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Objective: We tested the effect of 27-hydroxycholesterol (27OHC) on the expression and synthesis of two membrane transporters involved in sterols extrusion from the intestinal epithelium into the gut lumen: ATP-binding cassette A1 (ABCA1) and G8 (ABCG8). Special attention was given to ABCG8, a key player in the intestinal cell discharge of plant sterols. Methods: Differentiated CaCo-2 intestinal cells were supplemented with 27OHC, and added to the cell incubation medium at a final concentration of 1 or 5 μM. These 27OHC externally added amounts were proven to reach intracellular oxysterol levels within the range of those normally recovered in the human peripheral blood. Results: An up-regulation of the ABCA1 and ABCG8 mRNAs was observed in the CaCo-2 cells supplemented with 27OHC. Moreover, both 1 μM and 5 μM 27OHC induced a net, and steady, statistically significant, increase of both ABCA1 and ABCG8 protein levels. Of interest, the cellular pre-treatment with diphenylene iodonium, a selective inhibitor of NADPH oxidase, i.e. a major intracellular source of reactive oxygen species, fully inhibited the 27OHC enhancement of both ABCA1 and ABCG8 protein synthesis. Conclusion: This in vitro study shows for the first time that the addition of 27OHC to intestinal epithelial cells up-regulates ABCG8, the transporter discharging plant sterols into the gut lumen, besides confirming to induce ABCA1 as well. Importantly, the 27OHC-dependent up-regulation of the two transporters appears to involve a redox mechanism rather than the canonical liver-X-receptors-dependent pathway. Significance statement The 27OHC introduced with the diet might modulate the plant sterol extrusion in the gut, in parallel with that of cholesterol.

This paper proves the existence of solutions that solve the Nonlinear Partial differential equation on the exterior of the ball centered at the origin in R^{N} with radius R > 0, with boundary conditions u = 0 on the boundary, and u ( x ) approaches 0 as | x | approaches infinity. When the function is local Lipschitzian grows superlinear at infinity and singular at 0. Also N > 2, f ( u ) ~ (-1 ) / ( |u| ^{q-1} u ) for small u with 0 < q < 1, and f ( u ) ~ | u |^{ p-1} u for large | u | with p > 1. Also, K ( x ) ~ | x |^ { - ( Alpha) } with 2 < Alpha < 2 ( N - 1 ) for large | x |. We used the fixed point method and other techniques to prove the existence.

In this study, we analyzed the emotional and motivational aspects characterizing the profile of university students with Specific Learning Disorders (SLD). We assessed 61 university students, 32 with SLD (age = 23.6) and 29 in the control group (age = 23.00). The results highlighted that individuals with SLD exhibit higher levels of anxiety and depression and lower resilience compared to the control group. The Multidimensional Perfectionism Scale – Short Form, which explores perfectionism, did not reveal differences between the groups. Conversely, lower scores emerged in SLD students for the intrinsic motivation sub-scales of the Academic Motivation Scale. This indicates less engagement in studying out of personal cognitive curiosity. The Self-Regulated Knowledge Scale – University, which measures various cognitive strategies, showed significantly lower scores in the SLD group for knowledge linking, knowledge training, and knowledge critique. This suggests a lower frequency with which SLD students attempt to connect new knowledge with what they already possess, apply their knowledge, ask questions, and critically analyze what they have learned. Therefore, psychological and motivational consequences are evident in this population and can impact well-being and quality of life.

IntroductionSeasonal influenza generally represents an underestimated public health problem with significant socioeconomic implications. Monitoring and detecting influenza epidemics are important tasks that require integrated strategies. Wastewater-based epidemiology (WBE) is an emerging field that uses wastewater data to monitor the spread of disease and assess the health of a community. It can represent an integrative surveillance tool for better understanding the epidemiology of influenza and prevention strategies in public health.MethodsWe conducted a study that detected the presence of Influenza virus RNA using a wastewater-based approach. Samples were collected from five wastewater treatment plants in five different municipalities, serving a cumulative population of 555,673 Sicilian inhabitants in Italy. We used the RT-qPCR test to compare the combined weekly average of Influenza A and B viral RNA in wastewater samples with the average weekly incidence of Influenza-like illness (ILI) obtained from the Italian national Influenza surveillance system. We also compared the number of positive Influenza swabs with the viral RNA loads detected from wastewater. Our study investigated 189 wastewater samples.ResultsCumulative ILI cases substantially overlapped with the Influenza RNA load from wastewater samples. Influenza viral RNA trends in wastewater samples were similar to the rise of ILI cases in the population. Therefore, wastewater surveillance confirmed the co-circulation of Influenza A and B viruses during the season 2022/2023, with a similar trend to that reported for the weekly clinically confirmed cases.ConclusionWastewater-based epidemiology does not replace traditional epidemiological surveillance methods, such as laboratory testing of samples from infected individuals. However, it can be a valuable complement to obtaining additional information on the incidence of influenza in the population and preventing its spread.

Women, children and adolescents (WCA), especially in low-income and middle-income countries (LMICs), will bear the worst consequences of climate change during their lifetimes, despite contributing the least to global greenhouse gas emissions. Investing in WCA can address these inequities in climate risk, as well as generating large health, economic, social and environmental gains. However, women’s, children’s and adolescents’ health (WCAH) is currently not mainstreamed in climate policies and financing. There is also a need to consider new and innovative financing arrangements that support WCAH alongside climate goals.We provide an overview of the threats climate change represents for WCA, including the most vulnerable communities, and where health and climate investments should focus. We draw on evidence to explore the opportunities and challenges for health financing, climate finance and co-financing schemes to enhance equity and protect WCAH while supporting climate goals.WCA face threats from the rising burden of ill-health and healthcare demand, coupled with constraints to healthcare provision, impacting access to essential WCAH services and rising out-of-pocket payments for healthcare. Climate change also impacts on the economic context and livelihoods of WCA, increasing the risk of displacement and migration. These impacts require additional resources to support WCAH service delivery, to ensure continuity of care and protect households from the costs of care and enhance resilience. We identify a range of financing solutions, including leveraging climate finance for WCAH, adaptive social protection for health and adaptations to purchasing to promote climate action and support WCAH care needs.

