Search

Abstract Background Older subjects are at risk of elevated intestinal permeability (IP) which can lead to immune system activation and low-grade systemic inflammation. Dietary changes are a potential strategy to reduce IP. The MaPLE project evaluated the hypothesis that increasing (poly)phenol intake would beneficially impact on several important markers and pathways related to IP. The objective of the present study was to assess the effects of the MaPLE (poly)phenol-rich diet (PR-diet) on additional IP-related biomarkers and any relationships between biomarker responses. Methods A randomised, controlled, crossover study was performed involving 51 participants (≥ 60 y) with increased IP, as determined by serum zonulin levels. Participants were randomly assigned to one of two intervention groups: a control diet (C-diet) or a PR-diet. Each intervention lasted 8 weeks and was separated by an 8-week washout period. For the present study, serum and faecal samples were used to measure zonula occludens-1 (ZO-1), occludin, adiponectin, calprotectin, faecal calprotectin, soluble cluster of differentiation 14 (sCD14), interleukin-6 receptor (IL-6R), and vascular endothelial-cadherin (VEC) levels using quantitative ELISA assays. Data were analysed using ANOVA, and Spearman and network correlation analysis were performed to identify the relationship among biomarkers at baseline. Results Among the different markers analysed, a significant reduction was observed for faecal and serum calprotectin (p = 0.0378 and p = 0.0186, respectively) following the PR-diet, while a significant increase in ZO-1 was found (p = 0.001) after both the intervention periods (PR-diet and C-diet). In addition, a time effect was observed for VEC levels showing a reduction (p = 0.038) following the PR-diet. Based on network correlation analysis, two clusters of correlations were identified: one cluster with high levels of serum calprotectin, faecal calprotectin, sCD14, interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP) and bacterial DNAemia (16 S rRNA gene copies), with potential inflammatory-induced intestinal permeability. Differently, the other cluster had high levels of serum occludin, IL-6R, soluble intercellular adhesion molecule-1 (sICAM-1) and VEC, with potential inflammatory-induced endothelial dysfunction. Conclusions Overall, this study provides further support to the hypothesis that a (poly)phenol-rich diet may help to ameliorate intestinal permeability-associated conditions. In this regard, calprotectin might represent a promising biomarker since it is a protein that typically increases with age and it is considered indicative of intestinal and systemic inflammation. Further research is needed to develop targeted (poly)phenol-rich diets against age-related gut dysfunction and inflammation. Trial registration 28/04/2017; ISRCTN10214981; https://doi.org/10.1186/ISRCTN10214981 .

Abstract Images collected during NASA’s Double Asteroid Redirection Test (DART) mission provide the first resolved views of the Didymos binary asteroid system. These images reveal that the primary asteroid, Didymos, is flattened and has plausible undulations along its equatorial perimeter. At high elevations, its surface is rough and contains large boulders and craters; at low elevations its surface is smooth and possesses fewer large boulders and craters. Didymos’ moon, Dimorphos, possesses an intimate mixture of boulders, several asteroid-wide lineaments, and a handful of craters. The surfaces of both asteroids include boulders that are large relative to their host body, suggesting that both asteroids are rubble piles. Based on these observations, our models indicate that Didymos has a surface cohesion ≤ 1 Pa and an interior cohesion of ∼10 Pa, while Dimorphos has a surface cohesion of

Abstract Background Anti-IgLON5 disease is an autoimmune encephalitis overlapping with neurodegenerative disorders due to pathological accumulation of hyperphosphorylated tau. It is characterized by several clinical manifestations determined by involvement of different brain areas, and mild response to first-line immunotherapies. We report a case of anti-IgLON5 disease with a multifaceted semiology and an unusually good response to glucocorticoid monotherapy. Case presentation A 68-year-old man with type 2 diabetes was evaluated for an 8-month history of progressive gait disorder causing frequent falls. He also suffered from obstructive sleep apneas and complained of dysphonia, dysarthria, occasional dysphagia, urinary incontinence, and upper limb action tremor. Neurological examination demonstrated bilateral eyelid ptosis, limitation of ocular horizontal smooth pursuit movements, slow horizontal saccades, and lack of inhibition of the vestibulo-ocular reflex during rapid horizontal head torsions. The patient also displayed involuntary, slow, rhythmic movements of the left periorbital and perioral muscles, spreading to the ipsilateral hemipalate and hemitongue, along with bilateral negative upper limb myoclonus. There were proximal muscle wasting in the upper limbs, proximal weakness of the four limbs, and diffuse fasciculations. Ataxia of stance and gait and of the four limbs was noted. MRI of the brain and spine was unremarkable; nerve conduction studies revealed a chronic, predominantly demyelinating, sensory-motor polyneuropathy, probably due to diabetes. Routine CSF examination was unrevealing and serum GFAP level was 89.6 pg/mL; however, the autoimmunity tests revealed a high-titer positivity for anti-IgLON5 autoantibodies in both CSF and serum, leading to the diagnosis of anti-IgLON5 disease. Symptoms improved significantly after intravenous methylprednisolone. Conclusions Hemifacial and hemiorolingual myorhythmia along with peculiar oculomotor abnormalities characterizes the multifaceted clinical picture of our case. The complex semiology of our patient may reflect multifocal targeting of the autoimmune process or sequential spreading of tau inclusions in different brain areas. Our patient’s optimal response to glucocorticoid monotherapy could be underpinned by a slightly different phenotype in which autoimmunity plays a greater pathogenic role than tauopathy, with a lower burden of tau deposition. In such patients, neurodegeneration and tau accumulation could be merely secondary to immune-mediated neuronal dysfunction, supporting the existence of a group of glucocorticoid-responsive patients.

Abstract Skeletal muscle contractions are initiated by action potentials, which are sensed by the voltage-gated calcium channel (CaV1.1) and are conformationally coupled to calcium release from intracellular stores. Notably, CaV1.1 contains four separate voltage-sensing domains (VSDs), which activate channel gating and excitation-contraction (EC-) coupling at different voltages and with distinct kinetics. Here we show that a single VSD of CaV1.1 controls skeletal muscle EC-coupling. Whereas mutations in VSDs I, II and IV affect the current properties but not EC-coupling, only mutations in VSD III alter the voltage-dependence of depolarization-induced calcium release. Molecular dynamics simulations reveal comprehensive, non-canonical state transitions of VSD III in response to membrane depolarization. Identifying the voltage sensor that activates EC-coupling and detecting its unique conformational changes opens the door to unraveling the downstream events linking VSD III motion to the opening of the calcium release channel, and thus resolving the signal transduction mechanism of skeletal muscle EC-coupling.

Brucellosis is an infectious disease of animals that can infect humans. The disease causes significant economic losses and threatens human health. A timely and accurate disease diagnosis plays a vital role in the identification of brucellosis. In addition to traditional diagnostic methods, molecular methods allow diagnosis and typing of the causative agent of brucellosis. This review will discuss various methods, such as Bruce-lаdder, Suiladder, high-resolution melt analysis, restriction fragment length polymorphism, multilocus sequence typing, multilocus variable-number tandem repeat analysis, and whole-genome sequencing single-nucleotide polymorphism, for the molecular typing of Brucella and discuss their advantages and disadvantages.

