Search

Abstract Cangrelor, the first intravenous P2Y12 inhibitor (P2Y12-I), has been approved on the basis of three large RCTs from the CHAMPION program which nevertheless have been criticized for the low bleeding risk of the enrolled patients, the large quote of chronic coronary syndromes, and the use of Clopidogrel as control arm even in the setting of acute coronary syndromes (ACS). We sought to investigate, in the setting of ACS, the comparative performance of Cangrelor in terms of in-hospital ischemic and haemorrhagic outcomes compared with the current gold-standard of oral P2Y12-I. The study retrospectively enrolled 686 consecutive patients admitted to the Divisions of Cardiology of Policlinico of Bari and L. Bonomo Hospital of Andria for ACS and treated with percutaneous coronary intervention. The study population was divided according to the P2Y12-I treatment strategy in two groups: patients given an oral P2Y12-I and patients receiving Cangrelor in the cath lab followed by an oral P2Y12-I. Clinical endpoints included death, ischemic and bleeding events occurring during hospital stay. Cangrelor treated patients presented higher clinical risk profile at presentation and faced higher death rate. However, after PS matching, in-hospital mortality resulted comparable between the groups and Cangrelor use was associated with reduced in-hospital definite stent thrombosis (p = 0.03). Data from our real-world registry highlight that, in the setting of ACS, Cangrelor is prevalently used in patients with very challenging clinical presentations. The adjusted analysis provides for the first time promising data on stent thrombosis reduction associated with Cangrelor use.

Abstract Nephron endowment at birth impacts long-term renal and cardiovascular health, and it is contingent on the nephron progenitor cell (NPC) pool. Glycolysis modulation is essential for determining NPC fate, but the underlying mechanism is unclear. Combining RNA sequencing and quantitative proteomics we identify 267 genes commonly targeted by Wnt activation or glycolysis inhibition in NPCs. Several of the impacted pathways converge at Acetyl-CoA, a co-product of glucose metabolism. Notably, glycolysis inhibition downregulates key genes of the Mevalonate/cholesterol pathway and stimulates NPC differentiation. Sodium acetate supplementation rescues glycolysis inhibition effects and favors NPC maintenance without hindering nephrogenesis. Six2Cre-mediated removal of ATP-citrate lyase (Acly), an enzyme that converts citrate to acetyl-CoA, leads to NPC pool depletion, glomeruli count reduction, and increases Wnt4 expression at birth. Sodium acetate supplementation counters the effects of Acly deletion on cap-mesenchyme. Our findings show a pivotal role of acetyl-CoA metabolism in kidney development and uncover new avenues for manipulating nephrogenesis and preventing adult kidney disease.

Abstract When agent-based models are developed to capture opinion formation in large-scale populations, the opinion update equations often need to embed several complex psychological traits. The resulting models are more realistic, but also challenging to assess analytically, and hence numerical analysis techniques have an increasing importance in their study. Here, we propose the Qualitative Outcome Likelihood (QOL) analysis, a novel probabilistic analysis technique aimed to unravel behavioural patterns and properties of agent-based opinion formation models, and to characterise possible outcomes when only limited information is available. The QOL analysis reveals which qualitative categories of opinion distributions a model can produce, brings to light their relation to model features such as initial conditions, agent parameters and underlying digraph, and allows us to compare the behaviour of different opinion formation models. We exemplify the proposed technique by applying it to four opinion formation models: the classical Friedkin-Johnsen model and Bounded Confidence model, as well as the recently proposed Backfire Effect and Biased Assimilation model and Classification-based model.

Abstract The COVID-19 pandemic has had a devastating impact on the health and wellbeing of the global population. This paper presents the results of a longitudinal transcultural study that was begun at the peak of the pandemic (in April, 2020). An online survey was used to collect data from English-, Spanish-, and Portuguese-speaking participants. The survey collected information about sociodemographics, lifestyle activities, COVID-19-related circumstances, and drug use (with an emphasis on hallucinogenic drugs), as well as involving psychometric questionnaires. Users of hallucinogenic drugs had higher psychological well-being and lower scores on psychopathology scales, both at baseline and during follow-ups. This difference was larger when users were distinguished by frequency of use, as regular users scored higher on psychological well-being and lower on psychopathology scales. Subjects with more psychological distress had lower scores for all scales of post-traumatic growth, but if they were regular hallucinogens users, they had higher scores for post-traumatic growth. When comparing the results between cultural contexts, heterogeneous results were obtained. There were more English-speaking regular users of hallucinogenic drugs. Further research should analyse the potential role of hallucinogens in large-scale catastrophes, with a special focus on post-traumatic growth.

Abstract Parents of very low birth weight (VLBW) infants in a neonatal intensive care unit experienced additional stress during the SARS-CoV-2 pandemic due to the related restrictions in hospital visiting policies. Our study aimed to compare parents' burdens before and during the pandemic. This survey included 121 parents of 76 VLBW infants in two European Level IV perinatal centers before and during the pandemic. We performed standardized parent questionnaires with mothers and fathers separately to evaluate their emotional stress and well-being. The pandemic worsened the emotional well-being of parents of VLBW infants, particularly of mothers. During the pandemic, mothers reported significantly higher state anxiety levels (48.9 vs. 42.9, p = 0.026) and hampered bonding with the child (6.3 vs. 5.2, 0 = 0.003) than before. In addition, mothers felt more personally restricted than fathers (6.1 vs. 5.2, p = 0.003). Fathers experienced lower levels of stress than mothers; they were equally burdened before and during the pandemic. Restrictions in visiting policies for families of VLBW infants during the SARS-CoV-2 pandemic have a significant negative impact on parental stress and should therefore be applied cautiously.

