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We propose probabilistic logic factored Markov decision processes (PL-fMDPs) as a behavior selection scheme for self-driving cars. Probabilistic logic combines logic programming with probability theory to achieve clear, rule-based knowledge descriptions of multivariate probability distributions, and a flexible mixture of deductive and probabilistic inferences. Factored Markov decision processes (fMDPs) are widely used to generate reward-optimal action policies for stochastic sequential decision problems. For evaluation, we developed a simulated self-driving car with reliable modules for behavior selection, perception, and control. The behavior selection module is composed of a two-level structure of four action policies obtained from PL-fMDPs. Three main tests were conducted focused on the selection of the appropriate actions in specific driving scenarios, and the overtaking of static obstacle vehicles and dynamic obstacle vehicles. We performed 520 repetitions of these tests. The self-driving car completed its task without collisions in 99.2% of the repetitions. Results show the suitability of the overall self-driving strategy and PL-fMDPs to construct safe action policies for self-driving cars.

Abstract Cystathionine γ-lyase (CTH) is a critical enzyme in the reverse transsulfuration pathway, the major route for the metabolism of sulfur-containing amino acids, notably converting cystathionine to cysteine. We reported that CTH supports gastritis induced by the pathogen Helicobacter pylori. Herein our aim was to investigate the role of CTH in colonic inflammation. First, we found that CTH is induced in the colon mucosa in mice with dextran sulfate sodium-induced colitis. Expression of CTH was completely absent in the colon of Cth –/– mice. We observed that clinical and histological parameters are ameliorated in Cth-deficient mice compared to wild-type animals. However, Cth deletion had no effect on tumorigenesis and the level of dysplasia in mice treated with azoxymethane-DSS, as a reliable model of colitis-associated carcinogenesis. Mechanistically, we determined that the deletion of the gene Slc7a11 encoding for solute carrier family 7 member 11, the transporter of the anionic form of cysteine, does not affect DSS colitis. Lastly, we found that the richness and diversity of the fecal microbiota were significantly increased in Cth –/– mice compared to both WT and Slc7a11 –/– mice. In conclusion, our data suggest that the enzyme CTH represents a target for clinical intervention in patients with inflammatory bowel disease, potentially by beneficially reshaping the composition of the gut microbiota.

Backgound/Objectives: Cycle threshold (Ct) values of SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction (RT-PCR) tests are associated with infectivity and viral load, and they could be an aid in forecasting the evolution of SARS-CoV-2 outbreaks. The objective was to know the Ct values related to the incidence and reinfection of SARS-CoV-2 in successive outbreaks, which took place in nursing homes in Castellon (Spain) during 2020–2022, and to test its usefulness as an instrument of epidemic surveillance in nursing homes. Methods: a retrospective cohort design with Poisson regression and multinomial logistic regression were used. Results: We studied four nursing home SARS-CoV-2 outbreaks, and the average infection rate, reinfection rate, and case fatality were 72.7%, 19.9%, and 5.5%, respectively; 98.9% of residents were vaccinated with three doses of a mRNA SARS-CoV-2 vaccine. Ct values for first infections and reinfections were 27.1 ± 6.6 and 31.9 ± 5.4 (p = 0.000). Considering Ct values ≥ 30 versus

This study aimed to investigate the effect of different forage sources and forage-to-concentrate ratios on digestibility, energy concentration, fermentation parameters, and in vitro estimate of methane. The experiment was carried out in a completely randomized design using a 3 × 6 factorial arrangement with three forages varying the chemical composition (pineapple crop waste silage [PS], corn silage [CS], and Tifton hay [TH]) associated with concentrate feed (C) in six combinations, using triplicates for each ratio. We evaluated in vitro digestibility, metabolizable and net energy, pH, redox potential, volatile fatty acids (VFA), and methane production. The in vitro neutral detergent fiber digestibility (IVNDFD) decreased (p = 0.0011) with the inclusion of concentrate. It was also affected by the forage source, but this fact was only observed in CS up to the 50:50 ratio. In TH, this fact occurred from the 80:20 ratio, and this behavior was not observed in the PS. Data on methane production, VFA, and fermentation parameters varied according to forage source and concentrate inclusion. In conclusion, the inclusion of concentrate reduces methane production, increasing the system’s energy contribution. Overall, the different forage sources and the inclusion of concentrate change digestion and fermentation parameters.

Background: Aortic valve stenosis (AVS) is a common valvular heart disease affecting millions of people worldwide. It leads to significant neurocognitive and neuropsychological impairments, impacting patients’ quality of life. Objective: The objective of this article is to identify and discuss the potential neurocognitive effects on patients with aortic stenosis before and after undergoing surgical aortic valve replacement (SAVR). Method: Our study involved the assessment of 64 patients undergoing aortic valve replacement (SAVR) using a neurocognitive evaluation comprising a battery of 11 different cognitive tests. These tests were designed to analyze the patients’ overall cognitive functioning, executive abilities, short- and long-term memory, and attentional performance. The tests were administered to patients before the aortic valve surgery (T0) and after the surgery (T1). From a statistical perspective, numerical variables are presented as means (±standard deviation) and medians (IQR), while categorical variables are presented as counts and percentages. Normality was assessed using the Shapiro–Wilk test. T0 and T1 scores were compared with the Wilcoxon signed rank test, with p < 0.05 considered significant. Analyses were performed using SAS version 9.4. Results: Conducted as part of a fully financed Italian Ministry of Health project (RF-2016-02361069), the study found that most patients showed normal cognitive functioning at baseline. Cognitive assessments showed that executive functions, attention, language, and semantic knowledge were within the normal range for the majority of participants. After SAVR, cognitive outcomes remained stable or improved, particularly in executive functions and language. Notably, verbal episodic memory demonstrated significant improvement, with the percentage of patients scoring within the normal range on the BSRT increasing from 73.4% at T0 to 92.2% at T1 (p < 0.0001). However, visuospatial and visuoconstructive abilities showed stability or slight decline, while attentional skills remained relatively stable. The Clock Drawing Test indicated the maintenance of cognitive functions. Conclusions: The findings of our study indicate a global stability in cognitive status among patients after undergoing SAVR, with significant improvement noted in verbal episodic memory. While other cognitive domains did not demonstrate statistically significant changes, these insights are valuable for understanding the cognitive effects of SAVR and can guide future research and clinical practice in selecting the most effective surgical and rehabilitative options for patients. Monitoring cognitive outcomes in patients undergoing aortic valve replacement surgery remains crucial.

