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Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing (“early treatment”) or reversing (“late treatment”) HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic (“early treatment”) or symptomatic (“late treatment”) stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments (“2 cycle treatment”) lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. Data availability: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors.

Abstract Urbanization and the expansion of human activities foster radical ecosystem changes with cascading effects also involving host‐pathogen interactions. Urban pollinator insects face several stressors related to landscape and local scale features such as green habitat loss, fragmentation and availability reduction of floral resources with unpredictable effects on parasite transmission. Furthermore, beekeeping may contribute to the spread of parasites to wild pollinators by increasing the number of parasite hosts. Here we used DNA‐based diagnostics tools to evaluate how the occurrence of parasites, namely microsporidians (Nosema spp.), trypanosomatids (Crithidia spp.) and neogregarines (Apicystis bombi), is shaped by the above‐mentioned stressors in two bumblebee species (i.e. Bombus terrestris and Bombus pascuorum). Infection rates of the two species were different and generally higher in B. terrestris. Moreover, they showed different responses towards the same ecological variables, possibly due to differences in body size and foraging habits supposed to affect their susceptibility to parasite infection. The probability of infection was found to be reduced in B. pascuorum by green habitat fragmentation, while increased along with floral resource availability. Unexpectedly, B. terrestris had a lower parasite richness nearby apiaries maybe due to the fact that parasites are prone to be transmitted among the most abundant species. Our finding supports the need to design proper conservation measures based on species‐specific knowledge, as suggested by the variation in the parasite occurrence of the two species. Moreover, conservation policies aiming at safeguarding pollinators through flower planting should consider the indirect effects of these measures for parasite transmission together with pollinator biodiversity issues.

ObjectiveWe investigated how physical activity can be effectively promoted with a message-based intervention, by combining the explanatory power of theory-based structural equation modeling with the predictive power of data-driven artificial intelligence.MethodsA sample of 564 participants took part in a two-week message intervention via a mobile app. We measured participants’ regulatory focus, attitude, perceived behavioral control, social norm, and intention to engage in physical activity. We then randomly assigned participants to four message conditions (gain, non-loss, non-gain, loss). After the intervention ended, we measured emotions triggered by the messages, involvement, deep processing, and any change in intention to engage in physical activity.ResultsData analysis confirmed the soundness of our theory-based structural equation model (SEM) and how the emotions triggered by the messages mediated the influence of regulatory focus on involvement, deep processing of the messages, and intention. We then developed a Dynamic Bayesian Network (DBN) that incorporated the SEM model and the message frame intervention as a structural backbone to obtain the best combination of in-sample explanatory power and out-of-sample predictive power. Using a Deep Reinforcement Learning (DRL) approach, we then developed an automated, fast-profiling strategy to quickly select the best message strategy, based on the characteristics of each potential respondent. Finally, the fast-profiling method was integrated into an AI-based chatbot.ConclusionCombining the explanatory power of theory-driven structural equation modeling with the predictive power of data-driven artificial intelligence is a promising strategy to effectively promote physical activity with message-based interventions.

Maldives islands host a unique biodiversity, but their integrity is threatened by climate change and impacting land-uses (e.g. cemented or agricultural areas). As pollinators provide key services for the ecosystems and for the inhabitants, it is crucial to know which pollinators occur in the islands, to characterise their genetic identity and to understand which plants they visit and the size of the human impact. Given that no significant faunistic surveys of Hymenoptera have been published for the country in more than 100 years and that Syrphidae were only partly investigated, we sampled islands in the central part of the Maldives country (Faafu and Daahlu atolls) and hand-netted flower-visiting bees, wasps and hoverflies (Hymenoptera: Anthophila, Crabronidae, Sphecidae, Vespidae, Scoliidae and Diptera: Syrphidae). Overall, we found 21 species; 76.4% of the collected specimens were Anthophila (bees), 12.7% belonged to several families of wasps and 10.8% of individuals were Syrphidae. It seems that one third of species are new for the Maldives, based on the published literature. Human land-uses seem to shape the local pollinator fauna since the assemblages of bees, wasps and hoverflies from urbanised and agricultural islands differed from those in resort and natural ones. These pollinators visited 30 plant species in total, although some invasive plants hosted the highest number of flower visitor species. Biogeographically, this pollinating fauna is mostly shared with Sri Lanka and India. Genetically, the used marker hinted for a unique fauna in relation to the rest of the distribution ranges in most cases, although generally within the level of intraspecific genetic variation. This study significantly contributes to increasing the knowledge on the pollinator diversity and genetic identity in Maldives islands also considering the important implications for the islands' land-use and the role of invasive plants. This study will be pivotal for future pollination studies and biodiversity conservation efforts in the region.