Abstract Background Even acknowledging the game-changing results achieved in the treatment of metastatic melanoma with the use of immune checkpoint inhibitors (ICI), a large proportion of patients (40–60%) still fail to respond or relapse due to the development of resistance. Alterations in the expression of Human Leukocyte Antigen class I (HLA-I) molecules are considered to play a major role in clinical resistance to ICI. Cellular immunotherapy with HLA-independent CAR-redirected lymphocytes is a promising alternative in this challenging setting and dedicated translational models are needed. Methods In this study, we propose an HLA-independent therapeutic strategy with Cytokine Induced Killer lymphocytes (CIK) genetically engineered with a Chimeric Antigen Receptor (CAR) targeting the tumor antigen CSPG4 as effector mechanism. We investigated the preclinical antitumor activity of CSPG4-CAR.CIK in vitro and in a xenograft murine model focusing on patient-derived melanoma cell lines (Mel) with defective expression of HLA-I molecules. Results We successfully generated CSPG4-CAR.CIK from patients with metastatic melanoma and reported their intense activity in vitro against a panel of CSPG4-expressing patient-derived Mel. The melanoma killing activity was intense, even at very low effector to target ratios, and not influenced by the expression level (high, low, defective) of HLA-I molecules on target cells. Furthermore, CAR.CIK conditioned medium was capable of upregulating the expression of HLA-I molecules on melanoma cells. A comparable immunomodulatory effect was replicated by treatment of Mel cells with exogenous IFN-γ and IFN-α. The antimelanoma activity of CSPG4-CAR.CIK was successfully confirmed in vivo, obtaining a significant tumor growth inhibition of an HLA-defective Mel xenograft in immunodeficient mice. Conclusions In this study we reported the intense preclinical activity of CSPG4-CAR.CIK against melanoma, including those with low or defective HLA-I expression. Our findings support CSPG4 as a valuable CAR target in melanoma and provide translational rationale for clinical studies exploring CAR-CIK cellular immunotherapies within the challenging setting of patients not responsive or relapsing to immune checkpoint inhibitors.

The issue of literacy challenges among dyslexic adults remains a significant concern. This study investigates spelling deficits among highly educated adults with dyslexia learning a transparent orthography. Thirty-eight Italian dyslexic university students were examined and compared to a group of age- and education-matched typical readers. Firstly, we analyzed spelling performance using a Passage Dictation Test. Additionally, lists of words varying in length and word frequency were dictated under two experimental conditions: a normal condition (NC) and an articulatory suppression condition (ASC). The ASC assessed the participants’ ability to spell with interference to the phonological (sublexical) spelling procedure, i.e., the most likely compensated spelling strategy of Italian dyslexic spellers. The results clearly indicated that, in spelling the meaningful passage, dyslexic participants underperformed compared to the controls, with a prevalence of lexical errors, despite the comparison with the normative reference data showing only mild spelling difficulties. In spelling isolated words in normal conditions, dyslexic participants performed within the reference norms and as accurately as control participants across all stimuli (short words, high- and low-frequency words), except for long words, where their spelling difficulties were evident. Articulatory suppression significantly impaired dyslexics’ performance on short stimuli, reducing the usual sublexical advantage associated with them, and exacerbated misspellings on long words. Additionally, articulatory suppression disproportionately affected dyslexics’ performance on high-frequency words, diminishing the typical lexical advantage associated with these words. Results are discussed in terms of their theoretical, clinical, and educational implications.

This work reports the results of the analyses performed on a set of glass finds from the “Gaetano Chierici” collection in the Civic Museums of Reggio Emilia. Forty-eight typologically heterogeneous glass finds were included in the list of the analyzed objects, dating from the fifth century BCE to the first century CE. The objects primarily consisted of glass beads; however, bangles, pinheads, and one vessel fragment were also included in the set. The items were analyzed using non-invasive spectroscopic methods that were implemented with portable equipment on the museum’s premises. Fiber optic reflectance spectroscopy was used to identify the coloring species in the glass matrix, while X-ray fluorescence spectrometry provided compositional information. Both techniques allowed for a discussion of the mechanisms of coloring and opacification, as well as the raw materials used for this purpose. The results provided a complex picture of the various colorants used to manipulate the appearance of the glass, which was a crucial aspect in the creation of the personal adornments represented by these glass items. The data revealed evidence of different sources of raw glass and colorants. Most of the samples were colored with cobalt, but iron and copper also influenced the color of many of them. Both white and yellow were utilized for the glass decorations, and these colors were achieved with the addition of either antimony-containing crystals or tin-containing ones. This finding suggests that the transition from antimonate to stannate started as early as the second century BCE. The “Gaetano Chierici” collection contains representative objects distributed throughout the investigated period. The results obtained here are a starting point for future studies of glass technology and provenance in the area.

Prostate cancer (PC) is the most common type of tumor in men. In the early stage of the disease, it is sensitive to androgen deprivation therapy. In patients with metastatic castration-sensitive prostate cancer (mHSPC), chemotherapy and second-generation androgen receptor therapy have led to increased survival. However, despite advances in the management of mHSPC, castration resistance is unavoidable and many patients develop metastatic castration-resistant disease (mCRPC). In the past few decades, immunotherapy has dramatically changed the oncology landscape and has increased the survival rate of many types of cancer. However, immunotherapy in prostate cancer has not yet given the revolutionary results it has in other types of tumors. Research into new treatments is very important for patients with mCRPC because of its poor prognosis. In this review, we focus on the reasons for the apparent intrinsic resistance of prostate cancer to immunotherapy, the possibilities for overcoming this resistance, and the clinical evidence and new therapeutic perspectives regarding immunotherapy in prostate cancer with a look toward the future.