Background: In the transition to a professional learning environment, healthcare professionals in their first year of specialized postgraduate clinical training (known as residents in Spain) are suddenly required to handle confidential information with little or no prior training in the safe and appropriate use of digital media with respect to confidentiality issues. The aims of this study were: (1) to explore the usefulness of an advanced clinical simulation program for educating residents from different healthcare disciplines about confidentiality and the dissemination of clinical data or patient images; (2) to explore the use of social networks in healthcare settings; and (3) to explore participants’ knowledge and attitudes on current regulations regarding confidentiality, image dissemination, and the use of social networks; Methods: This was a cross-sectional study. Data were collected from all 49 first-year residents of different health professions at a Spanish hospital between June and August 2022. High-fidelity clinical simulation sessions designed to address confidentiality and health information dissemination issues in hospital settings, including the use of social networks, were developed and implemented. Data were assessed using a 12-item ad hoc questionnaire on confidentiality and the use of social media in the healthcare setting. Descriptive of general data and chi-square test or Fisher’s exact test were performed using the SPSS 25.0 software; Results: All the participants reported using the messaging application WhatsApp regularly during their working day. A total of 20.4% of the participants stated that they had taken photos of clinical data (radiographs, analyses, etc.) without permission, with 40.8% claiming that they were unaware of the legal consequences of improper access to clinical records. After the course, the participants reported intending to modify their behavior when sharing patient data without their consent and with respect to how patients are informed; Conclusions: The use of advanced simulation in the training of interprofessional teams of residents is as an effective tool for initiating attitudinal change and increasing knowledge related to patient privacy and confidentiality. Further follow-up studies are needed to see how these attitudes are incorporated into clinical practice.

Reducing carbon emissions is a critical issue for the near future as climate change is an imminent reality. To reduce our carbon footprint, society must change its habits and behaviours to optimise energy consumption, and the current progress in embedded systems and artificial intelligence has the potential to make this easier. The smart building concept and intelligent energy management are key points to increase the use of renewable sources of energy as opposed to fossil fuels. In addition, cyber-physical systems (CPSs) provide an abstraction of the management of services that allows the integration of both virtual and physical systems in a seamless control architecture. In this paper, we propose to use multiagent reinforcement learning (MARL) to model the CPS services control plane in a smart house, with the purpose of minimising, by shifting or shutdown services, the use of non-renewable energy (fuel generator) by exploiting solar production and batteries. Furthermore, our proposal dynamically adapts its behaviour in real time according to current and historic energy production, thus being able to handle occasional changes in energy production due to meteorological phenomena or unexpected energy consumption. In order to evaluate our proposal, we have developed an open-source smart building energy simulator and deployed our use case. Finally, several simulations with different configurations are evaluated to verify the performance. The simulation results show that the reinforcement learning solution outperformed the priority-based and the heuristic-based solutions in both power consumption and adaptability in all configurations.

Considerada por la crítica especializada como el primer testimonio literario peninsular (1774) en torno a una juega flamenca, el texto de Cadalso, además de configurar una detallada descripción costumbrista, después desarrollada en las Escenas andaluzas (1847) de Estébanez Calderón, añade una reflexión moral final muy negativa en torno a este tipo de manifestaciones populares. Todo ello dentro de la dura dialéctica en torno al problema de la educación de la juventud que sacude el pretendido proceso modernizador de la Ilustración. Un estigma que va a perdurar a lo largo del tiempo donde se asocian los estereotipos flamencos, en cuanto manifestación primitiva y bárbara, a la incultura y el atraso español.

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Abstract Introduction To compare the long-term efficacy of navigated subthreshold micropulse laser (NSML) and continuous oral eplerenone (EPL) in chronic central serous chorioretinopathy (cCSC). Methods This retrospective observational study included 44 eyes with cCSC (EPL: n = 26; NSML: n = 18). Best-corrected visual acuity (BCVA), central macular thickness (CMT), subretinal fluid (SRF) height, and subfoveal choroidal thickness (SFCT) were evaluated over 12 months. Results Both groups showed significant improvements in BCVA and CMT (p 0.05). Conclusions Both NSML and EPL improved retinal morphology and visual function in patients with cCSC. NSML achieved faster SRF resolution, while EPL resulted in more significant choroidal thickness reduction. These findings suggest distinct mechanisms of action: NSML primarily affects the retinal pigment epithelium, while EPL modulates choroidal vasculature. Treatment choice may depend on individual patient characteristics and treatment goals.

Abstract Aims The use of loop diuretics in pulmonary arterial hypertension (PAH) is less frequent compared with heart failure. The clinical and prognostic characteristics of PAH patients according to loop diuretic use remain unexplored. In this study, we retrospectively analysed the characteristics and survival of PAH patients requiring different doses of loop diuretics. Methods and results Patients diagnosed with PAH between 2001 and 2022 at seven European centres for the management of PAH. According to the median equivalent dose of furosemide in the overall cohort, patients were divided into two subgroups: no/low‐dose loop diuretic and high‐dose loop diuretic. Primary outcome was 5 year all‐cause mortality. Among the 397 patients included, 227 (57%) were treated with loop diuretics. Median daily furosemide equivalent dose was 25 mg, and accordingly patients were divided in no/low dose (i.e. ≤25 mg, n = 257, 65%) vs. high dose (i.e. >25 mg, n = 140, 35%). Patients in the high‐dose group were older, more likely to have comorbidities, and had a more severe disease according to the ESC/ERS risk category. Crude 5 year survival was significantly shorter in patients in the high‐dose group, but after adjustment for age, sex, and risk category, high loop diuretic dose was not significantly associated with the primary outcome. Conclusions Use of high dose of loop diuretics in PAH is associated with a higher burden of comorbidities, more severe disease, and worse survival. However, in PAH, the need of high loop diuretic dose is a marker of disease severity and not an independent prognostic factor.