We investigate and characterize the emergence of finite-component dissipative phase transitions (DPTs) in nonlinear photon resonators subject to $n$-photon driving and dissipation. Exploiting a semiclassical approach, we derive general results on the occurrence of second-order DPTs in this class of systems. We show that for all odd $n$, no second-order DPT can occur while, for even $n$, the competition between higher-order nonlinearities determines the nature of the criticality and allows for second-order DPTs to emerge only for $n=2$ and $n=4$. As pivotal examples, we study the full quantum dynamics of three- and four-photon driven-dissipative Kerr resonators, confirming the prediction of the semiclassical analysis on the nature of the transitions. The stability of the vacuum and the typical timescales needed to access the different phases are also discussed. We also show a first-order DPT where multiple solutions emerge around zero, low, and high-photon numbers. Our results highlight the crucial role played by $strong$ and $weak$ symmetries in triggering critical behaviors, providing a Liouvillian framework to study the effects of high-order nonlinear processes in driven-dissipative systems, that can be applied to problems in quantum sensing and information processing.

The pathophysiology of tremor in Parkinson’s disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um2, p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic–rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients.

In this work we characterize the false vacuum decay in the ferromagnetic quantum Ising chain with a weak longitudinal field subject to continuous monitoring of the local magnetization. Initializing the system in a metastable state, the false vacuum, we study the competition between coherent dynamics, which tends to create resonant bubbles of the true vacuum, and measurements which induce heating and reduce the amount of quantum correlations. To this end we exploit a numerical approach based on the combination of matrix product states with stochastic quantum trajectories which allows for the simulation of the trajectory-resolved non-equilibrium dynamics of interacting many-body systems in the presence of continuous measurements. We show how the presence of measurements affects the false vacuum decay: At short times the departure from the local minimum is accelerated while at long times the system thermalizes to an infinite-temperature incoherent mixture. For large measurement rates the system enters a quantum Zeno regime. The false vacuum decay and the thermalization physics are characterized in terms of the magnetization, connected correlation function, and the trajectory-resolved entanglement entropy.

Oxytocin (OT) is a neuropeptide widely known for its peripheral hormonal effects (i.e., parturition and lactation) and central neuromodulatory functions, related especially to social behavior and social, spatial, and episodic memory. The hippocampus is a key structure for these functions, it is innervated by oxytocinergic fibers, and contains OT receptors (OTRs). The hippocampal OTR distribution is not homogeneous among its subregions and types of neuronal cells, reflecting the specificity of oxytocin’s modulatory action. In this review, we describe the most recent discoveries in OT/OTR signaling in the hippocampus, focusing primarily on the electrophysiological oxytocinergic modulation of the OTR-expressing hippocampal neurons. We then look at the effect this modulation has on the balance of excitation/inhibition and synaptic plasticity in each hippocampal subregion. Additionally, we review OTR downstream signaling, which underlies the OT effects observed in different types of hippocampal neuron. Overall, this review comprehensively summarizes the advancements in unraveling the neuromodulatory functions exerted by OT on specific hippocampal networks.

