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Abstract Background Tumor Budding (TB) and Immunoscore are independent prognostic markers in colon cancer (CC). Given their respective representation of tumor aggressiveness and immune response, we examined their combination in association with patient disease-free survival (DFS) in pTNM stage I-III CC. Methods In a series of pTNM stage I-III CCs (n = 654), the Immunoscore was computed and TB detected automatically using a deep learning network. Two-tiered systems for both biomarkers were used with cut-offs of 25% and ten buds for Immunoscore and TB according to clinical guidelines, respectively. Associations of Immunoscore with TB with 5-year DFS were examined using Kaplan–Meier survival analysis in addition to multivariable modeling and relative contribution analysis using Cox regression. Results Immunoscore and TB independently are prognostic with hazard ratio (HR) = 2.0, 95% confidence interval (CI) 1.4–2.8 and HR 2.5, with 95% CI 1.4–4.5, respectively; P value

Abstract NK cells are endowed with tumor killing ability, nevertheless most cancers impair NK cell functionality, and cell-based therapies have limited efficacy in solid tumors. How cancers render NK cell dysfunctional is unclear, and overcoming resistance is an important immune-therapeutic aim. Here, we identify autophagy as a central regulator of NK cell anti-tumor function. Analysis of differentially expressed genes in tumor-infiltrating versus non-tumor NK cells from our previously published scRNA-seq data of advanced human prostate cancer shows deregulation of the autophagic pathway in tumor-infiltrating NK cells. We confirm this by flow cytometry in patients and in diverse cancer models in mice. We further demonstrate that exposure of NK cells to cancer deregulates the autophagic process, decreases mitochondrial polarization and impairs effector functions. Mechanistically, CCAAT enhancer binding protein beta (C/EBPβ), downstream of CXCL12-CXCR4 interaction, acts as regulator of NK cell metabolism. Accordingly, inhibition of CXCR4 and C/EBPβ restores NK cell fitness. Finally, genetic and pharmacological activation of autophagy improves NK cell effector and cytotoxic functions, which enables tumour control by NK and CAR-NK cells. In conclusion, our study identifies autophagy as an intracellular checkpoint in NK cells and introduces autophagy regulation as an approach to strengthen NK-cell-based immunotherapies.

Electric vehicles (EVs) are quickly replacing internal combustion cars, which will soon become obsolete. Nonetheless, how drivers' perception and cognition deal with certain features of EVs remains largely unknown. In this study we focus on the role of in-car sound, specifically the artificial engine sounds, on drivers' speed perception and control. Previous studies indicate that removing or reducing engine sound leads drivers to underestimate speed and, consequently, to drive faster. Furthermore, evidence suggests that specific sound frequencies could play a role in this process, highlighting the importance of in-car sound features. We consider benefits and limitations of different research paradigms used in the field (mostly video based technique and driving simulation) and we propose an experimental protocol to systematically investigate the phenomenon. Finally, we suggest that the wider use of psychophysical methods on video recordings would benefit the research in the field and overcome some limitations of simulation studies.

Abstract Recent views recognize that abstract concepts encompass a variety of exemplars, each relying on different dimensions, including not only sensorimotor but also inner, linguistic, and social experiences. How these dimensions characterize types of abstract concepts, and whether their weight varies across contexts and individuals remains an open question. We investigated the role of linguistic and social situations in the processing of institutional concepts, such as justice, by individuals with different levels of expertise. In a priming study, legal experts and non-experts were asked to respond to target words (go-trials) consisting of different kinds of abstract (institutional, theoretical) and concrete concepts (food, tools) and to ignore filler words (no-go trials). The verbal stimuli were primed by pictures depicting social-action, linguistic-social, linguistic-textual situations, and a control condition. As predicted, critical priming modulated performance on abstract concepts, likely due to their highly context-dependent meaning. Interestingly, we found that the processing of institutional concepts was selectively facilitated by social action prime, suggesting that this situational content may be integrated to support their representation. Crucially, the dialogic context, the linguistic social prime, affected more non-experts than law-experts, who tended to frame institutional concepts as shared idea for regulating social practices. Our results show that linguistic and social inputs become differently salient for institutional concepts representation depending on individual competence.