Abstract Several types of (mostly) blue-green glass beads from Iron-Age archaeological sites in Central Italy were studied using a range of spectroscopic techniques: portable X-Ray Fluorescence spectrometry, Fibre Optics Reflectance Spectroscopy, Scanning Electron Microscopy coupled with Energy Dispersive X-ray Spectrometry, micro-Raman spectroscopy and Laser Ablation Inductively Coupled Plasma Mass Spectrometry. Complementary information was gathered from each technique and discussed in the frame of the archaeological typology of the objects. The systematic evaluation of the results allowed us to draw some conclusions on the raw materials employed for primary production and to highlight some provenance indicators in the glass. Some of the beads found in the Iron Age (IA) contexts were preliminarily attributed to the Final Bronze Age (FBA) production based on their typology, and the compositional data obtained in this work confirmed that they were low magnesium high potassium (LMHK) glass, typical of FBA in the Italian peninsula. Other beads were assigned to low magnesium glass (LMG) or high magnesium glass (HMG), thus giving further information on the fluxing agents employed in the Early Iron Age (EIA) and beyond. Colour variations among the beads reflected their chemical composition, with different bead typologies coloured in a specific way. In some instances, it was possible to establish different origins for the colouring raw materials. The provenance of the samples was difficult to place, but the chemical evidence suggested a subdivision within the raw glass used to produce the beads: for one set of samples, a local origin of the glass could be hypothesised, whereas several production sites in the Near East were suggested for most of the beads considered in this study. Some preliminary clues for the local working of imported glass were also highlighted for one typological group.

Food distribution and abundance can affect intra- and inter-dietary variation in non-human primates, influencing feeding ecology and altering behaviour. Natural and/or human-induced actions can influence the dynamics between primates and the environment, with associated impacts on socio-ecology and demography. This relationship in anthropogenic landscapes, however, is poorly understood. Here, we use DNA metabarcoding to obtain high resolution dietary diversity data, and multivariate generalised linear models to investigate variation in the diet of this threatened primate. We characterise the diet of the western red colobus (Piliocolobus badius) in both the better preserved Gola Rainforest National Park (GRNP, Sierra Leone), and in the fragmented forests of Cantanhez National Park (CNP, Guinea-Bissau), and evaluate biological, ecological and temporal differences. Dietary plant species richness was high in both protected areas, and the type of plants consumed varied significantly across seasons, space, and time. Although we identify dependence on a few key plants, red colobus in CNP consumed a higher average number of plant taxa than in GRNP, and 11% of the diet consisted of cultivated foods (e.g. mango). This is the first time a molecular approach has been used to investigate red colobus diet, and reveal dietary flexibility in degraded forests. Predicting the consequences of dietary change on long-term population persistence, however, remains a significant knowledge gap. Nevertheless, our results provide critical information to inform targeted regional conservation planning and implementation.

IntroductionRecombination activating genes (RAG) 1 and 2 defects are the most frequent form of severe combined immunodeficiency (SCID). Patients with residual RAG activity have a spectrum of clinical manifestations ranging from Omenn syndrome to delayed-onset combined immunodeficiency, often associated with granulomas and/or autoimmunity (CID-G/AI). Lentiviral vector (LV) gene therapy (GT) has been proposed as an alternative treatment to the standard hematopoietic stem cell transplant and a clinical trial for RAG1 SCID patients recently started. However, GT in patients with hypomorphic RAG mutations poses additional risks, because of the residual endogenous RAG1 expression and the general state of immune dysregulation and associated inflammation.MethodsIn this study, we assessed the efficacy of GT in 2 hypomorphic Rag1 murine models (Rag1F971L/F971L and Rag1R972Q/R972Q), exploiting the same LV used in the clinical trial encoding RAG1 under control of the MND promoter.Results and discussionStarting 6 weeks after transplant, GT-treated mice showed a decrease in proportion of myeloid cells and a concomitant increase of B, T and total white blood cells. However, counts remained lower than in mice transplanted with WT Lin- cells. At euthanasia, we observed a general redistribution of immune subsets in tissues, with the appearance of mature recirculating B cells in the bone marrow. In the thymus, we demonstrated correction of the block at double negative stage, with a modest improvement in the cortical/medullary ratio. Analysis of antigenspecific IgM and IgG serum levels after in vivo challenge showed an amelioration of antibody responses, suggesting that the partial immune correction could confer a clinical benefit. Notably, no overt signs of autoimmunity were detected, with B-cell activating factor decreasing to normal levels and autoantibodies remaining stable after GT. On the other hand, thymic enlargement was frequently observed, although not due to vector integration and insertional mutagenesis. In conclusion, our work shows that GT could partially alleviate the combined immunodeficiency of hypomorphic RAG1 patients and that extensive efficacy and safety studies with alternative models are required before commencing RAG gene therapy in thesehighly complex patients.

High-energy particle impacts due to background or cosmic radiation have been identified as sources of correlated errors in superconducting qubit arrays. Iaia et al. achieve a suppression of correlated error rate by channeling the energy away from the qubits via a thick metal layer at the bottom of the chip.

Stocking of native and non-native fish species is a widespread practice commonly used to enhance inland recreational fisheries, appropriate when intense harvesting and the degradation or lack of suitable habitat decrease the abundance of the managed species below carrying capacity. In spite of its popularity, this practice is often poorly informed by scientific information. Salmonids are arguably the most popular and commercially valuable freshwater fishes being managed for recreational fisheries. Stocking of both native and non-native taxa has been practiced for almost two centuries in Europe, dramatically altering the structure and function of riverine and lacustrine ecosystems. In the Verbano-Cusio Ossola Province, northern Italy, within the Lake Maggiore catchment, we measured large numerical mismatches between stocking of cultured native (Salmo marmoratus) plus non-native trout taxa (S. trutta, S. ghigii, Oncorhynchus mykiss) and the number of fishes captured by local anglers. These observations highlight the need for future studies to estimate the stocking effectiveness of S. marmoratus, a critically endangered species of significant cultural and economic value.

Salmonid species are main actors in the Italian socio-ecological landscape of inland fisheries. We present novel data on the size-age structure of one of the remnant Italian populations of the critically endangered marble trout Salmo marmoratus, which co-occurs with other stocked non-native salmonids in a large glacial river of the Lake Maggiore basin (Northern Italy-Southern Switzerland). Like other Italian native trout populations, the Toce River marble trout population is affected by anthropogenic introgression with the non-native brown trout S. trutta. Our sample includes 579 individuals, mainly collected in the Toce River main channel. We estimated the length-weight relationship, described the population size-age structure, estimated the age-specific growth trajectories, and fit an exponential mortality model. A subset of the sample was also used to measure numerical and biomass density. The estimated asymptotic maximum length is ~105 cm total length (TL). Mean length at first maturity is ~55 cm TL, and mean length at maximum yield per recruit is ~68 cm TL. Approximately 45–70% of the population are estimated to die annually, along with a fishing annual mortality of ~37%, with an exploitation ratio of ~0.5. The frequency distribution of length classes in a sample collected by angling shows that ~80% of the individuals that could be retained according to the current recreational fishing regulations likely never reproduced, and large fish disproportionally contributing to recruitment are fished and retained. We identify possible overfishing risks posed by present regulations, and propose updated harvest-slot length limits to mitigate such risks. More detailed and long-term datasets on this system are needed to more specifically inform the fishery management and monitor the effects of any change in the management strategy on the size-age structure of the marble trout population of the Toce River.