Increasing evidence suggests that early neurodevelopmental defects in Huntington's disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD.

This paper presents a survey of innovative concepts and technologies involved in virtual museums (ViM) that shows their advantages and disadvantages in comparison with physical museums. We describe important lessons learned during the creation of three major virtual museums between 2010 and 2020 with partners at universities from Armenia, Germany, and Chile. Based on their categories and features, we distinguish between content-, communication- and collaboration-centric museums with a special focus on learning and co-curation. We give an overview of a generative approach to ViMs using the ViMCOX metadata format, the curator software suite ViMEDEAS, and a comprehensive validation and verification management. Theoretical considerations include exhibition design and new room concepts, positioning objects in their context, artwork authenticity, digital instances and rights management, distributed items, private museum and universal access, immersion, and tour and interaction design for people of all ages. As a result, this survey identifies different approaches and advocates for stakeholders’ collaboration throughout the life cycle in determining the ViM's direction and evolution, its concepts, collection type, and the technologies used with their requirements and evaluation methods. The paper ends with a brief perspective on the use of artificial intelligence in ViMs.

Food systems in Europe are largely unjust and not sustainable. Despite substantial negative consequences for individual health, the environment and public sector health and care services, large multi-national corporations continue to benefit from the way food systems are designed—perpetuating “Lose–Lose–Lose–Win” food systems that see these large corporations benefit at the expense of health, the environment and public sector finances. Transitioning to “Win–Win–Win–Win” food systems is challenging because of the heterogeneity, complexity and unpredictable nature of food systems—one-size fits-all solutions to correct imbalances and injustices cannot exist. To address these challenges, we propose the use of heuristics—solutions that can flexibly account for different contexts, preferences and needs. Within food systems, food democracy could be a heuristic solution that provides the processes and can form the basis for driving just transitions. However, ensuring that these transition processes are fair, equitable, sustainable and constructive, requires an approach that can be used across vertical and horizontal governance spheres to ensure the voices of key stakeholders across space, time and spheres of power are accounted for. In this manuscript we outline a new Horizon project, FEAST, that aims to use multilevel governance approaches across vertical and horizontal spheres of governance to realize constructive food democracy. We envisage this as a means to inform just processes that can be used to design and implement policies, in line with food democracy, to facilitate transitions to “Win–Win–Win–Win” food systems across Europe that makes it easy for every European to eat a healthy and sustainable diet.

Although the study of the affective components involved in predicting physical activity is spreading faster and faster, there is a lack of studies testing their role when promoting physical activity through message interventions. In the present study, we considered these components by focusing on how anticipated affective reactions and emotional processing of the messages influence receivers’ affective attitude toward physical activity, concurrent behavior, and future intention. A sample of 250 participants was involved in an intervention relying on prefactual (i.e., “If … then…”) messages promoting physical activity. All messages were sent through a research app and were focused on the expected consequences of exercising (or not exercising). Four experimental conditions involving messages differing as to their outcome sensitivity framing (i.e., gain, non-loss, non-gain, and loss) were compared to a control condition. Results showed that reading gain and non-gain messages enhanced the positive affective attitude toward physical activity, compared to control. Enhanced affective attitude after the intervention increased, in turn, self-reported physical activity and future intention. Interestingly, gain messages were even more persuasive for people with a low level of positive anticipated affective reactions. Furthermore, their effectiveness was especially attributable to the elicitation of hope in receivers. Discussion focuses on the advantages of considering affective components and their implications when promoting physical activity.