Abstract The biological aspects of infancy within late Upper Palaeolithic populations and the role of southern refugia at the end of the Last Glacial Maximum are not yet fully understood. This study presents a multidisciplinary, high temporal resolution investigation of an Upper Palaeolithic infant from Grotta delle Mura (Apulia, southern Italy) combining palaeogenomics, dental palaeohistology, spatially-resolved geochemical analyses, direct radiocarbon dating, and traditional anthropological studies. The skeletal remains of the infant – Le Mura 1 – were directly dated to 17,320-16,910 cal BP. The results portray a biological history of the infant’s development, early life, health and death (estimated at ~72 weeks). They identify, several phenotypic traits and a potential congenital disease in the infant, the mother’s low mobility during gestation, and a high level of endogamy. Furthermore, the genomic data indicates an early spread of the Villabruna-like components along the Italian peninsula, confirming a population turnover around the time of the Last Glacial Maximum, and highlighting a general reduction in genetic variability from northern to southern Italy. Overall, Le Mura 1 contributes to our better understanding of the early stages of life and the genetic puzzle in the Italian peninsula at the end of the Last Glacial Maximum.

RESUMO O referido projeto se caracteriza nas implicações relacionais do desenvolvimento sociomoral da teoria psicogenética em Piaget sobre a construção cognoscente da ética nos vieses pessoais e em referenciais da dialética discursiva na linguística. Foram parametrizados a dados funcionais de treinamento e teste em um classificador de categorias urbano-sociais em uma abordagem analítica textual por Processamento de Linguagem Natural (PLN), e baseado no mecanismo de atenção adaptada Transformers. Nessa perspectiva, desenvolveu-se uma metodologia de mitigação de viés para a reestruturação do crivo e critério que datasets multimodais são retreinados, retestados e reavaliados. Finalmente, verificou-se e validou-se a heterogeneidade da ética comum coletiva humana, sobre inferências interpretativas, insights e tendências sociais reais que a relação cidade/cidadão aborda o “social sensing” na identificação de problemas público-sociais.

BACKGROUND: The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists visual assessment of CD3+- and CD8+-stained colon tumors, compared to IS quantification. METHODS: An international group of expert pathologists evaluated 540 images from 270 randomly selected colon cancer (CC) cases. Concordance between pathologists T-score, corresponding hematoxylin-eosin (H&E) slides, and the digital IS was evaluated for two- and three-category IS. RESULTS: Non-concordant T-scores were reported in more than 92% of cases. Disagreement between semi-quantitative visual assessment of T-score and the reference IS was observed in 91% and 96% of cases before and after training, respectively. Statistical analyses showed that the concordance index between pathologists and the digital IS was weak in two- and three-category IS, respectively. After training, 42% of cases had a change in T-score, but no improvement was observed with a Kappa of 0.465 and 0.374. For the 20% of patients around the cut points, no concordance was observed between pathologists and digital pathology analysis in both two- and three-category IS, before or after training (all Kappa < 0.12). CONCLUSIONS: The standardized IS assay outperformed expert pathologists T-score evaluation in the clinical setting. This study demonstrates that digital pathology, in particular digital IS, represents a novel generation of immune pathology tools for reproducible and quantitative assessment of tumor-infiltrated immune cell subtypes.

Bullous pemphigoid (BP) is an autoimmune bullous disease, typically affecting the elderly, characterized by the production of autoantibodies directed against structural components of the dermal–epidermal junction. An association between BP and psoriasis has been described several times, but the mechanisms underlying this association have yet to be clearly defined. The pathophysiological mechanism underlying psoriasis may be implicated in the pathogenesis of BP, as psoriasis precedes BP in most cases; in particular, a promoting role has been hypothesized by biologic therapies, which may induce a switch from a T helper 1 (TH1)/TH17-dominant cytokine milieu, typical of patients with psoriasis, to a TH2-dominant one, typical of patients with BP. IL-17 inhibitors, in particular, have also been successfully used to treat BP in patients with psoriasis. The use of these drugs in these patients has been based on in vitro studies. However, cases of new-onset BP or relapses of BP already diagnosed in patients with psoriasis treated with biologic drugs have also been reported, and they occurred mainly in patients on anti-TNF drugs, yet very few cases with anti-IL-174 drugs have been described. We hereby describe two cases of new-onset BP in two patients treated with anti-IL-17 drugs for psoriasis.