Abstract We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

Abstract There is a raised interest in literature to use Virtual Reality (VR) technology as an assessment tool for cognitive domains. One of the essential advantages of transforming tests in an immersive virtual environment is the possibility of automatically calculating the test’s score, a time-consuming process under natural conditions. Although the characteristics of VR can deliver different degrees of immersion in a virtual environment, the sense of presence could jeopardize the evolution of these practices. The sense of presence results from a complex interaction between human, contextual factors, and the VR environment. The present study has two aims: firstly, it contributes to the validation of a virtual version of the naturalistic action test (i.e., virtual reality action test); second, it aims to evaluate the role of sense of presence as a critical booster of the expression of cognitive abilities during virtual reality tasks. The study relies on healthy adults tested in virtual and real conditions in a cross-over research design. The study’s results support the validity of the virtual reality action test. Furthermore, two structural equation models are tested to comprehend the role of sense of presence as a moderator in the relationship between cognitive abilities and virtual task performance.

Abstract Extreme waves are intense and unexpected wavepackets ubiquitous in complex systems. In optics, these rogue waves are promising as robust and noise-resistant beams for probing and manipulating the underlying material. Localizing large optical power is crucial especially in biomedical systems, where, however, extremely intense beams have not yet been observed. We here discover that tumor-cell spheroids manifest optical rogue waves when illuminated by randomly modulated laser beams. The intensity of light transmitted through bio-printed three-dimensional tumor models follows a signature Weibull statistical distribution, where extreme events correspond to spatially-localized optical modes propagating within the cell network. Experiments varying the input beam power and size indicate that the rogue waves have a nonlinear origin. We show that these nonlinear optical filaments form high-transmission channels with enhanced transmission. They deliver large optical power through the tumor spheroid, and can be exploited to achieve a local temperature increase controlled by the input wave shape. Our findings shed light on optical propagation in biological aggregates and demonstrate how nonlinear extreme event formation allows light concentration in deep tissues, paving the way to using rogue waves in biomedical applications, such as light-activated therapies.

Abstract Mammographic breast cancer screening is effective in reducing breast cancer mortality. Nevertheless, several limitations are known. Therefore, developing an alternative or complementary non-invasive tool capable of increasing the accuracy of the screening process is highly desirable. The objective of this study was to identify circulating microRNA (miRs) ratios associated with BC in women attending mammography screening. A nested case–control study was conducted within the ANDROMEDA cohort (women of age 46–67 attending BC screening). Pre-diagnostic plasma samples, information on life-styles and common BC risk factors were collected. Small-RNA sequencing was carried out on plasma samples from 65 cases and 66 controls. miR ratios associated with BC were selected by two-sample Wilcoxon test and lasso logistic regression. Subsequent assessment by RT-qPCR of the miRs contained in the selected miR ratios was carried out as a platform validation. To identify the most promising biomarkers, penalised logistic regression was further applied to candidate miR ratios alone, or in combination with non-molecular factors. Small-RNA sequencing yielded 20 candidate miR ratios associated with BC, which were further assessed by RT-qPCR. In the resulting model, penalised logistic regression selected seven miR ratios (miR-199a-3p_let-7a-5p, miR-26b-5p_miR-142-5p, let-7b-5p_miR-19b-3p, miR-101-3p_miR-19b-3p, miR-93-5p_miR-19b-3p, let-7a-5p_miR-22-3p and miR-21-5p_miR-23a-3p), together with body mass index (BMI), menopausal status (MS), the interaction term BMI * MS, life-style score and breast density. The ROC AUC of the model was 0.79 with a sensitivity and specificity of 71.9% and 76.6%, respectively. We identified biomarkers potentially useful for BC screening measured through a widespread and low-cost technique. This is the first study reporting circulating miRs for BC detection in a screening setting. Validation in a wider sample is warranted. Trial registration: The Andromeda prospective cohort study protocol was retrospectively registered on 27-11-2015 (NCT02618538).

Abstract Glial Fibrillary Acidic Protein (GFAP) and Ubiquitin C-terminal hydrolase (UCH-L1) have been FDA-approved for clinical use in mild and moderate traumatic brain injury (TBI). Understanding sex differences in their diagnostic accuracy over time will help inform clinical practice. We sought to evaluate the sex differences in the temporal profile of GFAP and UCH-L1 in a large cohort of trauma patients presenting to the emergency department. To compare the biomarkers’ diagnostic accuracy in male versus female patients for detecting mild TBI (MTBI), and traumatic intracranial lesions on head CT. This prospective cohort study enrolled female and male adult trauma patients presenting to a Level 1 Trauma Center. All patients underwent rigorous screening to determine whether or not they had experienced a MTBI. Of 3025 trauma patients assessed, 1030 met eligibility criteria and 446 declined. Initial blood samples were obtained in 584 patients enrolled within 4 h of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180-h post-injury. The main outcomes included the diagnostic accuracy in detection of MTBI and traumatic intracranial lesions on head CT scan. A total of 1831 samples were drawn in 584 patients over 7 days, 362 (62%) were male and 222 (38%) were female. The pattern of elevation was similar in both sexes. Although the pattern of elevation was similar between male and female for both biomarkers, male patients had significantly higher concentrations of UCH-L1 compared to female patients at several timepoints post-injury, particularly within 24 h of injury. There were no significant differences in diagnostic accuracy for detecting MTBI or for detecting CT lesions between male and female patients at any timepoint for both GFAP and UCH-L1. Although patterns of GFAP and UCH-L1 release in trauma patients over a week post-injury was similar between the sexes, there were significantly higher concentrations of UCH-L1 in males at several timepoints post-injury. Despite this, the overall diagnostic accuracies of both GFAP and UCH-L1 over time for detecting MTBI and CT lesions were not significantly different between male and female trauma patients.