Background and objective: Patients diagnosed with grade group (GG) 1 prostate cancer (PCa) following treatment for benign disease (“incidental” PCa) are typically managed with active surveillance (AS). It is not known how their outcomes compare with those observed in patients diagnosed with GG1 on biopsy. We aimed at determining whether long-term oncologic outcomes of AS for patients with GG1 PCa differ according to the type of diagnosis: incidental versus biopsy detected. Methods: A retrospective, multi-institutional analysis of PCa patients with GG1 on AS at eight institutions was conducted. Competing risk analyses estimated the incidence of metastases, PCa mortality, and conversion to treatment. As a secondary analysis, we estimated the risk of GG ≥2 on the first follow-up biopsy according to the type of initial diagnosis. Key findings and limitations: A total of 213 versus 1900 patients with incidental versus biopsy-diagnosed GG1 were identified. Patients with incidental cancers were followed with repeated biopsies and multiparametric magnetic resonance imaging less frequently than those diagnosed on biopsy. The 10-yr incidence of treatment was 22% for incidental cancers versus 53% for biopsy (subdistribution hazard ratio [sHR] 0.34, 95% confidence interval [CI] 0.26–0.46, p

Abstract Background Exercise is widely considered to have beneficial impact on skeletal muscle aging. In addition, there are also several studies demonstrating a positive effect of exercise on muscular dystrophies. Oculopharyngeal muscular dystrophy (OPMD) is a late‐onset autosomal dominant inherited neuromuscular disorder caused by mutations in the PAPBN1 gene. These mutations consist in short (1‐8) and meiotically stable GCN trinucleotide repeat expansions in its coding region responsible for the formation of PAPBN1 intranuclear aggregates. This study aims to characterize the effects of two types of chronic exercise, resistance and endurance, on the OPMD skeletal muscle phenotype using a relevant murine model of OPMD. Methods In this study, we tested two protocols of exercise. In the first, based on endurance exercise, FvB (wild‐type) and A17 (OPMD) mice underwent a 6‐week‐long motorized treadmill protocol consisting in three sessions per week of running 20 cm/s for 20 min. In the second protocol, based on resistance exercise generated by chronic mechanical overload (OVL), surgical removal of gastrocnemius and soleus muscles was performed, inducing hypertrophy of the plantaris muscle. In both types of exercise, muscles of A17 and FvB mice were compared with those of respective sedentary mice. For all the groups, force measurement, muscle histology, and molecular analyses were conducted. Results Following the endurance exercise protocol, we did not observe any major changes in the muscle physiological parameters, but an increase in the number of PABPN1 intranuclear aggregates in both tibialis anterior (+24%, **P = 0.0026) and gastrocnemius (+18%, ****P

Abstract Objective Rare and complex epilepsies encompass a diverse range of disorders characterized by seizures. We aimed to establish a consensus on key issues related to these conditions through collaboration among experienced neurologists, neuropediatricians, and patient advocacy representatives. Methods Employing a modified Delphi method, a scientific board comprising 20 physicians and 4 patient advocacy representatives synthesized existing literature with their expertise to formulate statements on contentious topics. A final 32‐member expert panel, representing diverse regions of Italy, validated these statements through a two‐round voting process, with consensus defined as an average score ≥7. Results Sixteen statements reached a consensus, emphasizing the necessity for epidemiological studies to ascertain the true prevalence of rare epilepsies. Etiology emerged as a crucial factor influencing therapeutic strategies and outcome prediction, with particular concern regarding prolonged and tonic–clonic seizures. The importance of early implementation of specific drugs and non‐pharmacological interventions in the treatment algorithm for developmental and epileptic encephalopathies (DEEs) was underscored. Multidisciplinary care involving experts with diverse skills was deemed essential, emphasizing non‐seizure outcomes in adolescence and adulthood. Significance This national consensus underscores the imperative for personalized, comprehensive, and multidisciplinary management of rare epilepsies/DEEs. It advocates for increased research, particularly in epidemiology and therapeutic approaches, to inform clinical decision‐making and healthcare policies, ultimately enhancing patients' outcomes. Plain Language Summary The modified Delphi method is broadly used to evaluate debated topics. In this work, we sought the consensus on integrated and social care in epilepsy management. Both representatives of high‐level epilepsy centers and patients' caregivers were directly involved.

Abstract We investigate a field-theoretical model that describes the interaction between kinks and antikinks and between kinks and other heterogeneous fields and impurities. We show that the long-range kink can tunnel through a barrier created by heterogeneous fields and impurities even when the energy of the center of mass of the kink is less than the height of the energy barrier. We also study the conditions under which the kink can pass freely through a disordered medium. We introduce the concept of “effective translational symmetry”. We compare our results with those from recent papers published in this journal, where the Bogomol’nyi-Prasad-Sommerfield property is discussed.

Abstract Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic disease associated with its principal tick vector, Hyalomma spp. with increasing fatal incidence worldwide. Accordingly, CCHF is a World Health Organization-prioritized disease with the absence of effective preventive interventions and approved vaccines or effective treatments. This perspective raised from a multidisciplinary gap analysis considering a One Health approach beneficial for human and animal health and the environment exploring international collaborations, gaps and recommendations.

Abstract Climate change is currently one of humanity’s greatest threats. To help scholars understand the psychology of climate change, we conducted an online quasi-experimental survey on 59,508 participants from 63 countries (collected between July 2022 and July 2023). In a between-subjects design, we tested 11 interventions designed to promote climate change mitigation across four outcomes: climate change belief, support for climate policies, willingness to share information on social media, and performance on an effortful pro-environmental behavioural task. Participants also reported their demographic information (e.g., age, gender) and several other independent variables (e.g., political orientation, perceptions about the scientific consensus). In the no-intervention control group, we also measured important additional variables, such as environmentalist identity and trust in climate science. We report the collaboration procedure, study design, raw and cleaned data, all survey materials, relevant analysis scripts, and data visualisations. This dataset can be used to further the understanding of psychological, demographic, and national-level factors related to individual-level climate action and how these differ across countries.

Abstract Background The potential efficacy of early combination therapy, based on an antiviral plus a monoclonal antibody, for COVID-19 in severely immunocompromised patients is matter of debate. Objectives Our aim was to describe the impact on clinical outcomes of COVID-19 treatments in severely immunocompromised individuals, evaluating differences between a combination and a monotherapy. Methods We included severely immunocompromised outpatients with mild-to-moderate COVID-19 who received an early treatment (either monotherapy with nirmatrelvir/ritonavir or remdesivir or the combination of an antiviral plus sotrovimab). We then assessed differences between the two treatment strategies on three main outcomes (30-day mortality, access to emergency department, hospitalization), separately and as a composite by using a propensity score weighted (PSW) approach. Results Eighty one severely immunocompromised patients were included, 39 receiving early combination therapy and 42 receiving monotherapy. No significant difference was observed in the 30-day mortality rate and hospitalization rate between subjects in the two groups, while access to the emergency department following treatment administration was significantly higher in people who received a combination therapy. After applying the PSW, it was observed that combination therapy impacted favourably on the composite outcome, in a statistically significant fashion. In addition, PSW approach for mortality showed that age was the only significant factor influencing the death as stand-alone outcome. Conclusions Early combination therapy showed a favourable impact on a composite outcome (including mortality, hospitalizations and access to emergency department) in severely immunocompromised hosts who were all vaccinated. However, further studies are needed to support our results.

