named GCN4) in the gH of R-LM113; this recombinant was retargeted to HER2 through insertion in gD of a single-chain antibody (scFv) to HER2. Next, we generated a Vero cell line expressing an artificial receptor (GCN4R) whose N terminus consists of an scFv to GCN4 and therefore is capable of interacting with GCN4 present in gH of R-213. R-213 replicated as well as R-LM113 in SK-OV-3 cells, implying that addition of the GCN4 peptide was not detrimental to gH. R-213 grew to relatively high titers in Vero-GCN4R cells, efficiently spread from cell to cell, and killed both Vero-GCN4R and SK-OV-3 cells, as expected for an oncolytic virus. Altogether, Vero-GCN4R cells represent an efficient system for cultivation of retargeted oncolytic HSVs in non-cancer cells. IMPORTANCE There is growing interest in viruses as oncolytic agents, which can be administered in combination with immunotherapeutic compounds, including immune checkpoint inhibitors. The oncolytic HSV approved for clinical practice and those in clinical trials are attenuated viruses. An alternative to attenuation is a cancer specificity achieved by tropism retargeting to selected cancer receptors. However, the retargeted oncolytic HSVs strictly depend on cancer receptors for infection. Here, we devised a strategy for in vitro cultivation of retargeted HSVs in non-cancer cells. The strategy envisions a double-retargeting approach: one retargeting is via gD to the cancer receptor, and the second retargeting is via gH to an artificial receptor expressed in Vero cells. The double-retargeted HSV uses alternatively the two receptors to infect cancer cells or producer cells. A universal non-cancer cell line for growth of clinical-grade retargeted HSVs represents a step forward in the translational phase.

Replication-competent oncolytic herpes simplex viruses (HSVs) are considered a promising therapeutic approach for treatment of high-grade gliomas (HGGs), which are usually resistant to all the available treatments. We previously demonstrated that R-LM113, a recombinant HSV-1 fully retargeted to the human epidermal growth factor receptor 2 (HER2), is safe and prolongs survival of immunodeficient NOD/SCID mice in an intracranial model of HGG. However, because the treatment is designed to be employed on immunocompetent patients, it is necessary to test whether the host immune system impairs the viral efficacy or triggers a potentially fatal reaction. Here we confirmed the safety of R-LM113 in the immunocompetent mouse strain BALB/c, where it does not trigger encephalitis when intracranially inoculated. Then, we set up a syngeneic HGG model expressing HER2 in adult BALB/c mice and evaluated R-LM113 therapeutic efficacy. We found that R-LM113 leads to a significant improvement in animal survival when administered at the time of tumor inoculation, as well as when injected into an already established tumor. This study suggests that the host immune defenses do not curtail the oncolytic antitumor activity of replication-competent HSV R-LM113, which results effective in counteracting tumor growth.

Noble metal nanoparticles (MNPs) with controlled diameters in the range 5-15 nm, have been prepared by chemical wet reduction reactions starting from Au precursor in the presence of bifunctional thiolate, i.e. biphenyl-4,4′-dithiol. MNPs have been deposited on electrospinned titania nanofibers by dipping. The composite has been investigated at room temperature in resistive type device under UV irradiation. IV curves show properties of photoconduction and upon exposure towards sulphur dioxide (SO 2 ) a sensing behaviour has been observed. The devices shoved an exponential decay for increasing values of SO 2 concentration.

Naturally occurring antioxidants are extensively studied for their capacity to protect organisms and cells from damage induced by oxygen reactive species. In fact, oxidative stress is considered a cause of aging, degenerative disease and cancer. We have focused our attention on two agents, ascorbic acid and β-carotene, commonly considered to be antioxidants, but whose protective activity against cancer is insufficiently known. This paper reports on the ability of these agents to act against damage induced by H 2 O 2 and bleomycin, in Chinese hamster ovary cells cultivated in vitro. Cytogenetic and cytofluorimetric analyses were performed. Both vitamins proved effective in reducing H 2 O 2 .induced sister chromatid exchanges, but increased H 2 O 2 . and bleomycin-induced chromosomal aberrations. Cytofluorimetric data, in contrast, showed that ascorbic acid and β-carotene act as scavengers of endogeneous and H 2 O 2 -induced oxygen species.