Abstract We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Abstract Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations—eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.

Abstract A growing body of evidence links gut microbiota changes with inflammatory bowel disease (IBD), raising the potential benefit of exploiting metagenomics data for non-invasive IBD diagnostics. The sbv IMPROVER metagenomics diagnosis for inflammatory bowel disease challenge investigated computational metagenomics methods for discriminating IBD and nonIBD subjects. Participants in this challenge were given independent training and test metagenomics data from IBD and nonIBD subjects, which could be wither either raw read data (sub-challenge 1, SC1) or processed Taxonomy- and Function-based profiles (sub-challenge 2, SC2). A total of 81 anonymized submissions were received between September 2019 and March 2020. Most participants’ predictions performed better than random predictions in classifying IBD versus nonIBD, Ulcerative Colitis (UC) versus nonIBD, and Crohn’s Disease (CD) versus nonIBD. However, discrimination between UC and CD remains challenging, with the classification quality similar to the set of random predictions. We analyzed the class prediction accuracy, the metagenomics features by the teams, and computational methods used. These results will be openly shared with the scientific community to help advance IBD research and illustrate the application of a range of computational methodologies for effective metagenomic classification.

Abstract Spintronics-based microwave devices, such as oscillators and detectors, have been the subject of intensive investigation in recent years owing to the potential reductions in size and power consumption. However, only a few concepts for spintronic amplifiers have been proposed, typically requiring complex device configurations or material stacks. Here, we demonstrate a spintronic amplifier based on two-terminal magnetic tunnel junctions (MTJs) produced with CMOS-compatible material stacks that have already been used for spin-transfer torque memories. We achieve a record gain (|S 11 | > 2) for input power on the order of nW (

Abstract Diluted pyroclastic density currents are capable to cause huge devastation and mortality around volcanoes, and temperature is a crucial parameter in assessing their lethal power. Reflectance analysis on carbonized wood from ancient Herculaneum allowed a new reconstruction of the thermal events that affected buildings and humans during the 79CE Vesuvius eruption. Here we show that the first PDC entered the town was a short-lived, ash cloud surge, with temperatures of 555–495 °C, capable of causing instant death of people, while leaving only a few decimeters of ash on ground, which we interpret as detached from high concentration currents. The subsequent pyroclastic currents that progressively buried the town were mostly higher concentration PDCs at lower temperatures, between 465 and 390 and 350–315 °C. Charcoal proved to be the only proxy capable of recording multiple, ephemeral extreme thermal events, thus revealing for the first time the real thermal impact of the 79CE eruption. The lethal impact documented for diluted PDC produced during ancient and recent volcanic eruptions suggests that such hazard deserves greater consideration at Vesuvius and elsewhere, especially the underestimated hazard associated with hot detached ash cloud surges, which, though short lived, may expose buildings to severe heat damages and people to death.

Abstract Chess is a centuries-old game that continues to be widely played worldwide. Opening Theory is one of the pillars of chess and requires years of study to be mastered. In this paper, we use the games played in an online chess platform to exploit the “wisdom of the crowd” and answer questions traditionally tackled only by chess experts. We first define a relatedness network of chess openings that quantifies how similar two openings are to play. Using this network, we identify communities of nodes corresponding to the most common opening choices and their mutual relationships. Furthermore, we demonstrate how the relatedness network can be used to forecast future openings players will start to play, with back-tested predictions outperforming a random predictor. We then apply the Economic Fitness and Complexity algorithm to measure the difficulty of openings and players’ skill levels. Our study not only provides a new perspective on chess analysis but also opens the possibility of suggesting personalized opening recommendations using complex network theory.

Abstract We introduce a classical-quantum hybrid approach to computation, allowing for a quadratic performance improvement in the decision process of a learning agent. Using the paradigm of quantum accelerators, we introduce a routine that runs on a quantum computer, which allows for the encoding of probability distributions. This quantum routine is then employed, in a reinforcement learning set-up, to encode the distributions that drive action choices. Our routine is well-suited in the case of a large, although finite, number of actions and can be employed in any scenario where a probability distribution with a large support is needed. We describe the routine and assess its performance in terms of computational complexity, needed quantum resource, and accuracy. Finally, we design an algorithm showing how to exploit it in the context of Q-learning.

Charge noise degrades the performance of spin qubits hindering scalability. Here the authors engineer the heterogeneous material stack in 28Si/SiGe gate-defined quantum dots, to improve the scattering properties and to reduce charge noise.