Introduction Repeated sprints exercise (RSE) performed in hypoxia (RSH) induce greater performance improvement than in normoxia (Brocherie et al., 2017). It has been previously argued that RSH efficiency depend on the oxidative-glycolytic balance which is influenced by sprint duration and exercise-to-rest-ratio (E:R). Indeed, we recently showed that long sprint duration (e.g. 20 s vs 10 s or 5 s) blunts the additional impact of hypoxia on RSH with a constant large E:R of 1:22. However, E:R also influence acute response to RSH. Therefore, this study aims to compare acute responses during RSE to exhaustion with a short E:R (1:6) in normoxia (RSN) and hypoxia (FiO2 = 0.13) and the same sprint durations (5, 10 or 20 s) previously used. Methods On separate visits, 10 active participants completed in random order three RSH and three RSN sessions to exhaustion on a cycle-ergometer (Excalibur Sport, Lode) with three sprint durations and a constant short E:R of 1:6 (5:30; 10:60 and 20:120). Vastus lateralis muscle de-reoxygenation (Oxymon, Artinis Medical Systems) and power output were continuously recorded. Lower limb and breathing discomfort, blood lactate, and ratings of perceived exertion were evaluated immediately after exhaustion. Results Number of sprints and peak power output were higher while blood lactate was lower (all p < 0.001) during 5:30 compared to 10:60 or 20:120. No condition or interaction effects were reported for blood lactate and exercise-related sensation. Blood lactate and muscle deoxyhemoglobin increase (p < 0.001) and total hemoglobin decrease (p = 0.002) during sprint were more pronounced when sprint duration increased (no hypoxia effect). Discussion Similar deoxygenation changes during recovery were reported in hypoxia compared to normoxia suggesting that 1:6 ratio and the associated long recovery period seemed to allow myoglobin O2 store restauration, even with a FiO2 = 13%. Sprint effort should be interspersed by incomplete recovery making impossible the full O2 reloading myoglobin and PCr resynthesis. The increase in blood lactate and the concomitant decrease in muscle oxygenation during sprint with longer duration confirmed a switch in the oxidative-glycolytic balance for energy supply. Since short exercise-to-rest ratio blunt hypoxic effect during RSH due to too long recovery period, hypoxia did not participate to the switch from oxidative to glycolytic energy supply. Conclusion During RSE to exhaustion, a short exercise-to-rest ratio (i.e., 1:6) blunts the specific psychophysiological responses induced by hypoxia, probably due to too long of recovery period. Manipulating effort duration rather than hypoxic exposure is preferable to alter both anaerobic energy system solicitation and power produced during repeated cycling sprints to exhaustion using a short exercise-to-rest ratio. References Brocherie, F., Girard, O., Faiss, R., & Millet, G. P. (2017). Effects of repeated-sprint training in hypoxia on sea-level performance: A meta-analysis. Sports Medicine, 47, 1651-1660. https://doi.org/10.1007/s40279-017-0685-3

IntroductionIn individuals with intellectual disabilities (ID), efficient reading and writing skills promote social integration, self-autonomy, and independence. However, research has mainly focused on reading skills, while evidence on spelling skills is scarce and mostly on English-speaking subjects. In the present research project, we compared the spelling skills of children with intellectual disabilities (ID) learning in Italian, a regular orthography, to those of typically developing children matched for school level.MethodsIn the first study, the performance on a Passage Dictation Test of forty-four children with ID attending regular classrooms from 4th to 8th grades (mean age = 12.16 years; SD = 1.57) were compared with controls matched for sex and grade. In the second study, a Words and Nonwords Dictation Test was administered (with stimuli varying for lexicality, orthographic complexity, regularity of transcription, and the presence of different types of phonetic-phonological difficulties) to twenty-two children with ID attending regular classrooms from 4th to 8th grades (mean age = 12.2 years; SD = 1.37) and 22 controls matched for sex and grade. In both studies, an error analysis was performed to characterize types of misspellings. Separate ANOVAs were performed on z scores.ResultsChildren with ID generally had a lower performance than controls. In the Passage Dictation Test, they showed a higher number of phonological (and phonetic-phonological) errors than phonologically plausible ones, indicating, as a group, predominant phonological difficulties as compared to lexical-orthographic ones. In the Words and Nonwords Dictation Test, they performed poorly on regular stimuli presenting specific types of phonetic-to-phonological difficulties (geminates, non-continuant consonants) and committed more minimal distance, context-sensitive and simple conversion misspellings. However, deficits in the orthographic-lexical procedure, as indicated by a low performance in words with unpredictable spelling, were present in a high percentage of children.DiscussionIt is concluded that children with ID have significant spelling difficulties not confined to the orthographic process but also in phoneme-to-grapheme mapping that, in a regular orthography like Italian, should be acquired early and easily.

Single flux quantum (SFQ) digital logic has been proposed for the scalable control of next-generation superconducting-qubit arrays. In the initial implementation, SFQ-based gate fidelity was limited by quasiparticle (QP) poisoning induced by the dissipative on-chip SFQ driver circuit. In this work, we introduce a multichip-module architecture to suppress phonon-mediated QP poisoning. Here, the SFQ elements and qubits are fabricated on separate chips that are joined with In-bump bonds. We use interleaved randomized benchmarking to characterize the fidelity of SFQ-based gates and we demonstrate an error per Clifford gate of 1.2(1)%, an order-of-magnitude reduction over the gate error achieved in the initial realization of SFQ-based qubit control. We use purity benchmarking to quantify the contribution of incoherent error at 0.96(2)%; we attribute this error to photon-mediated QP poisoning mediated by the resonant millimeter-wave antenna modes of the qubit and SFQ-qubit coupler. We anticipate that a straightforward redesign of the SFQ driver circuit to limit the bandwidth of the SFQ pulses will eliminate this source of infidelity, allowing SFQ-based gates with error approaching approximate known theoretical limits, of order 0.1% for resonant sequences and 0.01% for more complex pulse sequences involving variable pulse-to-pulse separation.