Oncolytic herpes simplex viruses (HSVs) represent a novel frontier against tumors resistant to standard therapies, like glioblastoma (GBM). The oncolytic HSVs that entered clinical trials so far showed encouraging results; however, they are marred by the fact that they are highly attenuated. We engineered HSVs that maintain unimpaired lytic efficacy and specifically target cells that express tumor-specific receptors, thus limiting the cytotoxicity only to cancer cells, and leaving unharmed the neighboring tissues. We report on the safety and efficacy in a high-grade glioma (HGG) model of R-LM113, an HSV recombinant retargeted to human epidermal growth factor receptor 2 (HER2), frequently expressed in GBMs. We demonstrated that R-LM113 is safe in vivo as it does not cause encephalitis when intracranially injected in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, extremely sensitive to wild-type HSV. The efficacy of R-LM113 was assessed in a platelet-derived growth factor (PDGF)-induced infiltrative glioma model engineered to express HER2 and transplanted intracranially in adult NOD/SCID mice. Mice injected with HER2-engineered glioma cells infected with R-LM113 showed a doubled survival time compared with mice injected with uninfected cells. A doubling in survival time from the beginning of treatment was obtained also when R-LM113 was administered into already established tumors. These data demonstrate the efficacy of R-LM113 in thwarting tumor growth.

Genetic aspects may influence the effect of early adverse events on psychological well being in adulthood. In particular, a common polymorphism within the serotonin transporter gene (5-HTTLPR short/long) has been associated to the risk for stress-induced psychopathology. In the present study we investigated the role of childhood traumas and 5-HTTLPR on measures of psychological resilience and depression in a sample of individuals at a high risk for psychological distress (763 male prisoners). The 5-HTTLPR genotype did not influence resilience and depressive severity. However, a significant interaction was observed between 5-HTTLPR and childhood traumas on both resilience and depressive severity. In particular, among subjects exposed to severe childhood trauma only, the long-allele was associated to lower resilience scores and increased current depressive severity as compared to short/short homozygous. Sex specific effects, difference in type and duration of stressors and the specific composition of the sample may explain discrepancy with many studies reporting the short-allele as a vulnerability factor for reactivity to stress. We here speculated that in males the long-allele may confer lower resilience and therefore higher vulnerability for depressive symptoms in subjects exposed to early stress and currently living in stressful environments.

HSVs enter cells in a receptor-dependent [nectin1 or herpesviruses entry mediator (HVEM)] fashion by fusion of the viral envelope with plasma membrane (neutral pH compartment), by endocytosis into neutral or acidic compartments, or by macropinocytosis/phagocytosis. The cellular determinants of the route of entry are unknown. Here, we asked what cellular factors determine the pathway of HSV entry. CHO cells lack β 3 -integrin and the respective α-subunits’ heterodimers. We report that, in the absence of α V β 3 -integrin, HSV enters CHO-nectin1 cells through a pathway independent of cholesterol-rich rafts and dynamin2. In the presence of α V β 3 -integrin, HSV enters CHO-nectin1 cells through a pathway dependent on cholesterol-rich rafts and dynamin2. HSV enters J-nectin1 and 293T cells through a neutral compartment independent of cholesterol-rich rafts and dynamin2. α V β 3 -integrin overexpression in these cells modifies the route of entry to an acidic compartment dependent on cholesterol-rich rafts and dynamin2, hence similar to that in α V β 3 -integrin–positive CHO-nectin1 cells. In some cells, the diversion of entry from an integrin- and raft-independent pathway to an acidic compartment requiring cholesterol-rich lipids rafts and dynamin2 is irreversible. Indeed, HSV cannot infect CHO-nectin1-α V β 3 cells through any compartment when the αvβ3-integrin–dependent pathway is blocked by anti-integrin antibody, anti-dynamin2, or anti-acidification drugs. We conclude that the αvβ3-integrin is a determinant in the choice of HSV entry pathway into cells. Because the pathway dictated by αvβ3-integrin is through lipid rafts, the platforms for a number of Toll-like receptors, current findings raise the possibility that αvβ3-integrin acts as a sentinel of innate immunity.