Abstract In this paper, we present the results of toxicological analyses of preserved brain tissue and bone samples from the remains of the seventeenth century patients of the Ospedale Maggiore, the main hospital in Milan and one of the most innovative hospitals in Europe from the Renaissance period. Beneath it, the crypt functioned as the burial place for the deceased of the hospital. In this multidisciplinary study of the remains, toxicological analyses in particular were performed with HPLC–MS/MS on different biological samples from nine individuals. Anthropological, paleopathological, histological, radiological examinations and radiocarbon dating were also carried out. As a result, archeotoxicological analyses revealed the presence of codeine, morphine, noscapine and papaverine, derived from Papaver somniferum, a plant present in the hospital pharmacopeia used as a narcotic, analgesic, astringent, coagulant, and antitussive agent. Such analyses have shed light on the pharmacological therapies administered to the patients near the time of death and have implemented our knowledge of medical treatment and drug administration in the 1600’s.

Abstract Early detection of the emergence of a new variant of concern (VoC) is essential to develop strategies that contain epidemic outbreaks. For example, knowing in which region a VoC starts spreading enables prompt actions to circumscribe the geographical area where the new variant can spread, by containing it locally. This paper presents ‘funnel plots’ as a statistical process control method that, unlike tools whose purpose is to identify rises of the reproduction number ( $${R}_{t}$$ R t ), detects when a regional $${R}_{t}$$ R t departs from the national average and thus represents an anomaly. The name of the method refers to the funnel-like shape of the scatter plot that the data take on. Control limits with prescribed false alarm rate are derived from the observation that regional $${R}_{t}$$ R t 's are normally distributed with variance inversely proportional to the number of infectious cases. The method is validated on public COVID-19 data demonstrating its efficacy in the early detection of SARS-CoV-2 variants in India, South Africa, England, and Italy, as well as of a malfunctioning episode of the diagnostic infrastructure in England, during which the Immensa lab in Wolverhampton gave 43,000 incorrect negative tests relative to South West and West Midlands territories.

Abstract We have previously shown that Acinetobacter baumannii as well as other relevant clinical bacterial pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, perceive and respond to light at 37 °C, the normal temperature in mammal hosts. In this work, we present evidence indicating that the two-component system BfmRS transduces a light signal in A. baumannii at this temperature, showing selective involvement of the BfmR and BfmS components depending on the specific cellular process. In fact, both BfmR and BfmS participate in modulation of motility by light, while only BfmR is involved in light regulation of desiccation tolerance in this microorganism. Neither BfmR nor BfmS contain a photoreceptor domain and then most likely, the system is sensing light indirectly. Intriguingly, this system inhibits blsA expression at 37 °C, suggesting antagonistic functioning of both signaling systems. Furthermore, we present evidence indicating that the phosphorylatable form of BfmR represses motility. Overall, we provide experimental evidence on a new biological function of this multifaceted system that broadens our understanding of A. baumannii’s physiology and responses to light.

Spin qubits in Si/SiGe quantum dots suffer from variability in the valley splitting which will hinder device scalability. Here, by using 3D atomic characterization, the authors explain this variability by random Si and Ge atomic fluctuations and propose a strategy to statistically enhance the valley splitting

High entropy alloys are multi-element random alloys with a strong short range disorder. Here, the authors show that their heat carrying lattice waves, while strongly attenuated by the force-constant disorder, propagate until high energy.

Abstract Transcatheter aortic valve implantation (TAVI) requires thorough preprocedural planning with non-invasive imaging, including computed tomography (CT). The plethora of details obtained with thoraco-abdominal CT represents a challenge for accurate and synthetic decision-making. We devised and tested a comprehensive score suitable to summarize CT exams when planning TAVI. An original comprehensive scoring system (TAVI-CT score) was devised, including details on cardiac, aortic, iliac and femoral artery features. The score was applied to a prospectively collected series of patients undergoing TAVI at our institution, driving decision making on access and prosthesis choice. Different TAVI-CT score groups were compared in terms of procedural success, acute complications, and early clinical outcomes. We included a total of 200 undergoing TAVI between February 2020 and May 2021, with 74 (37.0%) having a low (0–2) TAVI-CT score, 50 (25.0%) having a moderate (3) TAVI-CT score, and 76 (38.0%) having a high (≥ 4) TAVI-CT score. Male gender was the only non-CT variable significantly associated with the TAVI-CT score (p = 0.001). As expected, access choice differed significantly across TAVI-CT scores (p = 0.009), as was device choice, with Portico more favored and Allegra less favored in the highest TAVI-CT score group (p = 0.036). Acute outcomes were similar in the 3 groups, including device and procedural success rates (respectively p = 0.717 and p = 1). One-month follow-up showed similar rates of death, myocardial infarction, stroke, and bleeding, as well as of a composite safety endpoint (all p > 0.05). However, vascular complications were significantly more common in the highest TAVI-CT score group (p = 0.041). The TAVI-CT score is a simple scoring system that could be routinely applied to CT imaging for TAVI planning, if the present hypothesis-generating findings are confirmed in larger prospective studies.

In a globalized context, characterized by dominant trends towards the homogenization of food products and taste, local and niche productions play a vital role in creating effective strategies of territorial development. Albanian food heritage is definitely one of the most various of the Western Balkans. The Ottoman domination and the Mediterranean position just in front of Italy led to an incredible mix of cultures and traditions. As Albania is a candidate to join the European Union, it has a stronger opportunity of protecting its excellent-quality food products with PDO and PGI marks. Moreover, Albania’s territory shares fundamental features with Gargano lakes, especially with relation to the county of Dibër, where Ulez and Shkopet lakes are located. Both the areas’ traditional food products are and can be an important factor of sustainable and participatory development, and the present contribution aims at exploring possible paths of territorial development at a cross-border level, in the framework of a sort of “dialogue” between the two regions through Geographical Indications (GIs).