Climate change is increasingly affecting mountain communities around the world with major implications for human livelihoods and wellbeing. With its predominantly rural population and limited resources, the Indian Himalayan Region is particularly vulnerable. While previous research has highlighted the destructive potential of climate change, we focused on the socioeconomic and ecological drivers of climate vulnerabilities and their links to migration and depopulation trends, which can be observed in the area. A mixed-methods case study approach was used to explore these relationships in the state of Uttarakhand in the western Indian Himalayan Region. Combining evidence from an aggregate vulnerability index, migration data, and insights from qualitative interviews, we found a close link between local climate vulnerabilities and migration. Considering different drivers, we show that limited adaptive capacities are the decisive factor shaping vulnerabilities and migration in the region, in particular, the high dependency on rainfed agriculture together with ecological, infrastructural, human, and financial constraints. With higher vulnerability, migrants tend to become younger, engage more in short-term migration, and increasingly employ migration in response to structural vulnerabilities and livelihood risks. The outmigration of young males has major implications for their origin communities, as the population left behind becomes older and more feminized.

Objective: to assess the relationship between anthropometric indicators and laboratorial markers of cardiovascular risk in overweight/obese children and adolescents, in order to verify whether any anthropometric indicator has a better potential for use in screening cardiovascular risk in the population. Method: retrospective cross-sectional study enrolling 237 individuals aged 7 to 18 years. Body mass index (BMI), waist circumference (WC), waist circumference/height index (WC/H), glucose, HOMA-IR, total cholesterol (TC), LDL, HDL, triglycerides and TC/HDL and LDL/HDL indexes were obtained. Associations between anthropometric and laboratory markers were tested in contingency tables using the chi-square test. Correlations were tested by Spearman's correlation. Results: higher WC (Freedman cutoffs) was associated with lower levels of HDL and higher score in the TC/HDL and LDL/HDL indexes, but, using +2 z-scores as the cutoff, there were associations with low HDL and higher HOMA-IR. WC/H indicator (0.5 cutoff) was not associated with any of the outcomes, but, using +2 z-scores, an association was found with HOMA-IR. Z-scores of WC, WC/H and BMI showed positive correlation with HOMA-IR, TC/HDL and HOMA-IR, respectively. Negative correlations were found between WC and WC/H z-scores with HDL. WC and WC/H z-score were related to changes in HDL and HOMA-IR. Conclusions: there seems to be an advantage in using WC alone as a possible predictor of dyslipidemia and insulin resistance in children and adolescents. It is not possible to state that WC, WC/H or BMI measurements differ in their abilities to identify Brazilian children and adolescents with risk factors for cardiovascular diseases.

Abstract A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre‐symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol‐loaded brain‐permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini‐pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate‐controlled manner. All tested doses prevented cognitive decline, while amelioration of disease‐related motor defects was dose‐dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose‐dependent, disease‐modifying effect and may be therapeutically relevant in HD.

This paper presents an overview of various types of virtual museums (ViM) as native artifacts or as digital twins (DT) of physical museums (PM). Depending on their mission and features, we discuss various enabling technologies and sensor equipment with their specific requirements and complexities, advantages and drawbacks in relation to each other at all stages of a DT’s life cycle. A DT is a virtual construct and embodies innovative concepts based on emerging technologies (ET) using adequate sensor configurations for (meta-)data import and exchange. Our keyword-based search for articles, conference papers, (chapters from) books and reviews yielded 43 contributions and 43 further important references from Industry 4.0, Tourism and Heritage 4.0. After closer examination, a reference corpus of 40 contributions was evaluated in detail and classified along with their variants of DT—content-, communication-, and collaboration-centric and risk-informed ViMs. Their system features correlate with different application areas (AA), new or improved technologies—mostly still under development—and sensors used. Our proposal suggests a template-based, generative approach to DTs using standardized metadata formats, expert/curator software and customers’/visitors’ engagement. It advocates for stakeholders’ collaboration as part of a comprehensive validation and verification assessment (V&VA) throughout the DT’s entire life cycle.