We consider two fluids in a 2-dimensional region: The lower fluid occupies an infinitely depth region, while the upper fluid occupies a region with a fixed upper boundary. We study the dynamics of the interface between the two fluids (interface problem) in the limit in which the interface has a space periodic profile, is close to horizontal, and has a "long wave profile". We use a Hamiltonian normal form approach to show that up to corrections of second order, the equations are approximated by two decoupled Benjamin-Ono equations.

Abstract An understanding of the extent to which target audiences consider different nutrition-related messages to be effective could assist campaign developers design more persuasive communications. Accordingly, this study sought to develop and assess the utility of the Perceived Effectiveness of Nutrition Messages Scale (PENMS). A longitudinal online survey was completed by Australian adults (n = 5,014 at Time 1 and 2,880 at Time 2). At T1, respondents saw one of two messages promoting healthy eating. They were then administered the PENMS, and asked how likely they were to engage in the behaviour specified in the message. Respondents completed the PENMS again at T2. An exploratory factor analysis was performed on PENMS scores and measures of reliability and validity obtained. Two factors were identified: ‘effects perceptions’ (Factor 1) and ‘message perceptions’ (Factor 2). Internal consistency of scores was 0.82 for Factor 1 and 0.70 for Factor 2. Test re-test reliability was 0.76 and 0.69 for Factors 1 and 2, respectively. Scores on both factors were moderately correlated with behavioural intentions. The favourable results for PENMS scores suggest the scale may be a useful tool for assessing the extent to which target audiences consider different nutrition-related messages to be effective.

Abstract Simulation Analysis and Modeling II (SAAM II) is a graphical modeling software used in life sciences for compartmental model analysis, particularly, but not exclusively, appreciated in pharmacokinetics (PK) and pharmacodynamics (PD), metabolism, and tracer modeling. Its intuitive “circles and arrows” visuals allow users to easily build, solve, and fit compartmental models without the need for coding. It is suitable for rapid prototyping of models for complex kinetic analysis or PK/PD problems, and in educating students and non‐modelers. Although it is straightforward in design, SAAM II incorporates sophisticated algorithms programmed in C to address ordinary differential equations, deal with complex systems via forcing functions, conduct multivariable regression featuring the Bayesian maximum a posteriori, perform identifiability and sensitivity analyses, and offer reporting functionalities, all within a single package. After 26 years from the last SAAM II tutorial paper, we demonstrate here SAAM II's updated applicability to current life sciences challenges. We review its features and present four contemporary case studies, including examples in target‐mediated PK/PD, CAR‐T‐cell therapy, viral dynamics, and transmission models in epidemiology. Through such examples, we demonstrate that SAAM II provides a suitable interface for rapid model selection and prototyping. By enabling the fast creation of detailed mathematical models, SAAM II addresses a unique requirement within the mathematical modeling community.

ABSTRACT The limited temporal completeness and taxonomic accuracy of species lists, made available in a traditional manner in scientific publications, has always represented a problem. These lists are invariably limited to a few taxonomic groups and do not represent up-to-date knowledge of all species and classifications. In this context, the Brazilian megadiverse fauna is no exception, and the Catálogo Taxonômico da Fauna do Brasil (CTFB) (http://fauna.jbrj.gov.br/), made public in 2015, represents a database on biodiversity anchored on a list of valid and expertly recognized scientific names of animals in Brazil. The CTFB is updated in near real time by a team of more than 800 specialists. By January 1, 2024, the CTFB compiled 133,691 nominal species, with 125,138 that were considered valid. Most of the valid species were arthropods (82.3%, with more than 102,000 species) and chordates (7.69%, with over 11,000 species). These taxa were followed by a cluster composed of Mollusca (3,567 species), Platyhelminthes (2,292 species), Annelida (1,833 species), and Nematoda (1,447 species). All remaining groups had less than 1,000 species reported in Brazil, with Cnidaria (831 species), Porifera (628 species), Rotifera (606 species), and Bryozoa (520 species) representing those with more than 500 species. Analysis of the CTFB database can facilitate and direct efforts towards the discovery of new species in Brazil, but it is also fundamental in providing the best available list of valid nominal species to users, including those in science, health, conservation efforts, and any initiative involving animals. The importance of the CTFB is evidenced by the elevated number of citations in the scientific literature in diverse areas of biology, law, anthropology, education, forensic science, and veterinary science, among others.

Abstract Background Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model. Methods In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves. Results After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca2+ homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076). Conclusions Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.

Abstract Total hip arthroplasty (THA) is the best surgical approach for treating advanced hip degeneration, providing pain relief, and improved function in most cases. In the past, MR imaging quality has been highly compromised by in-plane distortions, inadequate fat saturation, and other artifacts due to metal components of THA. Technological advancements have made pathologic conditions, which were previously hidden by periprosthetic artifacts, outstanding features due to the optimization of several sequences. To date, several short and long-term complications involving bony and soft-tissue structures may be detected through magnetic resonance imaging (MRI). The use of MRI with adapted sequences and protocols may drastically reduce artifacts thereby providing essential pre-operative elements for planning revision surgery of failed THA. This review has the purpose of conveying new insights to musculoskeletal radiologists about the techniques to suppress metal-related artifacts and the hallmark MRI findings of painful THA. Critical relevance statement Advancements in metal-suppression have given radiologists the opportunity to play an emerging role in THA management. This article provides technical and imaging insights into challenges that can be encountered in cases of THA, which may present complications and characteristic imaging findings. Key Points Imaging total hip arthroplasty requires adapted MRI protocol and awareness of the common complications. We have reported the available metal-suppression sequences for evaluating total hip arthroplasty. Many structures and conditions should be considered when dealing with painful aseptic or septic arthroplasty. Graphical Abstract

Abstract Background Knee osteoarthritis (KOA) represents a widespread degenerative condition among adults that significantly affects quality of life. This study aims to elucidate the biomechanical implications of proximal fibular osteotomy (PFO), a proposed cost-effective and straightforward intervention for KOA, comparing its effects against traditional high tibial osteotomy (HTO) through in-silico analysis. Methods Using medical imaging and finite element analysis (FEA), this research quantitatively evaluates the biomechanical outcomes of a simulated PFO procedure in patients with severe medial compartment genu-varum, who have undergone surgical correction with HTO. The study focused on evaluating changes in knee joint contact pressures, stress distribution, and anatomical positioning of the center of pressure (CoP). Three models are generated for each of the five patients investigated in this study, a preoperative original condition model, an in-silico PFO based on the same original condition data, and a reversed-engineered HTO in-silico model. Results The novel contribution of this investigation is the quantitative analysis of the impact of PFO on the biomechanics of the knee joint. The results provide mechanical evidence that PFO can effectively redistribute and homogenize joint stresses, while also repositioning the CoP towards the center of the knee, similar to what is observed post HTO. The findings propose PFO as a potentially viable and simpler alternative to conventional surgical methods for managing severe KOA, specifically in patients with medial compartment genu-varum. Conclusion This research also marks the first application of FEA that may support one of the underlying biomechanical theories of PFO, providing a foundation for future clinical and in-silico studies.