Abstract Posttranslational modifications (PTMs) on histone tails regulate eukaryotic gene expression by impacting the chromatin structure and by modulating interactions with other cellular proteins. One such PTM has been identified as serine and threonine glycosylation, the introduction of the ß-N-acetylglucosamine (GlcNAc) moiety on histone H3 tail at position Ser10 and Thr32. The addition of the ß-O-GlcNAc moiety on serine or threonine residues is facilitated by the O-GlcNAc transferase (OGT), and can be removed by the action of O-GlcNAcase (OGA). Conflicting reports on histone tail GlcNAc modification in vivo prompted us to investigate whether synthetic histone H3 tail peptides in conjunction with other PTMs are substrates for OGT and OGA in vitro. Our enzymatic assays with recombinantly expressed human OGT revealed that the unmodified and PTM-modified histone H3 tails are not substrates for OGT at both sites, Ser10 and Thr32. In addition, full length histone H3 was not a substrate for OGT. Conversely, our work demonstrates that synthetic peptides containing the GlcNAc functionality at Ser10 are substrates for recombinantly expressed human OGA, yielding deglycosylated histone H3 peptides. We also show that the catalytic domains of human histone lysine methyltransferases G9a, GLP and SETD7 and histone lysine acetyltransferases PCAF and GCN5 do somewhat tolerate glycosylated H3Ser10 close to lysine residues that undergo methylation and acetylation reactions, respectively. Overall, this work indicates that GlcNAcylation of histone H3 tail peptide in the presence of OGT does not occur in vitro.

Abstract We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA.

Abstract In early systemic sclerosis (Scleroderma, SSc), the vasculature is impaired. Although the exact etiology of endothelial cell damage in SSc remains unclear, it is hypothesized that endothelial to mesenchymal transition (EndoMT) plays a key role. To perform physiologically relevant angiogenic studies, we set out to develop an angiogenesis-on-a-chip platform that is suitable for assessing disease parameters that are relevant to SSc and other vasculopathies. In the model, we substituted Fetal Bovine Serum (FBS) with Human Serum without impairing the stability of the culture. We showed that 3D microvessels and angiogenic factor-induced sprouts exposed to key pro-inflammatory and pro-fibrotic cytokines (TNFα and TGFβ) undergo structural alterations consisting of destructive vasculopathy (loss of small vessels). We also showed that these detrimental effects can be prevented by compound-mediated inhibition of TGFβ-ALK5 signaling or addition of a TNFα neutralizing antibody to the 3D cultures. This demonstrates that our in vitro model is suitable for compound testing and identification of new drugs that can protect from microvascular destabilization or regression in disease-mimicking conditions. To support this, we demonstrated that sera obtained from SSc patients can exert an anti-angiogenic effect on the 3D vessel model, opening the doors to screening for potential SSc drugs, enabling direct patient translatability and personalization of drug treatment.

Measurement(s) gene expression, metabolic relationships Technology Type(s) Genome Scale Metabolic Models; Computational network biology Sample Characteristic - Organism Homo sapiens

Abstract Egyptian fruit bats have gained increasing interest being a natural reservoir for emerging zoonotic viruses. Anaesthesia is often required to allow safe handling of bats. We aimed to compare the sedative and cardiopulmonary effects of two balanced anaesthetic protocols in bats undergoing gonadectomy. Group DK (n = 10) received intramuscular dexmedetomidine (40 µg/kg) and ketamine (7 mg/kg), whereas group DBM (n = 10) received intramuscular dexmedetomidine (40 µg/kg), butorphanol (0.3 mg/kg) and midazolam (0.3 mg/kg). Induction time and cardiopulmonary parameters were recorded. If anaesthetic plan was inadequate, isoflurane was titrated-to-effect. At the end of surgery venous blood gas analysis was performed and atipamezole or atipamezole-flumazenil was administered for timed and scored recovery. In DBM group heart rate and peripheral oxygen saturation were significantly higher (p = 0.001; p = 0.003 respectively), while respiratory rate was significantly lower (p = 0.001). All bats required isoflurane supplementation with no significant differences between groups. Induction and recovery times showed no significant differences. In group DK a better recovery was scored (p = 0.034). Sodium and chloride were significantly higher in DBM group (p = 0.001; p = 0.002 respectively). Both anaesthetic protocols were comparable and can be recommended for minor procedures in bats.

A coherent quantum link between distant quantum processors is desirable for scaling up of quantum computation. Noiri et al. demonstrate a strategy to link distant quantum processors in silicon, by implementing a shuttling-based two-qubit gate between spin qubits in a Si/SiGe triple quantum dot.

Pesticide impact on honey bees under field conditions remains elusive. Here, the authors combine a systems biology approach and laboratory experiments to show that the immune suppressive effect of the pathogen deformed wing virus can be responsible for the disparity amongst honey bee experiments.