In the last years, the international guidelines encourage the reduction of food waste or processing by-products to promote a circular economy approach. Winemaking represents one of the sectors with the highest by-products generation, with several potential negative impact on the environment. Winemaking by-products are mainly used to produce distillates or fertilizers, but the interest in grape pomaceas a potential source of phenolic compounds has considerably increased. The aim of this study was the application of in vitro methods for the characterization of the phenolic fraction of winemaking by-products from different red grape varieties, and, in parallel, the evaluation of their antioxidant activity. The methods were: 1) Folin-Cocalteau's assay for the quantification of total polyphenol content; 2) the vanillin assay for the assessment of total flavan-3-ols (proanthocyanidins) content; 3) the pH differential method for the quantification of total anthocyanin content; 4) DPPH assay for the measurement of total antioxidant activity; 5) High Performance Thin Layer Chromatography for separation of phenolic substances and assessment of their antioxidant activity. Although a significant differences among varieties, grape pomace, particularly when containing seeds, are generally a good source of polyphenols with a significant antioxidant activity supporting itsuse in formulating healthy products.

Inflammation and oxidative stress are two mechanisms involved in the pathogenesis of celiac disease (CD). Since the direct effect of gliadin on the intestinal epithelia is less studied, the aims of this study were the development of a specific cellular model based on the use of gliadin as a pro-inflammatory stimulus and the evaluation of the potential antioxidant and anti-inflammatory properties of extracts from different black rice in the framework of CD. The rice extracts were in vitro digested, characterized in terms of phenolic compounds and antioxidant capacity, and tested on Caco-2 cells to investigate their inhibitory effect on Reactive Oxygen Species, the NF-κB transcription and the CXC chemokines (sICAM-1, IL-8, and CXCL-10). In addition, the role of the extracts in modulating the activation of epithelial cells in CD was confirmed by applying the K562(S) agglutination test. The black rice extracts showed inhibitory effects on the production of the oxidative and the inflammatory mediators considered, with particular reference to lymphocyte-attracting CXCL-10 both before and after digestion. The presence of anthocyanins and their digestion metabolites may account for the observed anti-inflammatory activity after in vitro digestion. This work provided preliminary data supporting the use of black rice as a healthy food or ingredient of food supplements for celiacs.

The perirhinal cortex (PRC) is a polymodal associative region of the temporal lobe that works as a gateway between cortical areas and hippocampus. In recent years, an increasing interest arose in the role played by the PRC in learning and memory processes, such as object recognition memory, in contrast with certain forms of hippocampus-dependent spatial and episodic memory. The integrative properties of the PRC should provide all necessary resources to select and enhance the information to be propagated to and from the hippocampus. Among these properties, we explore in this paper the ability of the PRC neurons to amplify the output voltage to current input at selected frequencies, known as membrane resonance. Within cerebral circuits the resonance of a neuron operates as a filter toward inputs signals at certain frequencies to coordinate network activity in the brain by affecting the rate of neuronal firing and the precision of spike timing. Furthermore, the ability of the PRC neurons to resonate could have a fundamental role in generating subthreshold oscillations and in the selection of cortical inputs directed to the hippocampus. Here, performing whole-cell patch-clamp recordings from perirhinal pyramidal neurons and GABAergic interneurons of GAD67-GFP+ mice, we found, for the first time, that the majority of PRC neurons are resonant at their resting potential, with a resonance frequency of 0.5–1.5 Hz at 23°C and of 1.5–2.8 Hz at 36°C. In the presence of ZD7288 (blocker of HCN channels) resonance was abolished in both pyramidal neurons and interneurons, suggesting that Ih current is critically involved in resonance generation. Otherwise, application of TTx (voltage-dependent Na+ channel blocker) attenuates the resonance in pyramidal neurons but not in interneurons, suggesting that only in pyramidal neurons the persistent sodium current has an amplifying effect. These experimental results have also been confirmed by a computational model. From a functional point of view, the resonance in the PRC would affect the reverberating activity between neocortex and hippocampus, especially during slow wave sleep, and could be involved in the redistribution and strengthening of memory representation in cortical regions.