Objective: To map the dimensions of quality of life in patients with heart failure (HF) and sarcopenia. Methods: The scoping review will adhere to the JBI Manual for Evidence Synthesis methodology and will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). Searches will encompass MEDLINE/PubMed, SCOPUS, EMBASE/Elsevier, LILACS, IBECS, BDENF (BVS), SciELO, Core Collection (Clarivate Analytics), CINAHL, Academic Search Premier (EBSCO), PsycINFO (APA), Cochrane Library, Epistemonikos, and academic search engines: Google Scholar and Bielefeld Academic Search Engine (BASE), without language or date restrictions. Inclusion criteria: Population — adults with HF and sarcopenia; Concept — Dimensions of quality of life including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression — defined based on the EQ-5D-3L questionnaire; Context — any health care setting. Two independent reviewers will select studies and extract data, with a third reviewer consulted in cases of discrepancies. Findings will be presented graphically with a narrative summary. Expected results: We aim to uncover key dimensions of quality of life in individuals with HF and sarcopenia through this scoping review. Anticipated outcomes include insights into mobility, self-care, usual activities, pain/discomfort, and anxiety/depression across diverse health care settings. Relevance: This review sheds light on the interplay between HF and sarcopenia and its impact on quality of life. The findings may guide interventions, inform evidence-based decision-making, and contribute to targeted strategies to improve the well-being of individuals managing both conditions. Review registration: Open Science Framework [https://archive.org/details/osf-registrations-jn387-v1].

Background: Sleep is a complex phenomenon that affects several aspects of life, including cognitive functioning, emotional regulation, and overall well-being. Sleep disturbances, especially during adolescence, can negatively impact emotional regulation, making it a critical factor in targeting psychopathology. Methods: This study explores the interplay between emotional dysregulation (ED) and sleep patterns in a sample of 90 adolescent patients by means of self- and parent-rated clinical measures. Results: Our findings reveal a bidirectional relationship between ED and sleep problems. Adolescents with higher affective instability experience poorer sleep quality, while those with worse sleep quality exhibit higher internalizing problems. Additionally, emotional reactivity is associated with disrupted circadian rhythms. Conclusions: These results emphasize the significance of addressing sleep problems in the context of psychopathology treatment, potentially leading to improved outcomes. Further research is needed to determine the most effective treatment strategies, including nonpharmacological and pharmacological interventions. Understanding the intricate relationship between sleep problems and emotion regulation offers insights for more targeted and effective treatment approaches for youths struggling with ED.

Higher education institutions have been investing in teachers’ professional development and pedagogical innovation, on the one hand, aiming to promote the quality of institutions and, on the other hand, aiming to promote students’ personal and academic development. One of the methodologies that has received particular attention is service-learning, which aims to promote students’ learning by providing a service to vulnerable community groups. In this study, we aim to present the results of the application of this methodology in a fourth-year social work course. To this end, a mixed-methods study was conducted with 10 students in the Contemporary Social Work III course using the service-learning methodology. Students experienced between 15 and 30 h of service-learning, most of them for 7 weeks or more in an elder care institution, with varied activities such as social consulting and home visits. When we tried to understand the students’ perceived impact, we found higher mean scores in the post-test, with statistically significant differences on several dimensions, particularly self-confidence, problem solving, adaptability and flexibility, dealing with diversity and multiculturalism, understanding complex social issues, and a sense of purpose and life. These data are aligned with the qualitative analysis, which identified six themes such as the integration of practice and theory, development of skills, positive impact on academic training, valuing practical experience, reflective and meaningful learning, and support and guidance. The results highlight the value of pedagogical innovation for students’ skills, especially when it is aligned with the identity and mission of the institution and the values of the study program.

The predatory firefly Photuris elliptica is common throughout the Atlantic Forest and has been proposed as a biomonitor due to the species’ narrow niche and elevational range. However, the species is only known from adults, and a more effective monitoring of its populations hinges on the lack of knowledge on their immature stages. Recent sampling in ferruginous caves and inserted in other lithologies, on sites in the Atlantic Forest and Cerrado, have led to the capture of firefly larvae later reared to adults in the lab. Firefly larvae have been reported in South American caves before; however, they have only been identified to family due to the adult-biased taxonomy of Lampyridae. Here, we provide an updated diagnosis of Photuris elliptica, describe its immature stages for the first time, and update the distribution of the species. The larvae of Photuris elliptica were observed to interact with guano of several bat species, including that of vampire bats. These observations are consistent with the less specialized feeding preferences of photurine larvae, unlike most other firefly taxa, which specialize in gastropods and earthworms. It is yet unclear whether P. elliptica are cave specialists. However, since its occurrence outside caves remains unknown, protecting cave environments must be considered in conservation strategies for this important biomonitor species.

This research investigates the suitability of PRISMA and Sentinel-2 satellite imagery for retrieving topsoil properties such as Organic Matter (OM), Nitrogen (N), Phosphorus (P), Potassium (K), and pH in croplands using different Machine Learning (ML) algorithms and signal pre-treatments. Ninety-five soil samples were collected in Quzhou County, Northeast China. Satellite images captured soil reflectance data when bare soil was visible. For PRISMA data, a Linear Mixture Model (LMM) was used to separate soil and Photosynthetic Vegetation (PV) endmembers, excluding Non-Photosynthetic Vegetation (NPV) using Band Depth values at the 2100 nm absorption peak of cellulose. Sentinel-2 bare soil reflectance spectra were obtained using thresholds based on NDVI and NBR2 indices. Results showed PRISMA data provided slightly better accuracy in retrieving topsoil nutrients than Sentinel-2. While no optimal predictive algorithm was best, absorbance data proved more effective than reflectance. PRISMA results demonstrated potential for predicting soil nutrients in real scenarios.

In this contribution, new data concerning the distribution of native vascular flora in Italy are presented. It includes new records, confirmations, and exclusions to the Italian administrative regions for taxa in the genera Anacyclus, Anthyllis, Bolboschoenus, Catapodium, Festuca, Hordeum, Lavandula, Ophrys, Pseudopodospermum, Rosa, Sorbus and Spergula. Nomenclatural and distribution updates, published elsewhere, and corrigenda are provided as Suppl. material 1.

Abstract Intermediate-depth seismicity is common in subducting slabs and the seismicity rate shows some statistically significant yet enigmatic global positive correlation with the maximal throw of outer-rise normal faults. Here, we have simulated the formation and subduction of outer-rise faults, using 2D thermomechanical numerical models of intra-oceanic subduction with coupled brittle-ductile damage of bending plates. We observed that outer-rise faults are formed episodically during slab segmentation and their maximal throw grows with time. When been subducted to intermediate depth, these faults are locally reactivated either by i) slab unbending/bending, simultaneous to the formation of new outer-rise faults or ii) episodic interplate coupling related to the rugged morphology of the faulted downgoing plate. Faults reactivation is concurrent with a local, transient deviatoric stress increase in intraslab domains among these structures. We suggest that slab domains affected by stress increase could be the appropriate location where potential brittle deformation can occur, generating intermediate-depth intraslab earthquakes, that are predominantly localized in heterogeneous regions of dense faulting formed within slab-segments boundaries. The temporal coincidence of stress growth at intermediate depths and throw-growth of, newly-formed, outer-rise faults at the surface may possibly explain the observed global positive correlation of intermediate-depth seismicity rate with maximal fault throw.