Although immunotherapy has proved to be a very efficient therapeutic strategy for many types of tumors, the results for pancreatic cancer (PC) have been very poor. Indeed, chemotherapy remains the standard treatment for this tumor in the advanced stage. Clinical data showed that only a small portion of PC patients with high microsatellite instability/mismatch repair deficiency benefit from immunotherapy. However, the low prevalence of these alterations was not sufficient to lead to a practice change in the treatment strategy of this tumor. The main reasons for the poor efficacy of immunotherapy probably lie in the peculiar features of the pancreatic tumor microenvironment in comparison with other malignancies. In addition, the biomarkers usually evaluated to define immunotherapy efficacy in other cancers appear to be useless in PC. This review aims to describe the main features of the pancreatic tumor microenvironment from an immunological point of view and to summarize the current data on immunotherapy efficacy and immune biomarkers in PC.

The present study aimed to investigate how playing positions differ in specific body composition variables in professional soccer players with respect to specific field zones and tactical lines. Five hundred and six Serie A and B professional soccer players were included in the study and analyzed according to their playing positions: goalkeepers (GKs), central backs (CBs), fullbacks (FBs), central midfielders (MIDs), wide midfielders (WMs), attacking midfielders (AMs), second strikers (SSs), external strikers (ESs), and central forwards (CFs), as well as their field zones (central and external) and tactical lines (defensive, middle, and offensive). Anthropometrics (stature and body mass) of each player were recorded. Then, body composition was obtained by means of bioelectric impedance analysis (BIA). GKs and CFs were the tallest and heaviest players, with no differences from each other. Likewise, GKs and CFs, along with CBs, were apparently more muscular (for both upper and lower limbs) and fatter at the same time compared with the other roles. Overall, players of the defensive line (CBs and FBs), along with those playing in central field zones (CBs, MIDs, AMs, SSs, and CFs), were significantly (p < 0.05) superior in almost all anthropometric and body composition variables than those of middle and offensive line and external zones, respectively.

Purpose: This observational longitudinal investigation aimed to investigate whether change in bioelectrical regional phase angle (PhA) is a predictor of change in vertical jump performance in elite soccer players. Methods: Fifteen soccer players (age: 28.7 ± 5.0 years, body weight: 82.4 ± 6.8 kg, height: 186.0 ± 0.1 cm, body mass index: 23.8 ± 1.2 kg/m2) competing in the first Italian division (Serie A) were included in this study and tested before the pre-season period and after the first half of the championship. Whole body and lower hemisoma PhA were obtained with a phase-sensitive 50 kHz bioelectrical impedance analyzer and legs lean soft tissue was estimated using specific bioimpedance-based equation developed for athletes. Vertical jump performance was assessed using the countermovement jump (CMJ). Results: The major findings of the study are that changes in lower hemisoma PhA are more strongly related with changes in jump performance (r2 = 0.617, p = 0.001) than changes in whole-body PhA (r2 = 0.270, p = 0.047), even after adjusting for legs lean soft tissue and for body mass index (β = 5.17, p = 0.004). Conclusions: These data suggest that changes in lower hemisoma PhA might be used as a tool for evaluating performance related parameters in sports where specific body segments are involved, in preference to the whole-body measured value.

Training for success has increasingly become a balance between maintaining high performance standards and avoiding the negative consequences of accumulated fatigue. The aim of this study is to develop a big data analytics framework to predict players’ wellness according to the external and internal workloads performed in previous days. Such a framework is useful for coaches and staff to simulate the players’ response to scheduled training in order to adapt the training stimulus to the players’ fatigue response. 17 players competing in the Italian championship (Serie A) were recruited for this study. Players’ Global Position System (GPS) data was recorded during each training and match. Moreover, every morning each player has filled in a questionnaire about their perceived wellness (WI) that consists of a 7-point Likert scale for 4 items (fatigue, sleep, stress, and muscle soreness). Finally, the rate of perceived exertion (RPE) was used to assess the effort performed by the players after each training or match. The main findings of this study are that it is possible to accurately estimate players’ WI considering their workload history as input. The machine learning framework proposed in this study is useful for sports scientists, athletic trainers, and coaches to maximise the periodization of the training based on the physiological requests of a specific period of the season.

The introduction and establishment of non-native fish species is a widespread phenomenon in freshwater ecosystems, including small and shallow lakes. However, these ecosystems are often not considered in conservation and ecological studies and a few information is available on their fish communities and the impacts of biological invasions. Here, standardized fish surveys (gillnetting and electrofishing) and stable isotopes analysis (SIA) of carbon and nitrogen (δ13C and δ15N) were combined to assess fish community composition, trophic structure and trophic diversity, and to characterize the interspecific trophic interactions (as isotopic niches and their relative asymmetric overlap) of the native and non-native species (NS and NNS, respectively) found in two protected small and shallow lakes, San Michele and Campagna (northern Italy). In San Michele, 92% of the fish caught were NNS and both the individual and biomass per unit effort were dominated by NNS, particularly by the invasive Lepomis gibbosus L. and Ictalurus punctatus (Rafinesque, 1818). In Campagna, 5.6% of the fish in the total catches belonged to NNS and the numeric and biomass abundances of the assemblage were dominated by the NS Alburnus alborella (Bonaparte, 1841). SIA revealed that NNS had greater trophic structure and were exploiting a wider range of resources (as per Layman metrics) and had a higher asymmetric overlap than NS assemblages in both lakes. This was also evident when species-specific isotopic ecology was considered, underlining that, in both lakes, NNS (particularly the NNS Ameiurus melas (Rafinesque, 1820)) may have a competitive advantage over NS in case of limiting resources. The results thus pointed to a worrying conservation status of these lakes that may mirror the condition of other Italian shallow and small lakes highlighting the need to implement management actions to preserve these valuable ecosystems.