Abstract Extensive genetic studies have elucidated cardiomyocyte differentiation and associated gene networks using single-cell RNA-seq, yet the intricate transcriptional mechanisms governing cardiac conduction system (CCS) development and working cardiomyocyte differentiation remain largely unexplored. Here we show that mice deleted for Dhx36 (encoding the Dhx36 helicase) in the embryonic or neonatal heart develop overt dilated cardiomyopathy, surface ECG alterations related to cardiac impulse propagation, and (in the embryonic heart) a lack of a ventricular conduction system (VCS). Heart snRNA-seq and snATAC-seq reveal the role of Dhx36 in CCS development and in the differentiation of working cardiomyocytes. Dhx36 deficiency directly influences cardiomyocyte gene networks by disrupting the resolution of promoter G-quadruplexes in key cardiac genes, impacting cardiomyocyte differentiation and CCS morphogenesis, and ultimately leading to dilated cardiomyopathy and atrioventricular block. These findings further identify crucial genes and pathways that regulate the development and function of the VCS/Purkinje fiber (PF) network.

Abstract We describe the geographical variation in tree species composition across Amazonian forests and show how environmental conditions are associated with species turnover. Our analyses are based on 2023 forest inventory plots (1 ha) that provide abundance data for a total of 5188 tree species. Within-plot species composition reflected both local environmental conditions (especially soil nutrients and hydrology) and geographical regions. A broader-scale view of species turnover was obtained by interpolating the relative tree species abundances over Amazonia into 47,441 0.1-degree grid cells. Two main dimensions of spatial change in tree species composition were identified. The first was a gradient between western Amazonia at the Andean forelands (with young geology and relatively nutrient-rich soils) and central–eastern Amazonia associated with the Guiana and Brazilian Shields (with more ancient geology and poor soils). The second gradient was between the wet forests of the northwest and the drier forests in southern Amazonia. Isolines linking cells of similar composition crossed major Amazonian rivers, suggesting that tree species distributions are not limited by rivers. Even though some areas of relatively sharp species turnover were identified, mostly the tree species composition changed gradually over large extents, which does not support delimiting clear discrete biogeographic regions within Amazonia.

Abstract To understand how oncogenes affect genome organization, it is essential to visualize fundamental processes such as DNA replication and transcription at high resolution in intact cells. At the same time, it is important to determine the progression of the cell along the cell cycle, as cell cycle regulation is crucial for the control of cell proliferation and oncogenesis. Here, we present a super-resolution imaging-based method to analyze single cell nuclei sorted according to specific phases of the cell cycle. The sorting is based on the evaluation of the number and the intensity of pixels in the replication foci image and the colocalization analysis is based on image cross-correlation spectroscopy (ICCS). We evaluate the colocalization between replication and transcription, at different cell cycle phases, in a model of PML-RARα oncogene activation. We find that colocalization between replication and transcription is higher in cells in early S phase compared to cells in middle and late S phase. When we turn on the PML-RARα oncogene, this colocalization pattern is preserved but we detect an increase of colocalization between replication and transcription in the early S phase which points to an effect of the PML-RARα oncogene on the coordination between replication and transcription.

Abstract Students play a key role in university social responsibility (USR), as they are the protagonists of change and the fundamental axis in the teaching-learning process. This study aims to assess the factors associated with the perception of university social responsibility among dental students from two universities in the Peruvian capital. This analytical cross-sectional study assessed 754 students from two Peruvian universities between May and July 2023. The study utilized a validated 51-item questionnaire to assess sociodemographic factors and dental students’ perception of USR. A Poisson regression model with robust variance and prevalence ratio (PR) was used to assess the influence of variables such as age, sex, marital status, type of university, academic year, and awareness of taking subjects related to USR. The significance was set at p

Abstract Owing to the maturity of complementary metal oxide semiconductor (CMOS) microelectronics, qubits realized with spins in silicon quantum dots (QDs) are considered among the most promising technologies for building scalable quantum computers. For this goal, ultra-low-power on-chip cryogenic CMOS (cryo-CMOS) electronics for control, read-out, and interfacing of the qubits is an important milestone. We report on-chip interfacing of tunable electron and hole QDs by a 64-channel cryo-CMOS multiplexer with less-than-detectable static power dissipation. We analyze charge noise and measure state-of-the-art addition energies and gate lever arm parameters in the QDs. We correlate low noise in QDs and sharp turn-on characteristics in cryogenic transistors, both fabricated with the same gate stack. Finally, we demonstrate that our hybrid quantum-CMOS technology provides a route to scalable interfacing of a large number of QD devices, enabling, for example, variability analysis and QD qubit geometry optimization, which are prerequisites for building large-scale silicon-based quantum computers.

Abstract Quantum technologies (QTs) hold the promise to transform a wide range of industries, such as computing, communications, finance, healthcare, defense, space, and beyond. Of the various QTs, the most relevant is presently quantum computing (QC), of significant projected market potential, with some estimates forecasting it to reach many billion dollars over the next few years. There are, however, risks to factor, as highlighted in this perspective, the most relevant technical, economic, and societal risks. Those financial and societal are projected to become increasingly relevant phased with the progressing solution of the technical issues. The synergy with artificial intelligence comes with further opportunities as development can be faster and more effective, but also increases risks. AI presents numerous opportunities, but it also comes with several risks and challenges. Some of the major risks associated with AI include bias and fairness, transparency and explainability, job displacement, security concerns, ethical concerns, privacy issues, lack of regulation and standards, and exponential growth and unintended consequences. Balancing the advantages of AI-driven quantum technologies with associated risks presents a significant challenge. It necessitates careful consideration of ethical, economic, and technical aspects to ensure that these technologies are developed and deployed in a manner that is beneficial and equitable for everyone. Graphical Abstract

Abstract Background Long-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD. Methods This retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported. Results Patients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients’ total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment. Conclusions The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations.