Abstract Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient’s specific factors.

Abstract Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence. Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity. G protein-coupled receptors (GPCRs) are among the main modulators of metabolism and energy balance. They, for instance, regulate appetite and satiety in certain hypothalamic neurons, as well as glucose and lipid metabolism and hormone secretion from adipocytes. Mutations in some GPCRs, such as the melanocortin receptor type 4 (MC4R), have been associated with early-onset obesity. Here, we identified the adhesion GPCR latrophilin 1 (ADGRL1/LPHN1) as a member of the regulating network governing food intake and the maintenance of energy balance. Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity, accompanied by dysregulation of glucose homeostasis. Consistently, we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity. Therefore, we propose that LPHN1 dysfunction is a risk factor for obesity development.

Abstract In vitro models of pediatric brain tumors (pBT) are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor. We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples, including 155 tumors and 86 pBT-derived cell cultures, considering serum vs serum-free conditions, late vs early passages, and dimensionality (2D vs 3D cultures). We performed a t-SNE classification and identified differentially methylated regions in tumors compared to cell models. Early cell cultures recapitulate the original tumor, but serum media and 2D culturing were demonstrated to significantly contribute to the divergence of DNAm profiles from the parental ones. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration. In conclusion, DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.

Abstract Background A major contributing factor to glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive environment, where GBM-associated myeloid cells, including resident microglia and peripheral monocyte-derived macrophages, play critical pro-tumoral roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical in GBM patients and whether this heterogeneity is recapitulated in patient-derived orthotopic xenografts (PDOXs). A thorough understanding of the GBM ecosystem and its recapitulation in preclinical models is currently missing, leading to inaccurate results and failures of clinical trials. Methods Here, we report systematic characterization of the tumor microenvironment (TME) in GBM PDOXs and patient tumors at the single-cell and spatial levels. We applied single-cell RNA sequencing, spatial transcriptomics, multicolor flow cytometry, immunohistochemistry, and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM PDOXs representing different tumor phenotypes were compared to glioma mouse GL261 syngeneic model and patient tumors. Results We show that GBM tumor cells reciprocally interact with host cells to create a GBM patient-specific TME in PDOXs. We detected the most prominent transcriptomic adaptations in myeloid cells, with brain-resident microglia representing the main population in the cellular tumor, while peripheral-derived myeloid cells infiltrated the brain at sites of blood–brain barrier disruption. More specifically, we show that GBM-educated microglia undergo transition to diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs. Additionally, we found novel microglial states expressing cell cycle programs, astrocytic or endothelial markers. Lastly, we show that temozolomide treatment leads to transcriptomic plasticity and altered crosstalk between GBM tumor cells and adjacent TME components. Conclusions Our data provide novel insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumors. We show the key role of microglial phenotypic states in supporting GBM tumor growth and response to treatment. Our data place PDOXs as relevant models to assess the functionality of the TME and changes in the GBM ecosystem upon treatment. Graphical Abstract

Thanks to the frequent revisiting, satellite microwave radiometers have great potential for surface soil moisture (SM) monitoring. However, their spatial resolution is not sufficient for hydrological studies in small catchments as well as applications to precision farming. In this study, a disaggregation technique based on machine learning is proposed: the technique combines Sentinel-1 (S-1) SAR data with SM generated from advanced microwave scanning radiometer 2 by the IFACs HydroAlgo algorithm, with the aim of enhancing the SM spatial resolution from the original 10 km to about 30 m. To this scope, two machine-learning techniques have been considered for the implementation, namely artificial neural networks (ANNs) and random forests (RF). Training is carried out by aggregating and coregistering S-1 data with the HydroAlgo SM at 10-km resolution. After training, the ANN and RF algorithms are applied pixel-by-pixel to the S-1 images at full resolution for generating the enhanced SM maps. The method has been implemented and validated in two agricultural areas located in Central Italy, where a series of experiments has been carried out between 2019 and 2020 for collecting the main soil and vegetation parameters at the same time of satellite overpasses. To assess the actual resolution of the output SM, the validation against in situ measurements has been carried out by aggregating data at 10, 30, 50, and 70 m. The results confirmed the effectiveness of the proposed method: validation carried out at 30 m obtained R≃0.82 and RMSE≃0.05 m3/m3 that represent a noticeable improvement with respect to the results obtained by HydroAlgo at 10 km (R≃0.56 and RMSE >> 0.1 m3/m3). Validation results also pointed out the superior performances of the ANN based with respect to the RF-based disaggregation.

ABSTRACT In 2000, Cleide Costa published a paper presenting the state of knowledge of the Neotropical Coleopte ra, with a focus on the Brazilian fauna. Twenty-four years later, thanks to the development of the Coleoptera section of the Taxonomic Catalog of the Brazilian Fauna (CTFB - Catálogo Taxonômico da Fauna do Brasil) through the collaboration of 100 coleopterists from all over the globe, we can build on Costa’s work and present an updated overview of the state of knowledge of the beetles from Brazil. There are currently 35,699 species in 4,958 genera and 116 families known to occur in the country, including representatives of all extant suborders and superfamilies. Our data show that the Brazilian beetle fauna is the richest on the planet, concentrating 9% of the world species diversity, with some estimates accounting to up to 15% of the global total. The most diverse family in numbers of genera is Cerambycidae (1,056 genera), while in number of species it is Chrysomelidae (6,079 species). Conotrachelus Dejean, 1835 (Curculionidae) is the most species-rich genus, with 570 species. The French entomologist Maurice Pic is the author who has contributed the most to the naming of species recorded from Brazil, with 1,794 valid names in 36 families, whereas the Brazilians Ubirajara R. Martins and Maria Helena M. Galileo are the only ones among the top-ten authors to have named species in the 21st century. Currently, approximately 144 new species of Brazilian beetles are described each year, and this average is projected to increase in the next decade to 180 species per year, or about one new Brazilian beetle every two days.

The virtual Cross Array Task (CAT) is an educational platform designed to evaluate algorithmic thinking (AT) skills among students within Swiss compulsory education. This tool introduces an adaptable multi-interface system, enabling users to interact via intuitive gesture-based commands or through a visual programming interface that uses drag-and-drop blocks, facilitating a versatile approach to constructing and understanding algorithms. The platform encompasses a comprehensive training module for skill acquisition and a validation module for assessment. The system offers real-time feedback to users during activities, adjusting dynamically based on their actions, providing insights into progress and areas for improvement, thereby facilitating learning and performance enhancement. With multilingual capabilities extended to English, German, French, and Italian, the virtual CAT is intricately crafted to meet the diverse needs of educational contexts across various regions. Preliminary application and evaluation through a small-scale study indicate the virtual CAT’s potential to offer scalable assessment and a robust platform for integrating AT into broader educational and research methodologies, setting the stage for its integration into academic research and daily pedagogical practice.