Almost 17% of Western patients affected by non-small cell lung cancer (NSCLC) have an activating epidermal growth factor receptor (EGFR) gene mutation. Del19 and L858R are the most-common ones; they are positive predictive factors for EGFR tyrosine kinase inhibitors (TKIs). Currently, osimertinib, a third-generation TKI, is the standard first-line therapy for advanced NSCLC patients with common EGFR mutations. This drug is also administered as a second-line treatment for those patients with the T790M EGFR mutation and previously treated with first- (erlotinib, gefitinib) or second- (afatinib) generation TKIs. However, despite the high clinical efficacy, the prognosis remains severe due to intrinsic or acquired resistance to EGRF-TKIs. Various mechanisms of resistance have been reported including the activation of other signalling pathways, the development of secondary mutations, the alteration of the downstream pathways, and phenotypic transformation. However, further data are needed to achieve the goal of overcoming resistance to EGFR-TKIs, hence the necessity of discovering novel genetic targets and developing new-generation drugs. This review aimed to deepen the knowledge of intrinsic and acquired molecular mechanisms of resistance to EGFR-TKIs and the development of new therapeutic strategies to overcome TKIs’ resistance.

Visuo-spatial working memory is one of the main domain-general cognitive mechanisms underlying mathematical abilities and their development in children. However, if visuo-spatial working memory involves different processes and components, then the term ‘mathematics’ refers to a broad concept that includes multiple domains and skills. The aim of this present study was to investigate the relationship between different visuo-spatial working memory components and several mathematical abilities in a sample of third- to fifth-grade Italian children. To assess the relationships between different visuo-spatial working memory components and different mathematical abilities, we relied on Network Analysis (NA). Results indicate that some but not all visuo-spatial working memory components are associated with some mathematical abilities.

In this article we study the existence of radial solutions of $\Delta u + K(|x|)f(u)= 0$ on the exterior of the ball of radius R>0 centered at the origin in $\mathbb{R}^N$ with u=0 on $\partial B_{R}$, and $\lim_{|x| \to \infty} u(x)=0$ where N>2, $f(u) \sim \frac{-1}{|u|^{q-1}u} $ for u near 0 with 0

Abstract Metal-to-insulator transitions (MIT) can be driven by a number of different mechanisms, each resulting in a different type of insulator—Change in chemical potential can induce a transition from a metal to a band insulator; strong correlations can drive a metal into a Mott insulator with an energy gap; an Anderson transition, on the other hand, due to disorder leads to a localized insulator without a gap in the spectrum. Here, we report the discovery of an alternative route for MIT driven by the creation of a network of narrow channels. Transport data on Pt substituted for Ti in 1T-TiSe2 shows a dramatic increase of resistivity by five orders of magnitude for few % of Pt substitution, with a power-law dependence of the temperature-dependent resistivity ρ(T). Our scanning tunneling microscopy data show that Pt induces an irregular network of nanometer-thick domain walls (DWs) of charge density wave (CDW) order, which pull charge carriers out of the bulk and into the DWs. While the CDW domains are gapped, the charges confined to the narrow DWs interact strongly, with pseudogap-like suppression in the local density of states, even when they were weakly interacting in the bulk, and scatter at the DW network interconnects thereby generating the highly resistive state. Angle-resolved photoemission spectroscopy spectra exhibit pseudogap behavior corroborating the spatial coexistence of gapped domains and narrow domain walls with excess charge carriers.

Hans Jonas: Ethics and Theology in the thought “after Auschwitz” Hans Jonas radically transformed the question of theodicy into the question of the justification of man, rejecting the notion of God's power in history. Starting from a speculative myth, he unfolded a process of theogony and cosmology for which God, in the course of evolution, withdraws completely back into himself, relinquishes his own omnipotence, and makes the world subject to human responsibility alone. However, Jonas does not wants to present an alternative (metaphysical or theological) schema about God, nor attempts to make sense of the events of the Shoah. He just wants to better understand the meaning of a God known as “omnipotent” but who cannot avoid the acid test of ethical demands, which challenges us not to seek comfort in ourselves, but to live in hope (and responsibility) for others.

In questo articolo, mi propongo anzitutto di analizzare ciò che Weil pensa essere la condizione necessaria e sufficiente dell’esperienza estetica e dell’amore per la bellezza, ossia la rinuncia all’immaginazione, elemento questo rilevante perché fornisce alcune importanti indicazioni sulla natura della bellezza stessa e sul perché l’amore per la bellezza sia paritetico all’amore per il prossimo. In secondo luogo, cercherò di delineare quella che per Simone Weil è l’autentica natura della bellezza, “spigolando” nei suoi scritti. Diventerà evidente che, per Weil, la bellezza è una proprietà di Dio ed è inestricabilmente legata alla creazione divina.

In this article we study radial solutions of $\Delta u + K(r)f(u)= 0$ on the exterior of the ball of radius R>0 centered at the origin in ${\mathbb R}^N$ where f is odd with f$ on $(\beta, \delta)$, $f\equiv 0$ for $u> \delta$, and where the function K(r) is assumed to be positive and $K(r)\to 0$ as $r \to \infty$. The primitive $F(u) = \int_0^u f(t) \, dt$ has a ``hilltop'' at $u=\delta$. With mild assumptions on f we prove that if $K(r)\sim r^{-\alpha}$ with $2< \alpha< 2(N-1)$ then there are n solutions of $\Delta u + K(r)f(u)= 0$ on the exterior of the ball of radius R such that $u\to 0$ as $r \to \infty$ if R>0 is sufficiently small. We also show there are no solutions if R>0 is sufficiently large.

O objetivo do trabalho foi compreender a relação entre autoestima, congruência dos orgânicos e a intenção de compra dos consumidores desse tipo de alimento. Para isso, foi realizado um estudo com duas etapas, a primeira utilizando a técnica laddering com 30 entrevistados a fim de destacar os atributos mais importantes para os consumidores; em sua segunda etapa foi utilizado o equipamento EyeTracker com 20 participantes, com objetivo de identificar o destino de maior interesse dos mesmos, analisado por meio de uma elevada frequência de fixação naquela área. Os resultados da primeira etapa evidenciaram cinco atributos mais importantes, entre eles estão: saboroso, natural, sem agrotóxico, nutritivo e ecologicamente correto. Já na segunda etapa observou-se que a maioria dos participantes apresentaram alta autoestima, com maior apelo atencional em atributos congruentes, assim como também um maior engajamento na intenção de compra.