Abstract Several studies argued that cardiovascular evaluation of patients with nonfunctioning adrenal incidentaloma is of particular importance. Therefore, we aimed to evaluate the possibility of stratifying the cardiometabolic risk using metanephrine levels in this setting of patients. A retrospective cross-sectional study was designed, collecting data of metanephrine values in 828 patients with nonfunctioning adrenal incidentaloma, referred to our Division within the University of Turin between 2007 and 2021. The univariate analysis showed associations between urine metanephrines and cardiometabolic variables/parameters, particularly considering the noradrenaline metabolite. At the univariate regression, normetanephrine was associated with metabolic syndrome (OR = 1.13, p = 0.002), hypertensive cardiomyopathy (OR = 1.09, p = 0.026), microalbuminuria (OR = 1.14, p = 0.024), and eGFR

The grain size, nutrients, and metals contents of sediments are important tracers for reconstructing the origin of the contaminants and the pathway of the sediments from the source to the sink. This is particularly important in areas with high geological variability and a high demographic pressure. The origin and distribution of contaminants and nutrients allow us to identify the source-to-sink pathway of the sediments. In particular, the Sarno River is one of the main contributing sources of anthropogenic contaminants due to the outflow from the large surrounding large industrial area. Geochemical and physical parameters of sediments were analyzed along a transect from the coastline to a water depth of 112 m, with the objective of exploring the spatial variability of sediment contamination in the continental shelf of Naples Bay. The latter is characterized by a complex geological area and is subject to river inflow from a highly industrialized area. The data have been analyzed using principal component analysis (PCA), hierarchical correlation analysis (CA), and analysis of variance (ANOVA). To distinguish between a natural and anthropogenic origin of contaminants and to construct the source-to-sink pathway, the relationship between geochemical and physical data and their distribution was examined, and the results were compared with published data collected onshore. Four distinct sectors with different associations of metals, grain size, and total organic carbon have been recognized: I) offshore Vesuvius volcano, the occurrence of coarse-grained sediments, associated with As, Fe, Mn, and low TOC values, suggests a natural origin of the contaminant due to the volcanic nature of the substrate; II) offshore the Sarno River, the presence of Cr, Cd, Cu, Pb and Zn, associated with the high TOC content, suggests an anthropogenic origin for the contaminants; III) offshore Sorrento Peninsula, the presence of As, Fe, Mn, and some gravel made up of pumice and bioclasts indicate a predominance of contaminants of natural origin; and IV) finally, the distal part is not subjected to a primary terrestrial input. Metals contamination of anthropogenic origin and the organic matter in sediments decreased rapidly with distance from the coast highlighting the main deposition area close to the river discharge.

A Etnomatemática, segundo Ubiratan D’Ambrosio, constitui uma subárea da História da Matemática e da Educação Matemática politicamente engajada, voltada para transformação social e para a recuperação da dignidade cultural dos indivíduos. Entretanto, em um dos momentos mais críticos para o povo brasileiro, em plena crise sanitária e econômica da pandemia de Covid-19, por uma infeliz coincidência, atravessamos uma ampla reforma curricular impulsionada publicação da “Base Nacional Comum Curricular – BNCC”, em 2018, documento norteador dos currículos nacionais que ignorou a História da Matemática, bem como nossa grande tradição em pesquisa e ensino etnomatemáticos. Por outro lado, os documentos curriculares complementares publicados em 2019: “Referenciais Curriculares para a Elaboração de Itinerários Formativos” e “Temas Contemporâneos Transversais na BNCC: Contexto Histórico e Pressupostos Pedagógicos” colocaram os professores brasileiros diante de um vazio fértil, repleto de desafios e possibilidades. Discutir esse cenário educacional é o objetivo central deste artigo. Trata-se de uma pesquisa qualitativa, de cunho bibliográfico e documental, que se debruça sobre documentos curriculares brasileiros e pesquisas embasadas na Etnomatemática, para tentar responder à nossa questão de pesquisa “Quais os principais desafios e possibilidades para a promoção da Etnomatemática na Educação Básica brasileira, no contexto da atual reforma curricular, em uma perspectiva interdisciplinar e transdisciplinar?”. Nosso foco é a rede estadual de ensino de São Paulo, por se tratar da maior rede de ensino do Brasil e por ser uma das primeiras e elaborar um currículo pautado pela BNCC, além de um projeto próprio para a exploração dos temas curriculares transversais, implantação e implementação do Novo Ensino Médio. Nossos resultados mostram que, apesar do engessamento curricular promovido pela BNCC, ainda existe margem para desenvolvimento de propostas educacionais que contemplem as necessidades locais, que respeite as diferenças regionais e as peculiaridades da cultura escolar, em uma perspectiva etnomatemática.

Summary: The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies of oxygen, nutrients, and dietary essential fatty acids. Here we analyzed the lipidome of the mouse retina under healthy and pathological angiogenesis using the oxygen-induced retinopathy model. By matching lipid profiles to changes in mRNA transcriptome, we identified a lipid signature showing that pathological angiogenesis leads to intense lipid remodeling favoring pathways for neutral lipid synthesis, cholesterol import/export, and lipid droplet formation. Noteworthy, it also shows profound changes in pathways for long-chain fatty acid production, vital for retina homeostasis. The net result is accumulation of large quantities of mead acid, a marker of essential fatty acid deficiency, and a potential marker for retinopathy severity. Thus, our lipid signature might contribute to better understand diseases of the retina that lead to vision impairment or blindness.