Epizootic haemorrhagic disease (EHD), caused by the EHD virus (EHDV), is a vector-borne viral disease transmitted through Culicoides biting midges. EHDV comprises seven serotypes (1, 2, and 4–8), with EHDV-8 having recently emerged and spread in Europe over the last two years. Such event has raised concerns about the significant threat posed by EHDV-8 to livestock industry. In this study, an inactivated vaccine against EHDV-8 (vEHDV8-IZSAM) was developed. Safety and efficacy of the vaccine were evaluated in calves through clinical, serological, and virological monitoring following experimental challenge.The vaccine was proven safe, with only transient fever and localized reactions observed in a few animals, consistent with adjuvanted vaccine side effects. vEHDV8-IZSAM elicited a robust humoral response, as evidenced by the presence of neutralizing antibodies. After challenge with a virulent isolate, viraemia and clinical signs were evidenced in control animals but in none of the vaccinated animals.This study highlights the potential of vEHDV8-IZSAM as a safe and highly effective vaccine against EHDV-8 in cattle. It offers protection from clinical disease and effectively prevents viraemia. With the recent spread of EHDV-8 in European livestock, the use of an inactivated vaccine could be key in protecting animals from clinical disease and thus to mitigate the economic impact of the disease. Further investigations are warranted to assess the duration of the induced immunity and the applicability of this vaccine in real-world settings. Accordingly, joint efforts between public veterinary institutions and pharmaceutical companies are recommended to scale up vaccine production.

The study aimed at investigating the impact of an innovative Wake Vortex Alert (WVA) avionics on pilots' operation and mental states, intending to improve aviation safety by mitigating the risks associated with wake vortex encounters (WVEs). Wake vortices, generated by jet aircraft, pose a significant hazard to trailing or crossing aircrafts. Despite existing separation rules, incidents involving WVEs continue to occur, especially affecting smaller aircrafts like business jets, resulting in aircraft upsets and occasional cabin injuries. To address these challenges, the study focused on developing and validating an alert system that can be presented to air traffic controllers, enabling them to warn flight crews. This empowers the flight crews to either avoid the wake vortex or secure the cabin to prevent injuries. The research employed a multidimensional approach including an analysis of human performance and human factors (HF) issues to determine the potential impact of the alert on pilots' roles, tasks, and mental states. It also utilizes Human Assurance Levels (HALs) to evaluate the necessary human factors support based on the safety criticality of the new system. Realistic flight simulations were conducted to collect data of pilots' behavioural, subjective and neurophysiological responses during WVEs. The data allowed for an objective evaluation of the WVA impact on pilots' operation, behaviour and mental states (mental workload, stress levels and arousal). In particular, the results highlighted the effectiveness of the alert system in facilitating pilots' preparation, awareness and crew resource management (CRM). The results also highlighted the importance of avionics able to enhance aviation safety and reducing risks associated with wake vortex encounters. In particular, we demonstrated how providing timely information and improving situational awareness, the WVA will minimize the occurrence of WVEs and contribute to safer aviation operations.

ABSTRACT: Italian ryegrass (Lolium multiflorum Lam.) is considered one of the main winter cover crops in southern Brazil; however, it is a weed species with a record of being resistant to several herbicides. The settlement of this species in agricultural areas occurs through the seed bank in the soil, and measures that interfere with seed production can assist in its management. The present study evaluated the phytotoxicity, production, and quality of Italian ryegrass seeds through the application of herbicides 2,4-D and saflufenacil at different stages of development. Three trials were conducted, a completely randomized experimental design for the first two and randomized blocks for the third, all with four replications. The treatments were arranged in a 3x3 factorial scheme, in which factor A was composed of the herbicides saflufenacil (35 g a.i. ha-1), 2,4-D (1005 g a.e. ha-1), plus control without application; and factor B consisted of the booting, anthesis, and maturation Italian ryegrass development stages. The phytotoxicity of the herbicides to Italian ryegrass did not exceed 30%, with saflufenacil causing the greatest injury at anthesis. There was a reduction in Italian ryegrass seed yield when herbicides 2,4-D and saflufenacil were applied, and the application of 2,4-D and saflufenacil at anthesis reduced the percentage of full seeds. The number of empty Italian ryegrass seeds was higher when saflufenacil was applied at anthesis. The application of 2,4-D at maturity reduced Italian ryegrass germination and radicle length. From this perspective, these herbicides can help reduce the production and quality of Italian ryegrass seeds.

Site selection analysis is a fundamental methodology for the regeneration of Xylella fastidiosa subsp. pauca (Xfp) infected areas, with the introduction of Xfp immune/resistant tree crop species. The diffusion of these species could be assessed by combining ecological optima data, climate and soil attributes of the study area, and GIS tools. The study aimed to evaluate the potential suitability of eight Xfp immune tree crops, including Neglected and Underutilized Species (NUS) drought-resistant and new species, as follows: carob, hawthorn, prickly pear, mulberry, loquat, walnut, persimmon, and avocado. The use of GIS tools allowed the integration of different layers, such as climate and soil, to contribute to the identification of suitable areas for the cultivation of these tree crops helping the policy-makers to define plans for land use at a regional scale. Following the ecological optima, which represents the ideal environmental conditions for each species, this analysis provided valuable insights into the compatibility of the selected tree crops with the prevailing environmental factors in the affected area. Carob revealed its remarkable adaptability and drought resistance, presenting the broadest suitability. Hawthorn and Loquat also exhibited high adaptability, indicating their potential contribution to agricultural diversification and ecological balance. Conversely, crops like Avocado, Prickly pear, and Walnut, despite their economic value, demonstrated limited adaptability due to their specific soil and climate requirements. These findings can potentially contribute to the development of strategies for the policy-makers, aimed at diversifying and enhancing the resilience of agricultural systems, facing the problem of emerging quarantine pathogens and the incoming climate change, and highlighting the possibility of opening new cultivation scenarios in the zones affected by Xfp.

IntroductionIn recent years, Europe has experienced a significant flux of migrants, often hailing from regions endemic for schistosomiasis and strongyloidiasis, diseases frequently overshadowed by tuberculosis (TB) in healthcare priorities. While TB remains a prevalent concern among this population, chronic schistosomiasis and strongyloidiasis are frequently neglected. Motivated by this observation, we aimed to investigate the prevalence of schistosomiasis and strongyloidiasis in patients attending our TB outpatient clinic.MethodsWe conducted a retrospective, observational study spanning from June 2020 to January 2024, focusing on patients attending the TB outpatient clinic of Luigi Sacco Hospital of Milan, Italy. Serology tests were performed in patients with a history suggestive of exposure to either Schistosoma spp. or Strongyloides stercoralis.ResultsAmong the 228 patients included in the study, 84 (36.8%) individuals were born in Italy, one came from Spain, 80 (35.1%) from strongyloidiasis moderate or high endemic countries and 63 (27.6%) from areas endemic for schistosomiasis and strongyloidiasis. Of these patients, 160 (70.2%) were diagnosed with tuberculosis disease, while 68 (29.8%) had tuberculosis infection. The prevalence of schistosomiasis was 26.7%, while that of strongyloidiasis was 7.8%. Notably, 3 patients tested positive for both infections.ConclusionOur study highlights the often-underestimated prevalence of schistosomiasis and strongyloidiasis among migrants accessing healthcare for TB, underscoring the importance of increased awareness and targeted screening within this population.