Abstract Background To explore the relationship between adult Attention Deficit/ Hyperactivity Disorder (ADHD), antistreptococcal titers, ABGA, and recurrent infections during early childhood. Method Childhood history of recurrent infections and a blood sample were collected in a sample of DSM-IV adult outpatients with ADHD. The anti-streptolysin O (ASO), anti-deoxyribonuclease B (anti-DNase B), and anti-basal ganglia antibodies (ABGA) titers were determined in patient plasma by enzyme-linked immunosorbent assay (ELISA). Titers positivity was evaluated following manufacturer’s specifications. Absolute titers were also collected as continuous variables. Results Fourteen out of 22 (63.6%) have had recurrent infections in childhood (i.e., seven, 31.8%, have had tonsillitis or adenoiditis and seven, 31.8%, have had any other infections). Eighteen patients (81.9%) were positive for anti-DNase B, five (22.7%) for ASO, and 4 (18.2%) were positive for both of them. Five participants (22.7%) were ABGA positive, whereas only two (9.1%) were positive for all three antibodies. Conclusions patients with ADHD might be more prone to infections during childhood and subclinical streptococcal infections during adulthood. Moreover, they seem to have an increased risk for basal ganglia autoimmunity in adulthood. Both infections and the ensuing acquired autoimmunity could influence the neurodevelopmental process, by contributing, at least in part, to the ADHD pathogenesis.

In this article we prove the existence of an infinite number of radial solutions to $\Delta u+K(r)f(u)=0$ on $\mathbb{R}^{N}$ such that $\lim_{r \to \infty} u(r)=0$ with prescribed number of zeros on the exterior of the ball of radius R>0 where f is odd with f0 on $(\beta,\infty)$ with f superlinear for large $u$, and $K(r) \sim r^{-\alpha}$ with $ \alpha > 2(N-1)$.

Traduzione in lingua italiana del saggio Des variations du Beau di Eugéne Delacroix, pubblicato nella Revue des Deux Mondes, seconde période, Vol. 9, No. 4 (15 JUIN 1857), pp. 908-919.

Adoptive cell therapy in solid tumors, such as melanoma, is impaired, but little is known about the role that the fibroblasts present in the tumor microenvironment could exert. However, the mechanism at play is not well understood, partly due to the lack of relevant pre-clinical models. Three-dimensional culture and microfluidic chips are used to recapitulate the dynamic interactions among different types of cells in the tumor microenvironment in controlled and physiological settings. In this brief report, we propose a reductionist melanoma-on-a-chip model for evaluating the essential role of fibroblasts in the antitumor activity of lymphocytes. To this end, 3D melanoma spheroids were monocultured and co-cultured with human dermal fibroblasts and the NK-92 cell migration towards the tumor compartment was tested in a commercially available microfluidic device. Utilizing confocal microscopy, we observed the different recruitment of NK-92 cells in the presence and absence of fibroblasts. Our results show that fibroblasts’ presence inhibits immune effector recruiting by exploiting a 3D pre-clinical tumor model.

Nella Biblioteca di La-Chaux-de-Fonds è custodito (MS 71) un manoscritto del Système de la Mode, donato il 18 novembre 1962 da Roland Barthes per il tramite dello scrittore svizzero Yves Velan. Il manoscritto della Préface, presumibilmente scritto tra la fine del 1962 e la metà del 1963, è rimasto inedito fino al 1998, anno in cui la sua trascrizione francese venne pubblicata dalla rivista svizzera [VWA] nel numero monografico Le cabinet des manuscrits2. Quella che pubblichiamo costituisce quindi la sua prima traduzione in lingua italiana.

Il presente saggio si propone come rilettura del Système de la Mode di Roland Barthes, nel quale la ricchezza o – più esattamente – la sottigliezza dell'analisi trova la sua motivazione in una costruzione formale che identifica nel segno l’indicazione stessa della realtà sociale e nel suo sistema la certezza della sua realtà costruita. È per questo un’opera importante, con la quale Barthes ricorda che sul fashion system agiscono storicità e durata sociale e che l'apertura della forma al movimento concreto può dare accesso a un nuovo ambito di ricerca.

This paper proposes a cognitive-functional investigation of gamers’ uses of English in online communication, in order to enquire into the possibility of introducing a model that could be called COOPING (‘COOperation Principles between INternet Gamers’). COOPING was devised at the University of Salento, and it was conceived as a further development of both Grice’s maxims and Guido’s principles describing English lingua-franca uses in intercultural exchanges. The main research hypothesis is that the interactants’ awareness of the need to cooperate to reach shared targets prompts them to select a common linguistic means, which is usually a variation of English, when different linguacultural backgrounds come into contact. This paper will detail the four phases of COOPING—Evaluation, Acknowledgment, Negotiation, and Manner—which are expected to reflect the steps that players follow when they intend to cooperate in these virtual communities. Through an analysis of the selected corpus of conversations, this study will illustrate that gamers: (phases 1 and 2 of the Model) examine and evaluate the interlocutors’ behavior in order to assess their cooperative attitude; (phase 3) decide to select English when community members come from different linguistic and cultural backgrounds; and (phase 4) generate conversation turns that are characterized by specific features, from authentication, to meaning negotiation, to creative and critical modifications to the standard norms, trying to pursue reciprocal understanding and communication.

The aim of this study was to examine the impact of two different post-match training interventions on the subsequent recovery of perceptual and biochemical parameters after the game. In a crossover design, eight sub-elite players underwent a soccer-specific training (SST) and an active recovery (AR) regimen on the second day after a match (+48 h). Muscle soreness as well as muscle damage (creatine kinase, CK), inflammatory (C-reactive protein and interleukin 6), immunological (e.g., lymphocytes, neutrophils, and monocytes), and endocrine (cortisol) markers were obtained at baseline (−72 h), immediately after (0 h), and 72 h post-match (+72 h). AR promoted a higher restoration of muscle soreness values (P = 0.004, η2p = 0.49) together with a better restoration of CK within 72 h post-match compared with SST (P = 0.04, η2p = 0.36). Conversely, no significant (P > 0.05, η2p < 0.91) differences were observed in the recovery timeframe of inflammatory, immunological, and endocrine responses between SST and AR. Overall, AR elicited a quicker muscle soreness and CK restoration compared to SST intervention at 72 h post-match. Such information provides novel evidence-based findings on the appropriateness of different recovery strategies and may aid to improve the practitioners’ decision-making process when two consecutive games are played within 3 days.