Abstract Background Liquid biopsy based on cell-free DNA (cfDNA) analysis holds significant promise as a minimally invasive approach for the diagnosis, genotyping, and monitoring of solid malignancies. Human tumors release cfDNA in the bloodstream through a combination of events, including cell death, active and passive release. However, the precise mechanisms leading to cfDNA shedding remain to be characterized. Addressing this question in patients is confounded by several factors, such as tumor burden extent, anatomical and vasculature barriers, and release of nucleic acids from normal cells. In this work, we exploited cancer models to dissect basic mechanisms of DNA release. Methods We measured cell loss ratio, doubling time, and cfDNA release in the supernatant of a colorectal cancer (CRC) cell line collection (N = 76) representative of the molecular subtypes previously identified in cancer patients. Association analyses between quantitative parameters of cfDNA release, cell proliferation, and molecular features were evaluated. Functional experiments were performed to test the impact of modulating DNA methylation on cfDNA release. Results Higher levels of supernatant cfDNA were significantly associated with slower cell cycling and increased cell death. In addition, a higher cfDNA shedding was found in non-CpG Island Methylator Phenotype (CIMP) models. These results indicate a positive correlation between lower methylation and increased cfDNA levels. To explore this further, we exploited methylation microarrays to identify a subset of probes significantly associated with cfDNA shedding and derive a methylation signature capable of discriminating high from low cfDNA releasers. We applied this signature to an independent set of 176 CRC cell lines and patient derived organoids to select 14 models predicted to be low or high releasers. The methylation profile successfully predicted the amount of cfDNA released in the supernatant. At the functional level, genetic ablation of DNA methyl-transferases increased chromatin accessibility and DNA fragmentation, leading to increased cfDNA release in isogenic CRC cell lines. Furthermore, in vitro treatment of five low releaser CRC cells with a demethylating agent was able to induce a significant increase in cfDNA shedding. Conclusions Methylation status of cancer cell lines contributes to the variability of cfDNA shedding in vitro. Changes in methylation pattern are associated with cfDNA release levels and might be exploited to increase sensitivity of liquid biopsy assays.

Abstract Over the past few decades, extensive research has been devoted to the design of artificial reverberation algorithms aimed at emulating the room acoustics of physical environments. Despite significant advancements, automatic parameter tuning of delay-network models remains an open challenge. We introduce a novel method for finding the parameters of a feedback delay network (FDN) such that its output renders target attributes of a measured room impulse response. The proposed approach involves the implementation of a differentiable FDN with trainable delay lines, which, for the first time, allows us to simultaneously learn each and every delay-network parameter via backpropagation. The iterative optimization process seeks to minimize a perceptually motivated time-domain loss function incorporating differentiable terms accounting for energy decay and echo density. Through experimental validation, we show that the proposed method yields time-invariant frequency-independent FDNs capable of closely matching the desired acoustical characteristics and outperforms existing methods based on genetic algorithms and analytical FDN design.

Abstract The stress that the space environment can induce on plant physiology is of both abiotic and biotic nature. The abiotic space environment is characterized by ionizing radiation and altered gravity, geomagnetic field (GMF), pressure, and light conditions. Biotic interactions include both pathogenic and beneficial interactions. Here, we provide an overall picture of the effects of abiotic and biotic space-related factors on plant physiology. The knowledge required for the success of future space missions will lead to a better understanding of fundamental aspects of plant physiological responses, thus providing useful tools for plant breeding and agricultural practices on Earth.

Abstract Purpose The purpose of this study is to investigate the impact of Mayo Adhesive Probability (MAP) score and body mass index (BMI) on renal function decline after robotic assisted partial nephrectomy (RAPN). Methods We queried our prospective database for patients who underwent RAPN between January 2018 and December 2023. Outcomes were development of de novo CKD‐S3 (estimated glomerular filtration rate [eGFR]

The presence of discontinuities (e.g. faults, fractures, veins, layering) in crystalline rocks can be challenging for seismic interpretations because the wide range of their size, orientation, and intensity, which controls the mechanical properties of the rock and elastic wave propagation, resulting in equally varying seismic responses at different scales. The geometrical characterisation of adjacent outcrop discontinuity networks allows a better understanding of the nature of the subsurface rocks and aids seismic interpretation. In this study, we characterise the discontinuity network of the Balmuccia peridotite (BP) in the Ivrea–Verbano Zone (IVZ), northwestern Italy. This geological body is the focus of the Drilling the Ivrea–Verbano zonE (DIVE), an international continental scientific drilling project, and two active seismic surveys, SEismic imaging of the Ivrea ZonE (SEIZE) and high-resolution SEIZE (Hi-SEIZE), which aim to resolve the subsurface structure of the DIVE drilling target through high-resolution seismic imaging. For fracture characterisation, we developed two drone-based digital outcrop models (DOMs) at two different resolutions (10−3–10 m and 10−1–103 m), which allowed us to quantitatively characterise the orientation, size, and intensity of the main rock discontinuities. These properties affect the seismic velocity and consequently the interpretation of the seismic data. We found that (i) the outcropping BP discontinuity network is represented by three more sets of fractures with respect to those reported in the literature; (ii) the discontinuity sizes follow a power-law distribution, indicating similarity across scales, and (iii) discontinuity intensity is not uniformly distributed along the outcrop. Our results help to explain the seismic behaviour of the BP detected by the SEIZE survey, suggesting that the low P-wave velocities observed can be related to the discontinuity network, and provide the basic topological parameters (orientation, density, distribution, and aperture) of the fracture network unique to the BP. These, in turn, can be used for interpretation of the Hi-SEIZE seismic survey and forward modelling of the seismic response.

Abstract We consider computing the on-shell disk action of open-closed string field theory as a gauge-invariant way of capturing the shift in D-brane tension that is induced by a deformation of the bulk CFT. We study the effect of bulk matter deformations (both marginal and relevant) on a wide range of boundary conditions in a number of CFTs up to subleading (two-loop) order in perturbation theory. In all analyzed examples, we find that the shift in the g-function of the matter boundary state is always accompanied by a boundary-independent shift in the string coupling constant, whose leading behaviour is universally proportional to the sphere two-point function of the deforming bulk operator.

Abstract The synthetic lethal effect observed with the use of PARP inhibitors (PARPi) with tumors characterized by the loss of key players in the homologous recombination (HR) pathway, commonly referred to as “BRCAness”, is maintaining high interest in oncology. While BRCAness is a well-established feature in breast, ovarian, prostate, and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HR deficiency (HRD) from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology 500 HRD (TSO500-HRD) panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM and RAD51C immunohistochemical analysis as part of our “composite biomarker approach” to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.