We describe a surgical technique to repair medial meniscus posterior root tears through a transtibial pullout repair with a subcortical button for tibial fixation. This technique allows progressive tensioning of the repaired root without losing tension both during suturing of the knots above the button and after the procedure, owing to the specific button configuration.

In recent years, severe climate change leading to by water scarcity reduced water quality has increased the need for effective irrigation strategies for agricultural production. Among these, the reuse of reclaimed water represents a non-expensive and reliable solution. The effect of conventional or reclaimed water, applying convention or smart fertigation system, were investigated during two irrigation seasons on yield, qualitative and biochemical traits of pomegranates fruit (cv Wonderful One) at harvest, and after storage at 7 °C. The results of this study showed that using reclaimed waters with different fertigation systems did not affect the pH values, total soluble solids, and titratable acidity on pomegranates fruit showing slight decrease changes only during postharvest storage. On the other hand, the respiration rate was not affected by water quality. Furthermore, the antioxidant activity was also preserved during storage in pomegranates fruit from plants irrigated with reclaimed water by applying conventional or smart fertigation. The analysis also identified 52 compounds by UHPLC-MSn and HPLC-UV-Vis analyses. A slight decrease (about 17 %) at harvest and during storage in polyphenols content was shown in fruit grown using reclaimed water. The study demonstrates that using reclaimed water is a sustainable and effective way to limit the use of conventional water for irrigating pomegranate crops without significant reduction in yield, or in qualitative and nutritional values of the fruit at harvest and during storage.

Abstract Transbronchial lung cryobiopsy (TBLC) is a relatively new technique for obtaining lung biopsies, known for being the least invasive method while offering a high diagnostic yield, a favourable safety profile, and a significant reduction in morbidity, mortality, and hospital stay length compared to surgical lung biopsy. Radial‐EBUS (r‐EBUS) represent a cornerstone modality for accessing ‘invisible’ peripheral pulmonary lesions. However, a major drawback of these techniques is the lack of ‘real‐time’ visualization of the biopsy being obtained. In this case report, we present a young woman who was referred to us with a cough, haemoptysis, and a non‐resolving lung consolidation. She underwent TBLC under real‐time rEBUS guidance. This clinical case demonstrates that, in specific clinical scenarios, TBLC with real‐time rEBUS is an excellent diagnostic tool.

IntroductionThe almond tree is a major global nut crop, and its production has surged dramatically in recent years. Super high-density (SHD) planting systems, designed to optimize resource efficiency and enhance precocity, have gained prominence in almond cultivation. A shift in cropping systems toward sustainable intensification (SI) pathways is imperative, and so maximizing branching density within the canopies of SHD trees is crucial to establish and maintain productive potential, especially for hedge-pruned trees. This study investigates the influence of different almond cultivars grafted onto a novel growth-controlling rootstock on tree architectural and growth parameters in a SHD orchard. This open field research provided valuable insights for the development and application of new tools and methods to increase productivity and sustainability in almond growing.MethodsThree cultivars (Lauranne® Avijour, Guara Tuono, and Filippo Cea) were evaluated in Gravina in Puglia (BA) over a two-year period. Canopy growth parameters, such as canopy volume and trunk cross-sectional area, and architectural traits, like branching density, branching angle, number and length of subterminal shoots, and number of brachyblasts, were measured through qualitative and quantitative measurements.Results and discussionResults revealed significant differences in tree height, canopy thickness, width, volume, and vigor among the cultivars. Architectural traits, including branch parameters, brachyblast parameters, and subterminal shoots, varied among the cultivars. Lauranne displayed a more compact well-distributed canopy and exhibited the lowest vigor. Filippo Cea showed the highest vigor and the greatest canopy volume. Tuono had a higher number of buds and bud density. The best ideotype for SHD orchards is a smaller tree, with high branching density and smaller trunk diameters, i.e. the vigor. Cv. Lauranne seemed to be the best cultivar, mostly with the lowest tree vigor of all the cultivars involved. These findings provide valuable insights for almond growers and breeders seeking to optimize orchard design and management for enhanced SHD orchards productivity and sustainability. Future research will explore the relationship between canopy architecture and yield parameters, considering different scion/rootstock combinations in different environmental conditions.

The Neuropeptide Y/RFamide-like receptors belong to the Rhodopsin-like G protein-coupled receptors G protein-coupled receptors (GPCRs) and are involved in functions such as locomotion, feeding and reproduction. With 41 described receptors they form the best-studied group of neuropeptide GPCRs in Caenorhabditis elegans. In order to understand the expansion of the Neuropeptide Y/RFamide-like receptor family in nematodes, we started from the sequences of selected receptor paralogs in C. elegans as query and surveyed the corresponding orthologous sequences in another 159 representative nematode target genomes. To this end we employed a automated pipeline based on ExonMatchSolver, a tool that solves the paralog-to-contig assignment problem. Utilizing subclass-specific HMMs we were able to detect a total of 1557 Neuropeptide Y/RFamide-like receptor sequences (1100 NPRs, 375 FRPRs and 82 C09F12.3) in the 159 target nematode genomes investigated here. These sequences demonstrate a good conservation of the Neuropeptide Y/RFamide-like receptors across the Nematoda and highlight the diversification of the family in nematode evolution. No other genus shares all Neuropeptide Y/RFamide-like receptors with the genus Caenorhabditis. At the same time, we observe large numbers of clade specific duplications and losses of family members across the phylum Nematoda.

Objetivo: descrever as evidências acerca dos efeitos da Terapia por Pressão Negativa no desfecho clínico da Síndrome de Fournier. Método: trata-se de uma revisão integrativa da literatura, realizada entre os meses de março a junho de 2023, por dois pesquisadores de forma independente, com busca nas bases de dados Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science (WoS) e Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), utilizando descritores controlados cruzados entre si com os operadores booleanos AND e OR. Utilizou-se do software Rayann e do método PRISMA para seleção e apresentação de dados, respectivamente. Resultados: através da busca e após o processo de seleção e extração de dados, foram inclusos 2 estudos com análise retrospectiva que recomendam o uso da terapia com pressão subatmosférica por se tratar de uma terapêutica que promove neoangiogênese, controle do exsudato, reduz a necessidade de eventos cirúrgicos, além de prevenir maiores complicações como infecções, resultando em uma cicatrização eficaz e mais rápida. Conclusão: ainda não há evidências robustas que possam proporcionar segurança na sua indicação e implementação, tornando-se necessária a continuidade no desenvolvimento de novos estudos com melhor qualidade metodológica.