Abstract Comparing model predictions with real data is crucial to improve and validate a model. For opinion formation models, validation based on real data is uncommon and difficult to obtain, also due to the lack of systematic approaches for a meaningful comparison. We introduce a framework to assess opinion formation models, which can be used to determine the qualitative outcomes that an opinion formation model can produce, and compare model predictions with real data. The proposed approach relies on a histogram-based classification algorithm, and on transition tables. The algorithm classifies an opinion distribution as perfect consensus, consensus, polarization, clustering, or dissensus; these qualitative categories were identified from World Values Survey data. The transition tables capture the qualitative evolution of the opinion distribution between an initial and a final time. We compute the real transition tables based on World Values Survey data from different years, as well as the predicted transition tables produced by the French-DeGroot, Weighted-Median, Bounded Confidence, and Quantum Game models, and we compare them. Our results provide insight into the evolution of real-life opinions and highlight key directions to improve opinion formation models.

Abstract Steroids affect bone health causing osteoporosis and fractures. The study aims to compare dual-release hydrocortisone (DR-HC) and conventional steroids on bone metabolism in patients with primary adrenal insufficiency (PAI). Thirty-five patients with PAI on conventional steroids (group A) and 35 patients switched to DR-HC (group B), consecutively referred at our hospital, were evaluated at baseline and after 18, 36 and 60 months of treatment. After 60 months of follow-up, patients in group A had a significant increase in body mass index (p = 0.004) and waist circumference (WC) (p = 0.026) and a significant decrease in osteocalcin (p = 0.002), bone alkaline phosphatase (p = 0.029), lumbar spine bone mass density (BMD) T and Z scores (p

Abstract Several universities around the world have resumed in-person teaching after successful vaccination campaigns have covered 70/80% of the population. In this study, we combine a new compartmental model with an optimal control formulation to discover, among different non-pharmaceutical interventions, the best prevention strategy to maximize on-campus activities while keeping spread under control. Composed of two interconnected Susceptible-Exposed-Infected-Quarantined-Recovered (SEIQR) structures, the model enables staff-to-staff infections, student-to-staff cross infections, student-to-student infections, and environment-to-individual infections. Then, we model input variables representing the implementation of different non-pharmaceutical interventions and formulate and solve optimal control problems for four desired scenarios: minimum number of cases, minimum intervention, minimum non-quarantine intervention, and minimum quarantine intervention. Our results reveal the particular significance of mask wearing and social distancing in universities with vaccinated population (with proportions according to UK data). The study also reveals that quarantining infected students has a higher importance than quarantining staff. In contrast, other measures such as environmental disinfection seems to be less important.

Abstract Blockchains are among the most relevant emerging technologies of recent times and, according to many, they will have a central role in shaping the future of our society. Since the introduction of Bitcoin in 2009, the first notorious blockchain system bound to a cryptocurrency, the blockchain ecosystem has experienced a huge growth, driven by innovations both in conceptual and algorithmic terms, and in the creation of a large number of new cryptocoins. New blockchains and their associated cryptocoins, emerge mostly as the result of forking already existing projects. Here, we show that the appearance of new cryptocoins can be well described by a sub-linear power-law (Heaps’ law) of the total crypto-market capitalization. At the same time, we propose a model that well reproduces the evolution of the cryptocurrency ecosystem. Our model suggests that each cryptocurrency triggers, on average, the creation of ca. 1.58 novel cryptocoins, a result confirmed by the analysis of the Bitcoin historical forking tree. Moreover, we deduce that the largest cryptocurrency, nowadays Bitcoin, will comprise around the 50% of the whole crypto-market and that this fraction is going to stabilize in the near future, provided that the present fundamental macro-economic conditions do not change radically.

Abstract The aim of this study was to evaluate the cytotoxic activity and the chemical composition of the tomato extracts coming from, Pomodoro Giallo and San Marzano Cirio 3, and then to evaluate the potential changes when plants were grown in soils contaminated by cadmium, chromium and lead. Extracts were investigated by UHPLC-HRMS and UV–Vis. Cell viability (CellTiter-Glo Luminescent assay), enzyme aldehyde dehydrogenase activity (ALDEFLOUR Assay), cell cycle progression (Accuri C6 Flow Cytometer), apoptosis and necrosis (Annexin V-FITC assay) were evaluated on two gastric cancer (AGS and NCI-N87) and two colorectal cancer (HT-29 and HCT 116) cell lines. Different content of polyphenol and carotenoid constituents was observed. Extracts from uncontaminated soil induced cytotoxic activity towards all selected cancer cells, while extracts coming from contaminated soils showed the aberrant phenotype increased in colorectal cancer cells. Chloroform extracts exerted the highest cytotoxic activity. AGS and HT-29 were the most sensitive to cell cycle arrest and to apoptosis. No necrotic effect was observed in HCT 116. The contrasting effects on cancer cells were observed based on tomato variety, the extract polarity, heavy metal identity, and tested cell line. The investigation of potential adverse health effects due to Cd in the fruits should be explored.

Abstract We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples ESR1 and PI3KCA mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32–92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while PI3KCA mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs, miR-549a, miR-644a, miR-16-5p were negatively while let-7c-5p was positively associated with 18-month PFS. In addition, miR-520d-3p and miR-548g-3p values were significantly lower while miR-603, miR-181a-5p and miR-199a-miR-199b-3p values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by miR-603, miR-181a-5p and miR-199a-miR-199b-3p. Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts.