In this article we prove the existence of infinitely many radial solutions of $\Delta u + K(r)f(u)= 0$ on the exterior of the ball of radius R>0, $B_R$, centered at the origin in $\mathbb{R}^N$ with u=0 on $\partial B_R$ and $\lim_{r \to \infty} u(r)=0$ where N>2, f is odd with f0 on $(\beta, \infty)$, f is superlinear for large u, $f(u) \sim-1/(|u|^{q-1}u)$ with 0

Background: The present study aimed to determine the association of anthropometry-based characteristics with an aggregate score (AS) of physical performance in young elite soccer players. Methods: Sixteen under 15 elite players were enrolled. Among numerous anthropometrics variables, upper arm contracted (UACC) and relaxed circumference (UARC), corrected arm muscle area (AMAcorr), arm muscle circumference (AMC), thigh muscle circumference (TMC) and suprapatellar girths were also employed in this study. Players’ physical performance was assessed by the change of direction (COD), 10 m and 20 m sprint, countermovement jump (CMJ) test, sprint with 90∘ turns (with ball), and yo-yo intermittent recovery test level 1 (Yo-Yo IRT1). The AS was computed by Principal Components Analysis technique with one component on normalized performance results. A stepwise regression analysis was conducted to assess potential association between anthropometry-based variables and AS. Results: Large negative correlations (r < –0.68) of AS with UACC, UARC, AMAcorr, and AMC were detected. UACC and TMC permits to accurately estimate AS explaining 60% of the total variance (p < 0.001). Conclusions: These findings demonstrated the importance of including anthropometry-based measures of both upper and lower body to the physical performance potential expressed by AS in elite youth soccer.

During the last 150 years, the trout-culture industry focused on enhancing trout populations by stocking, in response to the growing anglers’ demand and the habitat degradation associated to the rapid urbanization and hydropower development. The industrialized north of Italy, home to the Italian Alpine and subalpine trout populations, is the source of most of the revenues of the national trout-culture industry. Its rapid growth, and the massive introduction of non-native interfertile trouts eroded the genetic diversity of native lineages, leading to harsh confrontations between scientists, institutions, and sportfishing associations. We review here the state of the art of the taxonomy and distribution of the northern Italian native trouts, presenting both scientific results and historical documentation. We think the only native trouts in this region are Salmo marmoratus, widespread in this region, plus small and fragmented populations of S. ghigii, present only in the South-western Alps. We strongly recommend the interruption of stocking of domesticated interfertile non-native trouts in this area, and recommend the adoption of Evolutionary Significant Units for salmonid fishery management. We further propose future research directions for a sustainable approach to the conservation and ecosystem management of the fishery resources and inland waters of northern Italy.

The BRCA1/2 germline and/or somatic pathogenic variants (PVs) are key players in the hereditary predisposition and therapeutic response for breast, ovarian and, more recently, pancreatic and prostate cancers. Aberrations in other genes involved in homologous recombination and DNA damage response (DDR) pathways are being investigated as promising targets in ongoing clinical trials. However, DDR genes are not routinely tested worldwide. Due to heterogeneity in cohort selection and dissimilar sequencing approaches across studies, neither the burden of PVs in DDR genes nor the prevalence of PVs in genes in common among pancreatic and prostate cancer can be easily quantified. We aim to contextualize these genes, altered in both pancreatic and prostate cancers, in the DDR process, to summarize their hereditary and somatic burden in different studies and harness their deficiency for cancer treatments in the context of currently ongoing clinical trials. We conclude that the inclusion of DDR genes, other than BRCA1/2, shared by both cancers considerably increases the detection rate of potentially actionable variants, which are triplicated in pancreatic and almost doubled in prostate cancer. Thus, DDR alterations are suitable targets for drug development and to improve the outcome in both pancreatic and prostate cancer patients. Importantly, this will increase the detection of germline pathogenic variants, thereby patient referral to genetic counseling.

Background: The objective of this study was to investigate the association between regional and total phase angle (PhA) with lower-body neuromuscular performance in young elite soccer players. Methods: Sixteen elite male soccer players (14.3 ± 1.0 years) participated in this study. Lower (LPhA)- and upper (UPhA)-hemisome PhA together with whole-body PhA (WBPhA) were measured by a bioelectrical-impedance analysis (BIA), while appendicular arm and leg lean soft tissue (ALST and LLST, respectively) were estimated. Urine osmolarity (UOsm) and urine-specific gravity (USG) were also considered. Sprints over 10 m and 20 m and countermovement jump (CMJ) tests were employed to evaluate neuromuscular performance. Results: LPhA (p = 0.003) and UOsm (p = 0.012) explained 62% of the variance in the 10 m sprint. UOsm (p = 0.001) and both LPhA (p < 0.001) and WBPhA (p = 0.024) explained 81% of the total variance in the 20 m sprint. The CMJ height was affected by LPhA (p < 0.001) and UOsm (p = 0.024), which overall explained 68% of its variance (p < 0.05), while 93% of the CMJ power variance was explained by LPhA (p < 0.001), ALST (p < 0.001), and WBPhA (p = 0.011). Conclusions: Regional PhA is a relevant and non-invasive tool to monitor lower-body neuromuscular performance in elite youth soccer. Specifically, LPhA may be favored over WBPhA as more informative.

Background In youth, the development of change of direction (COD) and sprint performance is a key component for successfully competing in soccer across age. During a COD, the presence of directional asymmetries may be detrimental due to the unpredictable nature of the sport. Therefore, the aims of the study were to investigate asymmetries in COD ability and to examine the differences in COD and sprint performance across age in young soccer players. Methods Sixty-eight sub-elite soccer players of different age categories (U18, U17, U16, U15) were tested on a 10-m linear sprint test and 90°COD (5-m entry and exit) test in both directions. Asymmetric index (AI) of COD deficit was obtained for dominant (fastest) and non-dominant directions (slowest). Results The results showed that U16 were more asymmetrical than U18, U17, and U15 from large to moderate effects. The sprint time improved linearly across age with U18 and U15 displaying the fastest and slowest 10-m sprint performance (p 0.05). Conclusion Given the results of this study, practitioners are encouraged to assess asymmetries between dominant and non-dominant directions rather than solely players’ COD ability in young soccer players.