Abstract Background The analysis of large and complex biological datasets in bioinformatics poses a significant challenge to achieving reproducible research outcomes due to inconsistencies and the lack of standardization in the analysis process. These issues can lead to discrepancies in results, undermining the credibility and impact of bioinformatics research and creating mistrust in the scientific process. To address these challenges, open science practices such as sharing data, code, and methods have been encouraged. Results CREDO, a Customizable, REproducible, DOcker file generator for bioinformatics applications, has been developed as a tool to moderate reproducibility issues by building and distributing docker containers with embedded bioinformatics tools. CREDO simplifies the process of generating Docker images, facilitating reproducibility and efficient research in bioinformatics. The crucial step in generating a Docker image is creating the Dockerfile, which requires incorporating heterogeneous packages and environments such as Bioconductor and Conda. CREDO stores all required package information and dependencies in a Github-compatible format to enhance Docker image reproducibility, allowing easy image creation from scratch. The user-friendly GUI and CREDO's ability to generate modular Docker images make it an ideal tool for life scientists to efficiently create Docker images. Overall, CREDO is a valuable tool for addressing reproducibility issues in bioinformatics research and promoting open science practices.

Este artigo, tem por objetivo discutir sobre a aprendizagem de futuros professores, ao produzirem materiais para o ensino de matemática para uma turma de licenciandos com um aluno cego. Fundamentados na perspectiva da Teoria Histórico-Cultural, proposta por Vigotski, e na Teoria da Atividade, desenvolvida por Leontiev, compreende-se que os sujeitos se desenvolvem e aprendem na interação com os seus pares. Partindo desta premissa, retrata-se aqui a experiência vivenciada por futuros professores durante a organização de materiais que foram utilizados em uma turma de um curso de licenciatura em que um dos estudantes é cego, durante a disciplina de Educação Matemática. A organização e o desenvolvimento das ações se deram por meio do projeto Clube de Matemática (CluMat) da Universidade Federal de Santa Maria (UFSM), do qual participavam um estudante e uma estudante do curso de Licenciatura em Matemática e duas do curso de Pedagogia. Para a produção de dados, foram utilizados planejamentos, relatórios, registros fotográficos e depoimentos dos integrantes do CluMat. Os resultados permitiram evidenciar alguns aspectos que se mostraram como indicativos de aprendizagens tais como: a relevância da constituição de um espaço coletivo de discussão sobre a elaboração de materiais; a mobilização de outros conhecimentos para além dos matemáticos, ao se colocarem no movimento de pensar sobre como envolver todos os estudantes da turma; a preocupação com relação à função que o material exerce no processo educativo; e a troca de conhecimentos, vivências e experiências, interagindo com sujeitos de distintas formações. Palavras-chave: Formação inicial de professores. Ensino de Matemática. Inclusão.

Ambrosia beetles are highly successful as invaders because they are often transported internationally with wood packaging and other wood products and because their inbreeding mating systems facilitates establishment of invading populations. In 2022, two independent insect surveys in canton Ticino (southern Switzerland) revealed the widespread occurrence of the invasive ambrosia beetle Anisandrus maiche (Kurentzov, 1941) from southern to central-upper Ticino. This species is native to east Asia and has previously been found as a non-native invasive species in the United States, Canada, western Russia, Ukraine and, in 2021, in northern Italy. Here, we present the results of several trapping studies using different trap types (bottle traps, funnel traps and Polytrap intercept traps) and attractants and a map of the distribution of the species. In total, 715 specimens of A. maiche, all female, were trapped, and the identity of selected individuals was confirmed by morphological and molecular identification based on three mitochondrial and nuclear markers (COI, 28S and CAD). Trap samples from early April to early September 2022 in intervals of two to four weeks showed that flights of A. maiche occurred mainly from June to mid-August. Isolation of fungal associates of A. maiche from beetles trapped alive revealed the presence of four fungal species, including the ambrosia fungus Ambrosiella cleistominuta, the known mutualist of A. maiche. The identity of A. cleistominuta was confirmed by comparing DNA sequences of its nuclear, internal transcribed spacer (ITS) gene with reference sequences in NCBI and BOLDSYSTEMS. This represents the first record of A. cleistominuta in Europe. Of the other fungal associates isolated from A. maiche in Ticino, Fusarium lateritium is of note as there is a possibility that A. maiche could act as a vector of this plant pathogen. We highlight several research needs that should be addressed to gain insight into the potential impact of these non-native species and to overcome problems with heteroplasmy in COI sequences in studies of invasion and population genetics of ambrosia beetles.

Abstract Background CRISPR-Cas9-based genome engineering represents a powerful therapeutic tool for cartilage tissue engineering and for understanding molecular pathways driving cartilage diseases. However, primary chondrocytes are difficult to transfect and rapidly dedifferentiate during monolayer (2D) cell culture, making the lengthy expansion of a single-cell-derived edited clonal population not feasible. For this reason, functional genetics studies focused on cartilage and rheumatic diseases have long been carried out in cellular models that poorly recapitulate the native molecular properties of human cartilaginous tissue (e.g., cell lines, induced pluripotent stem cells). Here, we set out to develop a non-viral CRISPR-Cas9, bulk-gene editing method suitable for chondrocyte populations from different cartilaginous sources. Methods We screened electroporation and lipid nanoparticles for ribonucleoprotein (RNP) delivery in primary polydactyly chondrocytes, and optimized RNP reagents assembly. We knocked out RELA (also known as p65), a subunit of the nuclear factor kappa B (NF-κB), in polydactyly chondrocytes and further characterized knockout (KO) cells with RT-qPCR and Western Blot. We tested RELA KO in chondrocytes from diverse cartilaginous sources and characterized their phenotype with RT-qPCR. We examined the chondrogenic potential of wild-type (WT) and KO cell pellets in presence and absence of interleukin-1β (IL-1β). Results We established electroporation as the optimal transfection technique for chondrocytes enhancing transfection and editing efficiency, while preserving high cell viability. We knocked out RELA with an unprecedented efficiency of ~90%, confirming lower inflammatory pathways activation upon IL-1β stimulation compared to unedited cells. Our protocol could be easily transferred to primary human chondrocytes harvested from osteoarthritis (OA) patients, human FE002 chondroprogenitor cells, bovine chondrocytes, and a human chondrocyte cell line, achieving comparable mean RELA KO editing levels using the same protocol. All KO pellets from primary human chondrocytes retained chondrogenic ability equivalent to WT cells, and additionally displayed enhanced matrix retention under inflamed conditions. Conclusions We showcased the applicability of our bulk gene editing method to develop effective autologous and allogeneic off-the-shelf gene therapies strategies and to enable functional genetics studies in human chondrocytes to unravel molecular mechanisms of cartilage diseases.