Abstract The Pain Catastrophizing Scale (PCS) is a widely studied tool to assess pain catastrophizing for chronic low back pain (LBP). Short forms of the PCS exist, but their measurement precision at individual level is unclear. This study aimed to analyze the Rasch psychometric characteristics of the PCS and three of its short forms (two 4-item and one 6-item) in a sample of 180 Italian-speaking patients with chronic LBP, and compare their measurement precision at the individual level. We performed a Rasch analysis on each version of the PCS and calculated test information functions (TIFs) to examine conditional measurement precision. Rasch analysis showed appropriate rating category functioning, unidimensionality, and acceptable fit to the Rasch model for all PCS versions. This represented a prerequisite for performing further advanced psychometric analyses. According to TIFs, the PCS full scale showed—at any score level—higher measurement precision in estimating individual pain catastrophizing than its short forms (which had unacceptably high standard errors of measurement). Our results show acceptable conditional precision of the PCS full scale in estimating pain catastrophizing. However, further studies are needed to confirm its diagnostic accuracy at individual level. On the other hand, the study warns against use of the three PCS short forms for clinical decision-making at the individual level.

Abstract In Gram-negative pathogens, the stringent response regulator DksA controls the expression of hundreds of genes, including virulence-related genes. Interestingly, Pseudomonas aeruginosa has two functional DksA paralogs: DksA1 is constitutively expressed and has a zinc-finger motif, while DksA2 is expressed only under zinc starvation conditions and does not contain zinc. DksA1 stimulates the production of virulence factors in vitro and is required for full pathogenicity in vivo. DksA2 can replace these DksA1 functions. Here, the role of dksA paralogs in P. aeruginosa tolerance to H2O2-induced oxidative stress has been investigated. The P. aeruginosa dksA1 dksA2 mutant showed impaired H2O2 tolerance in planktonic and biofilm-growing cultures and increased susceptibility to macrophages-mediated killing compared to the wild type. Complementation with either dksA1 or dksA2 genes restored the wild type phenotypes. The DksA-dependent tolerance to oxidative stress involves, at least in part, the positive transcriptional control of both katA and katE catalase-encoding genes. These data support the hypothesis that DksA1 and DksA2 are eco-paralogs with indistinguishable function but optimal activity under different environmental conditions, and highlight their mutual contribution to P. aeruginosa virulence.

In situ 4D experiments at high temperature and moderate pressure reveal that rapid dendritic crystallization in hydrous basaltic magmas promotes a rheological transition within minutes, controlling magma mobility within the Earth’s crust.

Summary: Ribonucleoprotein (RNP) condensates are crucial for controlling RNA metabolism and splicing events in animal cells. We used spatial proteomics and transcriptomic to elucidate RNP interaction networks at the centrosome, the main microtubule-organizing center in animal cells. We found a number of cell-type specific centrosome-associated spliceosome interactions localized in subcellular structures involved in nuclear division and ciliogenesis. A component of the nuclear spliceosome BUD31 was validated as an interactor of the centriolar satellite protein OFD1. Analysis of normal and disease cohorts identified the cholangiocarcinoma as target of centrosome-associated spliceosome alterations. Multiplexed single-cell fluorescent microscopy for the centriole linker CEP250 and spliceosome components including BCAS2, BUD31, SRSF2 and DHX35 recapitulated bioinformatic predictions on the centrosome-associated spliceosome components tissue-type specific composition. Collectively, centrosomes and cilia act as anchor for cell-type specific spliceosome components, and provide a helpful reference for explore cytoplasmic condensates functions in defining cell identity and in the origin of rare diseases.

Respiratory tract infections represent the main cause of death from infectious diseases worldwide. SARS-CoV-2 infection (i.e. COVID-19) added to the existing global burden of respiratory tract infections, including tuberculosis. Among nanomaterials for fabric functionalization, graphene, in combination with hydrophobic molecules such as phytochemicals, represents a promising low-cost alternative to antibiotics. In this work, we used graphene and curcumin to create fabric coatings on cotton and polyester for the production of personal protective equipment resistant to infective agents. These coatings ensure the trapping of microorganisms via interaction with SARS-CoV-2 or mycobacteria surface and inhibit microbial infections.

The Mre11-Rad50 (MR) complex has key functions in the detection, signaling and repair of DNA breaks. Here the authors use transmission electron microscopy to show MR oligomerization is governed by a small beta-sheet protruding from the head domain of Rad50 at the base of the MR structure, and reveal MR head domain oligomerization is required for efficient DNA end resection.

Abstract To establish whether obesity involves activation of endogenous ciliary neurotrophic factor (CNTF) signalling, we evaluated its plasma levels in patients with obesity and correlated its values with the major clinical and haematological indices of obesity, insulin resistance and systemic inflammation. This study involved 118 subjects: 39 healthy controls (19 men), 39 subjects with obesity (19 men) and 40 subjects with obesity and diabetes (20 men). Plasma CNTF and CNTF receptor α (CNTFRα) were measured using commercial ELISA kits. The results showed that plasma CNTF was significantly higher in males and females with obesity with and without diabetes than in healthy subjects. Women consistently exhibited higher levels of circulating CNTF. In both genders, CNTF levels correlated significantly and positively with obesity (BMI, WHR, leptin), diabetes (fasting insulin, HOMA index and HbA1c) and inflammation (IL-6 and hsCRP) indices. Circulating CNTFRα and the CNTF/CNTFRα molar ratio tended to be higher in the patient groups than in controls. In conclusion, endogenous CNTF signalling is activated in human obesity and may help counteract some adverse effects of obesity. Studies involving a higher number of selected patients may reveal circulating CNTF and/or CNTFRα as potential novel diagnostic and/or prognostic markers of obesity, diabetes and associated diseases.