Abstract High heterogeneity in clinical benefit characterizes the use of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We prospectively enrolled 113 advanced NSCLC patients treated with ICIs and performed liquid biopsy at the time of ICI start (T1), after 3 weeks (T2) and at the time of radiological evaluation (T3). Molecular variables were associated with outcome endpoints: cfDNA quantification, its dynamic change (∆T2–T1), variant allele frequency (VAF) of the gene with the highest frequency detected at baseline with NGS (maxVAF) and its dynamic change (∆T2–T1). At multivariate analysis, PD-L1 negativity, T1 cfDNA, cfDNA increase (∆T2–T1), and T2 VAF were significantly associated with shorter progression-free survival (PFS); PD-L1 negativity, squamous histology, T1 cfDNA, cfDNA (∆T2–T1) increase, and T2 maxVAF affected overall survival (OS). Among high PD-L1 expressing patients treated in first-line, elevated T2 maxVAF and cfDNA increase (∆T2–T1) correlated with worse PFS; higher T2 maxVAF and cfDNA increase (∆T2–T1) with worse OS. Derived integrated models were used to build nomograms and categorize different risk groups.

Abstract In 2014, the World Health Organisation (WHO) published target product profiles (TPP) for development of novel tuberculosis (TB) diagnostics. One of the key highlights is the need for point-of-care non-sputum-based tests capable of detecting all forms of TB through identification of characteristic biomarkers or biosignatures. Compared to the limitations associated with sputum-based TB tests, non-sputum samples are easy to collect, non-invasive, with potential to improve TB diagnosis among children and among people living with HIV/AIDS (PLHIV). This review gives an overview of the existing evidence on TB diagnostic studies of non-sputum-based samples collected non-invasively from or through the oral–gastrointestinal tract (GI) and nasal pharynx regions of humans and the biomarkers detected. We further summarized evidence of these biomarkers and sample types from research done in paediatric and PLHIV. The review identified; saliva, cough aerosols, oral swabs, oral wash, dental plaque, tongue swabs, face mask sampling, exhaled breath, and stool, as the non-sputum samples investigated. These biomarkers can be categorized into Deoxyribose Nucleic Acid (DNA), Ribonucleic Acid (RNA), inflammatory, antigen–antibody, volatile and non-volatile compounds, microbiome and microbiota. The biomarkers identified were derived both from the host and pathogen. Similar biomarkers were identified in the general population, children and among PLHIV. These biomarkers have been detected by either already approved simple point of care or sophisticated devices. Differences in methodology and sample types investigated, small sample size of children and PLHIV populations, bias due to confounding factors, were some of the identified challenges in these studies. There is need to conduct larger and standardized multi centre studies to evaluate non-sputum-based biomarker-based tests in children and PLHIV.

Abstract The field of photonic integrated circuits has witnessed significant progress in recent years, with a growing demand for devices that offer high-performance reconfigurability. Due to the inability of conventional tunable directional couplers (TDCs) to maintain a fixed phase while tuning the reflectivity, Mach-Zehnder interferometers (MZIs) are employed as the primary building blocks for reflectivity tuning in constructing large-scale circuits. However, MZIs are prone to fabrication errors due to the need for perfect balanced directional couplers to achieve 0-1 reflectivity, which hinders their scalability. In this study, we introduce a design of a TDC based on coupling constant tuning in the thin film Lithium Niobate platform and present an optimized design. Our optimized TDC design enables arbitrary reflectivity tuning while ensuring a consistent phase across a wide range of operating wavelengths. Furthermore, it exhibits fewer bending sections than MZIs and is inherently resilient to fabrication errors in waveguide geometry and coupling length compared to both MZIs and conventional TDCs. Our work contributes to developing high-performance photonic integrated circuits with implications for various fields, including optical communication systems and quantum information processing.

Abstract Multiplexed local charge storage, close to quantum processors at cryogenic temperatures could generate a multitude of control signals, for electronics or qubits, in an efficient manner. Such cryogenic electronics require generating quasi-static control signals with small area footprint, low noise, high stability, low power dissipation and, ideally, in a multiplexed fashion to reduce the number of input/outputs. In this work, we integrate capacitors with cryogenic high-electron mobility transistor (HEMT) arrays and demonstrate quasi-static bias generation using gate pulses controlled in time and frequency domains. Multi-channel bias generation is also demonstrated. Operation at 4 K exhibits improved bias signal variability and greatly reduced subthreshold swing, reaching values of ~6 mV/decade. Due to the very low threshold voltage of 80 mV at 4 K and the steep subthreshold swing, these circuits can provide an advantage over the silicon-based complementary metal-oxide-semiconductor equivalents by allowing operation at significantly reduced drive bias in the low output voltage regime

Abstract The ultrashort and intense pulses of X-rays produced at X-ray free electron lasers (XFELs) have enabled unique experiments on the atomic level structure and dynamics of matter, with time-resolved studies permitted in the femto- and attosecond regimes. To fully exploit them, it is paramount to obtain a comprehensive understanding of the complex nonlinear interactions that can occur at such extreme X-ray intensities. Herein, we report on the experimental observation of a resonant double-core excitation scheme in N2, where two 1σ core-level electrons are resonantly promoted to unoccupied $$1{\pi }_{g}^{* }$$ 1 π g * molecular orbitals by a single few-femtosecond broad-bandwidth XFEL pulse. The production of these neutral two-site double core hole states is evidenced through their characteristic decay channels, which are observed in good agreement with high-level theoretical calculations. Such multi-core excitation schemes, benefiting from the high interaction cross sections and state- and site-selective nature of resonant X-ray interactions, should be generally accessible in XFEL irradiated molecules, and provide interesting opportunities for chemical analysis and for monitoring ultrafast dynamic processes.

Abstract Purpose The goal of this retrospective study was to perform a CT imaging assessment of thoracic pedicles to provide a representative understanding of pedicle morphology for pedicle-based fixation systems commonly used in orthopedics, trauma and neurosurgery. This study aimed to better understand the morphology of the spine and give spine surgeons a better understanding of thoracic spine anatomy. Methods In this study, we retrospectively measured the thoracic spine pedicles of a total of 16 males and 16 females, totaling in 768 individual pedicles. For the measurements, we used standardized planes in computed tomography imaging with a maximum slice thickness of 1 mm. Results In brief, we identified significant differences in various measurements of male and female pedicle morphology. The medial cortical wall of the pedicles was significantly thicker than the lateral wall, and, in both sexes, the thoracic vertebral body number four was the vertebra with the least amount of cortical bone in the pedicle. Conclusions Surgeons performing operations involving pedicle screw placement should be aware of the sex-specific differences in thoracic spine pedicle morphology noted in this research.