van der Woude syndrome (VWS) is a rare autosomal dominant oral facial disorder characterized by high penetrance and variable expression, manifesting with lower lip pits, cleft lips with or without cleft palate, and isolated cleft palate. The phenotypic expression of clefts ranges from incomplete to complete. Different studies have demonstrated an association between VWS and mutations of the IRF6 (interferon regulatory factor) gene. In this study, we describe 2 novel Italian families with VWS harboring 2 distinct splice site mutations in the IRF6 gene. These results add to the previous 9 splicing mutations identified in patients with VWS and strengthen the importance of this type of alterations in the pathogenesis of the disease.

Oncolytic virotherapy exploits the ability of viruses to infect, replicate into, and kill tumor cells. Among the viruses that entered clinical trials are HSVs. HSVs can be engineered to become tumor-specific by deletion of selected genes or retargeting to tumor-specific receptors. A clinically relevant surface molecule is HER-2, hyperexpressed in one fourth of mammary and ovary carcinomas, and associated with high metastatic ability. As a previously undescribed strategy to generate HSV recombinants retargeted to HER-2 and detargeted from natural receptors, we replaced the Ig-folded core in the receptor-binding virion glycoprotein gD with anti-HER-2 single-chain antibody. The recombinant entered cells solely via HER-2 and lysed HER-2–positive cancer cells. Because of the high specificity, its safety profile in i.p. injected mice was very high, with a LD 50 >5 × 10 8 pfu, a figure at least 10,000-fold higher than that of corresponding WT-gD carrying virus (LD 50 ≈ 5 × 10 4 pfu). When administered intratumorally to nude mice bearing HER-2–hyperexpressing human tumors, it strongly inhibited progressive tumor growth. The results provide a generally applicable strategy to engineer HSV recombinants retargeted to a wide range of receptors for which a single-chain antibody is available, and show the potential for retargeted HSV to exert target-specific inhibition of human tumor growth. Therapy with HER-2-retargeted oncolytic HSV could be effective in combined or sequential protocols with monoclonal antibodies and small inhibitors, particularly in patients resistant to HER-2-targeted therapy because of alterations in HER-2 signaling pathway, or against brain metastases inaccessible to anti-HER-2 antibodies.

Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson's disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein alpha-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated alpha-synuclein increased in the same regions. VPA treatment counteracted both these alpha-synuclein alterations. Furthermore, monoubiquitinated alpha-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of alpha-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.

Y-chromosomal DNA haplotypes were determined in 74 infertile and 216 control Italian males using eight biallelic markers. A significant difference in haplotype frequency was found, but could be explained by the geographical origins of the samples. The Y chromosome is thus a sensitive marker for population substructuring and may be useful for determining whether two population samples come from a single population, for example in association studies.

Widespread adoption of green vehicles in urban logistics may contribute to the alleviation of problems such as environmental pollution, global warming, and oil dependency. However, the current adoption of green vehicles in the last mile logistics is relatively low despite many actions taken by public authorities to overcome the negative externalities of distributing goods in cities. This paper presents a comprehensive literature review on studies investigating the adoption of green vehicles in urban freight transportation, paying specific attention to e-commerce. To shed light on the adoption of green vehicles in city logistics, the paper conducts a systematic review of the empirical literature on the topic. The 159 articles reviewed were classified into the following: (a) Optimization and scheduling (67 papers); (b) policy (55 papers); (c) sustainability (37 papers). Among the 159 articles, a further selection of 17 papers dealing with e-commerce, i.e., studies that highlight the most relevant aspects related to the integration of green vehicles in e-commerce urban logistics, was performed. Our findings indicate that green vehicles are competitive in urban deliveries characterized by frequent stop-and-go movements and low consolidation levels while incentives are still necessary for their adoption. The use of autonomous vehicles results the most promising and challenging solution for last-mile logistics.