This first research on the organization of the Florentine army assigned to the defense of the dominions would like to answer two questions: firstly, how this aspect of defense was organized, and secondly, whether during the difficult period of constant warfare in the 1420s and 1430s, characterized by a very high fiscal pressure and inflationary phenomena, there were changes in this public sector and whether this also affected some social aspects. Specifically, starting with the valuable data offered by the Citizen’s Catasto of 1427 and comparing it with the expenses of the republic in 1430, we will consider whether there was an increase in soldiers among Florentine citizens in this period and try to understand the reasons for this decision.

One of the most delicate operations in the sugar beet harvesting process is removing the tops from the heads of the root crops without any mechanical damages. The aim of this study is to improve the design of the conveying and unloading system of the sugar beet topper machine. In this paper, a mathematical model of the motion of a cut beet tops particle M, along the conveying and unloading system, has been developed to support the evaluation of kinematic and design parameters, depending on the rotational speed of the thrower blade, the air flow speed, the required ejection speed of particle M, and the position of the trailer that moves alongside the harvester. It has been established that increasing the speed Va of the top particle M, which has left the end of the blade of the thrower, leads to an increase in the arc coordinate S(t) of its movement along the cylindrical section of the casing. Within the range of the speed change from 4 m·s–1 to 8 m·s–1, the value of the arc coordinate S(t) increases by 1.4 times during time t = 0.006 s. Moreover, a rapid decrease in speed V is observed with an increase in the length x of the discharge chute.

Abstract In the digital age, poor public communication catalyzes the spread of disinformation within public opinion. Anyone can produce political content that can reach a global audience, and social media has become a vital tool for political leaders to convey messages to the electorate. The 2022 Italian election campaign has seen the term “nuclear” debated with two different declinations: on the one hand, regarding nuclear energy for civilian use, and on the other hand, regarding the fear of an escalation of the conflict in Ukraine and the use of atomic weapons. This research aims to analyze the social media debate by exploring multiplatform dynamics to qualitatively identify and analyze the connections between social media platforms that we have termed Bridges, a concept drawn from Transmedia Theory to describe the narrative relationship between platforms. The methodological approach will follow an explanatory sequential design that will rely on digital methods to identify connections between platforms (bridges) and then apply an exploratory qualitative approach to enrich the data and capture the nuances of the debate. As expected, we found polarized positions and fragmentation on both issues of civilian nuclear energy and the atomic conflict narrative. Primary evidence shows bridges spreading affective, defective, and infective content across platforms in a multifaceted social media ecosystem. Affective refers to rhetoric that appeals to people’s feelings. Defective means the discussion that brings attention to hyper-partisan news channels, fake news, and misinformation. Infective means bridges with below-the-radar platforms, niche channels, or pseudo-information channels. They use bridges with mainstream platforms to gain the potential to go viral. The paper highlights the importance of cross-platform and interdisciplinary approaches to addressing disinformation in a media ecosystem where social media plays an increasing role in a country’s democratic dynamics.

Abstract Variational quantum metrology represents a powerful tool to optimize estimation strategies, resulting particularly beneficial for multiparameter estimation problems that often suffer from limitations due to the curse of dimensionality and computational complexity. To overcome these challenges, we develop a variational approach able to efficiently optimize a quantum multiphase sensor. Leveraging the reconfigurability of an integrated photonic device, we implement a hybrid quantum-classical feedback loop able to enhance the estimation performances. The quantum circuit evaluations are used to compute the system partial derivatives by applying the parameter-shift rule, and thus reconstruct experimentally the Fisher information matrix. This in turn is adopted as the cost function of a classical learning algorithm run to optimize the measurement settings. Our experimental results showcase significant improvements in estimation accuracy and noise robustness, highlighting the potential of variational techniques for practical applications in quantum sensing and more generally in quantum information processing using photonic circuits.

Abstract Aims The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real‐world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real‐world clinical practice in Italy. Methods and results An observational, retrospective, non‐interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow‐up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow‐up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow‐up. A sensitivity analysis (persistence during the last 4 months of follow‐up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow‐up, out of 606 patients with available data, 434 patients (71.6%) had an HF add‐on drug or drugs concomitant with sacubitril/valsartan. HF‐related hospitalization during follow‐up was numerically higher in non‐persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). Conclusions Real‐world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction.

While text-based CAPTCHAs have been the predominant type of human interaction proofs (HIPs) for many years, image recognition challenges have also gained significant attention. This trend is due, on one hand, to groundbreaking advancements in solving text CAPTCHAs and, on the other hand, to the intrinsic weakness of machines in dealing with cognitive tasks such as those presented in image CAPTCHAs. In addition to classic and even human-centric image CAPTCHA solvers, deep learning has recently emerged as a significant player, providing two unprecedented and, at the same time, contradictory advantages for designers and adversaries. Designers benefit from deep learning techniques to make CAPTCHAs as hard to break as possible, while adversaries utilize deep learning algorithms to attack novel and complicated image-based challenges. Given these premises, this paper presents an analytical study on the applications of deep learning for and against image CAPTCHAs. This study aims to provide a comprehensive overview of the latest advancements in the field, assisting researchers and practitioners in designing image CAPTCHAs that are both user-friendly and resilient against modern attacks.

Abstract Background Preclinical in vivo cancer models are essential tools for investigating tumor progression and response to treatment prior to clinical trials. Although treatment modalities are regularly assessed in mice upon tumor growth in vivo, surgical resection remains challenging, particularly in the orthotopic site. Here, we report a successful surgical resection of glioblastoma (GBM) in patient-derived orthotopic xenografts (PDOXs). Methods We derived a cohort of 46 GBM PDOX models that faithfully recapitulate human disease in mice. We assessed the detection and quantification of intracranial tumors using magnetic resonance imaging (MRI).To evaluate feasibility of surgical resection in PDOXs, we selected two models representing histopathological features of GBM tumors, including diffuse growth into the mouse brain. Surgical resection in the mouse brains was performed based on MRI-guided coordinates. Survival study followed by MRI and immunohistochemistry-based evaluation of recurrent tumors allowed for assessment of clinically relevant parameters. Results We demonstrate the utility of MRI for the noninvasive assessment of in vivo tumor growth, preoperative programming of resection coordinates and follow-up of tumor recurrence. We report tumor detection by MRI in 90% of GBM PDOX models (36/40), of which 55% (22/40) can be reliably quantified during tumor growth. We show that a surgical resection protocol in mice carrying diffuse primary GBM tumors in the brain leads to clinically relevant outcomes. Similar to neurosurgery in patients, we achieved a near total to complete extent of tumor resection, and mice with resected tumors presented significantly increased survival. The remaining unresected GBM cells that invaded the normal mouse brain prior to surgery regrew tumors with similar histopathological features and tumor microenvironments to the primary tumors. Conclusions Our data positions GBM PDOXs developed in mouse brains as a valuable preclinical model for conducting therapeutic studies that involve surgical tumor resection. The high detectability of tumors by MRI across a substantial number of PDOX models in mice will allow for scalability of our approach toward specific tumor types for efficacy studies in precision medicine-oriented approaches. Additionally, these models hold promise for the development of enhanced image-guided surgery protocols.