Abstract Objectives The purpose of this multicenter retrospective study was to perform a two-dimensional analysis of upper airway changes in adolescent patients following molar distalization with the Pendulum appliance. Materials and methods The study involved the cephalometric analysis of 88 patients, retrospectively categorized into two groups: skeletal Class II with a dental Class II molar relationship (36 patients, mean age 12.6 ± 1.1 years) and skeletal Class I with a dental Class II molar relationship (54 patients, mean age 12.3 ± 1.2 years). Changes were observed using lateral radiographs before (T0) and after Pendulum appliance removal (T1); treatment time averaged 7 months. Upper airways were subsequently analyzed by tracing lateral radiographs. The Shapiro-Wilk test showed a normal distribution of the data, therefore parametric tests were used for statistical analysis. Intragroup changes between T0 and T1 were evaluated using paired t-tests, and intergroup differences were assessed using independent student t-tests; statistical significance was set at 0.05. Results Statistically significant differences were observed in the skeletal measurements that characterized both groups, particularly in ANB and Wits appraisal, at T0 (P 0.05). Additionally, intergroup comparisons of airway changes at T1 did not show statistically significant differences (P > 0.05). Conclusions The Pendulum appliance does not significantly change the upper airway dimensions in Class I and Class II malocclusion patients, thereby minimizing potential respiratory risks.

Purpose The present study aimed to three-dimensionally evaluate the correlation between cephalometric measurements utilizing Sellion in place of Nasion.Material and methods A pilot study using 25 CBCTs was carried out to determine the required sample size, reaching a minimum of 136 patients was required to validate the correlation between Nasion(N)- and Sellion(Se)-related measurements. Eight landmarks were manually annotated on full cranium CBCTs, resulting in six skeletal and six cutaneous/skeletal measurements. Therefore, data were statistically analysed after outliers’ detection and intraclass correlation coefficient (ICC) calculation. Pearson correlation coefficient (r) was used to assess the correlation between Nasion and Sellion measurements. At the end, simple linear regression was performed. Values of p 0.80 were considered statistically and clinically relevant, respectively.Results ICC revealed a substantial degree of consistency. A total of 214 CBCTs were included in the present study. Pearson test revealed highly significant correlations for all the tested variables; the highest coefficient was found between N^Me^Go vs Se^Me^Go (r = 0.989, p

The aggregation of Amyloid-β (Aβ) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with Aβ species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the σ1 receptor chaperone and as σ1 agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the σ1 receptor. We report that Amylovis-201 is a potent σ1 agonist by several in silico, in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at σ1 receptors. Furthermore, we show for the first time that classical σ1 receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate Aβ25–35 fibrils. Interestingly, Amylovis-201 was the only compound inhibiting Aβ25–35 aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and σ1 receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.

Este trabajo articula una visión de larga duración explicando la compleja transformación de unas intensas relaciones mercantiles entre la cornisa cantábrica y Flandes a una vinculación de defensa militar de las posesiones hispanas fronterizas con Francia, en los Pirineos Occidentales y en el Flandes de finales del Seiscientos e inicios de la siguiente centuria. El rol estratégico de las provincias vascas como fuente de noticias públicas y privadas y principal regulador de la defensa de la frontera de finales del siglo XVII, junto a los estertores de Flandes como frente militar, se erigirá en la principal atalaya documental del trabajo. El uso de correspondencia privada e inédita enriquecerá el análisis de este momento de transformación histórica.

Abstract Hematological malignancies are associated with an increased risk of complications during SARS-CoV-2 infections. Primary series or monovalent booster vaccines reduce disease severity, hospitalization, and death among multiple myeloma patients. We characterized virus-neutralizing and spike-binding antibody profiles following monovalent (WA1) or bivalent (WA1/BA.5) SARS-CoV-2 booster vaccination in MM patients. Bivalent vaccination improved the breadth of binding antibodies but not neutralization activity against contemporary variants. Hybrid immunity and immune imprinting impact vaccine-elicited immunity.

Abstract Following up the previously published systematic review on the same topic and realizing that new studies and evidence had emerged on the matter, we conducted an update on the same research terms. With the objective of updating the information relating environmental risk factors on neurodegenerative diseases and the geographic approaches used to address them, we searched PubMed, Web of Science and Scopus for all scientific studies considering the following three domains: neurodegenerative disease, environmental atmospheric factor and geographical analysis, using the same keywords as in the previously published systematic review. From February 2020 to February 2023, 35 papers were included versus 34 in the previous period, with dementia (including Alzheimer’s disease) being the most focused disease (60.0%) in this update, opposed to multiple sclerosis on the last review (55.9%). Also, environmental pollutants such as PM2.5 and NO2 have gained prominence, being represented in 65.7% and 42.9% of the new studies, opposed to 9.8% and 12.2% in the previous review, compared to environmental factors such as sun exposure (5.7% in the update vs 15.9% in the original). The mostly used geographic approach remained the patient’s residence (82.9% in the update vs 21.2% in the original and 62.3% in total), and remote sensing was used in 45.7% of the new studies versus 19.7% in the original review, with 42.0% of studies using it globally, being the second most common approach, usually to compute the environmental variable. This review has been registered in PROSPERO with the number CRD42020196188.

Abstract This study employs computational hermeneutics to explore emotional representations in Fyodor Dostoevsky’s Crime and Punishment. Using advanced Natural Language Processing (NLP) techniques, including sentiment analysis powered by the BERT model and other tools, we examine the emotional and existential aspects embedded in the narrative. Our approach combines computational tools with traditional hermeneutic methods to deconstruct the emotional journey of the protagonist, Rodion Raskolnikov. We quantitatively analyze his emotional evolution before and after the pivotal crime, mapping his psychological transition from detachment to engagement. The study focuses on four key emotional dimensions: Attitude, Introspection, Sensitivity, and Temper. By transforming qualitative textual data into a quantitative framework, we provide a novel illustration of Raskolnikov’s psychological progression from a state of depersonalization to full emotional contact. This computational analysis is contextualized within a broader philosophical interpretation, drawing on concepts such as Stoic apatheia and Heideggerian Sorge. Our research serves a dual purpose: it enhances our understanding of Dostoevsky’s work while demonstrating the potential of computational methods in literary analysis. By bridging digital humanities and traditional literary criticism, this study contributes to the growing field of digital hermeneutics and opens new avenues for interdisciplinary research in literature, philosophy, and computational linguistics.

Abstract Classifying individuals based on metabotypes and lifestyle phenotypes using exploratory factor analyses, cluster definition, and machine-learning algorithms is promising for precision chronic disease prevention and management. This study analyzed data from the NUTRiMDEA online cohort (baseline: n = 17332 and 62 questions) to develop a clustering tool based on 32 accessible questions using machine-learning strategies. Participants ranged from 18 to over 70 years old, with 64.1% female and 35.5% male. Five clusters were identified, combining metabolic, lifestyle, and personal data: Cluster 1 (“Westernized Millennial”, n = 967) included healthy young individuals with fair lifestyle habits; Cluster 2 (“Healthy”, n = 10616) consisted of healthy adults; Cluster 3 (“Mediterranean Young Adult”, n = 2013) represented healthy young adults with a healthy lifestyle and showed the highest adherence to the Mediterranean diet; Cluster 4 (“Pre-morbid”, n = 600) was characterized by healthy adults with declined mood; Cluster 5 (“Pro-morbid”, n = 312) comprised older individuals (47% >55 years) with poorer lifestyle habits, worse health, and a lower health-related quality of life. A computational algorithm was elicited, which allowed quick cluster assignment based on responses (“lifemetabotypes”). This machine-learning approach facilitates personalized interventions and precision lifestyle recommendations, supporting online methods for targeted health maintenance and chronic disease prevention.

Abstract A Right Ear Advantage (REA) is well-established in perceptual tasks but it has been found also during imagery. It is ascribed to the left temporoparietal activity for language, and it can be absent/reversed in some clinical conditions including auditory hallucinations. We applied 1-Hz repetitive TMS over TP3/TP4 (left/right language areas) identified through neuronavigation in 18 healthy participants, before administering a modified white noise (WN) speech illusion paradigm: a voice was presented at one ear, at the same or lower intensities with respect to binaural WN. In some trials the voice was not presented, but participants were anyway instructed to report in which ear they believed perceiving it in all trials. Results confirmed the REA both when the voice was present (perceptual REA) and when it was absent (imaginative REA). Interestingly, results suggested that the correct localization of the voice when the stimulus was ambiguous (presented at low intensity and “masked” by WN) was better when TMS was applied over the right/left hemisphere, in male participants with a low/high proneness to unusual experiences (e.g., auditory hallucinations), respectively. This interaction must be further explored to shed light on the relationship between hemispheric asymmetries and auditory hallucinations, in healthy and clinical samples.

Abstract Elastic fibers are crucial for aortic valve (AoV) function and are generated and maintained by valvular interstitial cells (VICs). VICs exhibit diverse phenotypes, yet the specific subpopulation responsible for producing and regulating elastic fibers remains unclear. This gap in knowledge is significant, given that elastin (Eln) abnormalities lead to congenital AoV defects and initiate AoV diseases. This study characterizes the timing of Eln expression in murine AoV, revealing it peaks during late embryogenesis and early postnatal stages, decreasing in adulthood. Spatial transcriptomics and RT-qPCR indicate that Eln expression correlates with genes associated to elastogenesis, including Acta2, a smooth muscle cell marker. While Eln expression is not exclusive to a single VIC subpopulation, RNAscope and immunofluorescence demonstrate a population of Eln-expressing VICs that co-express alpha smooth muscle actin and melanocytic markers. As previously reported in adult mice, we show a relationship between AoV pigment and elastic fiber patterning during early postnatal stages and further show that melanocytes may play a critical role in elastogenesis. In summary, Eln is expressed in the AoV during early postnatal stages by cells co-expressing markers of various types, highlighting the complexity of VICs phenotypes and their role in elastic fiber regulation.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses resulting from nonspecific early symptoms and the absence of early diagnostic biomarkers. MicroRNAs (miRNAs) play a crucial role in regulating diverse biological processes, and their abnormal expression is observed in various diseases, including cancer. Cancer stem cells (CSCs) are thought to act as a driving force in PDAC spread and recurrence. In pursuing the goal of unravelling the complexities of PDAC and its underlying molecular mechanisms, our study aimed to identify PDAC-associated miRNAs and relate them to disease progression, focusing on their involvement in various PDAC stages in patients and in reliable in vitro models, including pancreatic CSC (PaCSC) models. Methods The miRNA profiling datasets of serum and solid biopsies of PDAC patients deposited in GEO DataSets were analyzed by REML-based meta-analysis. The panel was then investigated by Real Time PCR in serum and solid biopsies of 37 PDAC patients enrolled in the study, as well as on BxPC-3 and AsPC-1 PDAC cell lines. We extended our focus towards a possible role of PDAC-associated miRNAs in the CSC phenotype, by inducing CSC-enriched pancreatospheres from BxPC-3 and AsPC-1 PDAC cell lines and performed differential miRNA expression analysis between PaCSCs and monolayer-grown PDAC cell lines. Results Meta-analysis showed differentially expressed miRNAs in blood samples and cancerous tissues of PDAC patients, allowing the identification of a panel of 9 PDAC-associated miRNAs. The results emerging from our patients fully confirmed the meta-analysis for the majority of miRNAs under investigation. In vitro tasks confirmed the aberrant expression of the panel of PDAC-associated miRNAs, with a dramatic dysregulation in PaCSC models. Notably, PaCSCs have shown significant overexpression of miR-4486, miR-216a-5p, and miR-216b-5p compared to PDAC cell lines, suggesting the recruitment of such miRNAs in stemness-related molecular mechanisms. Globally, our results showed a dual behaviour of miR-216a-5p and miR-216b-5p in PDAC while miR-4486, miR-361-3p, miR-125a-5p, miR-320d expression changes during the disease suggest they could promote PDAC initiation and progression. Conclusions This study contributed to an enhanced comprehension of the role of miRNAs in the development and progression of PDAC, shedding new light on the miRNA landscape in PDAC and its intricate interplay with CSCs, and providing specific insights useful in the development of miRNA-based diagnostic biomarkers and therapeutic targets.