Abstract Background Urogenital schistosomiasis is caused by the parasitic trematode Schistosoma haematobium. Sensitive and specific point-of-care diagnostics are needed for elimination of this disease. Recombinase polymerase amplification (RPA) assays meet these criteria, and an assay to diagnose S. haematobium has been developed (Sh-RPA). However, false-positive results can occur, and optimisation of reaction conditions to mitigate these is needed. Ease of use and compatibility of DNA extraction methods must also be considered. Methods Using synthetic DNA, S. haematobium genomic DNA (gDNA), and urine samples from clinical cases, Sh-RPA reactions incorporating different betaine concentrations (0 M, 1 M, 2.5 M, 12.5 M) and the sample-to-water ratios were tested to determine effects on assay specificity and sensitivity. In addition, five commercial DNA extraction kits suitable for use in resource-limited settings were used to obtain gDNA from single S. haematobium eggs and evaluated in terms of DNA quality, quantity, and compatibility with the Sh-RPA assay. All samples were also evaluated by quantitative polymerase chain reaction (qPCR) to confirm DNA acquisition. Results The analytical sensitivity of the Sh-RPA with all betaine concentrations was ≥ 10 copies of the synthetic Dra1 standard and 0.1 pg of S. haematobium gDNA. The addition of betaine improved Sh-RPA assay specificity in all reaction conditions, and the addition of 2.5 M of betaine together with the maximal possible sample volume of 12.7 µl proved to be the optimum reaction conditions. DNA was successfully isolated from a single S. haematobium egg using all five commercial DNA extraction kits, but the Sh-RPA performance of these kits varied, with one proving to be incompatible with RPA reactions. Conclusions The addition of 2.5 M of betaine to Sh-RPA reactions improved reaction specificity whilst having no detrimental effect on sensitivity. This increases the robustness of the assay, advancing the feasibility of using the Sh-RPA assay in resource-limited settings. The testing of commercial extraction kits proved that crude, rapid, and simple methods are sufficient for obtaining DNA from single S. haematobium eggs, and that these extracts can be used with Sh-RPA in most cases. However, the observed incompatibility of specific kits with Sh-RPA highlights the need for each stage of a molecular diagnostic platform to be robustly tested prior to implementation. Graphical Abstract

Abstract Background to evaluate the predictability of expansion achieved in patients in early mixed dentition treated with Clear Aligners (CA), analyzing the efficiency of the expansion at the end of the first set of aligners and at the end of the therapy in the upper and lower arch. Methods 36 patients (20 F, 16 M; mean age 8.3 ± 1.5 years) were selected retrospectively from the Department of Orthodontics of the Hospital of Rome “Tor Vergata”. All subjects were treated with CA with no other auxiliaries than attachments. For each patient a standardized sequential expansion protocol was planned for both arches. Digital dental casts were created at three observation periods from an intraoral scanner: prior to treatment (T0), at the end of the first set of aligners (T1), at the end of treatment (T2). The 3D models in planned position determined by the first Clincheck (CC) were obtained for comparison with T1 and T2. Six linear transversal measurements were used to evaluate the dimensional changes and the predictability of expansion movements, comparing T1-CC and T2-CC. Results a statistically significant increase within the pre-treatment and the final outcomes for all the variables examined was found. In the upper arch, the greatest level of predictability was detected at the level of the first (46.44%) and second deciduous molar width (44.95%) at T1. The analysis of T2-CC changes showed a significant increase in the percentage of predictability of expansion at the level of the first permanent molars, at mesial (54.86%) and distal (58.92%) width. In the lower arch, a higher percentage of predictability than the upper arch was reported at T1-CC and T2-CC, with the greatest values at the level of second (T1-CC: 48.70%; T2-CC: 75.32%) and first deciduous molar width (T1-CC: 45.71%; T2-CC: 72.75%). Conclusions CA can induce significant transversal increments. The predictability of expansion is variable, but it did not exceed the 50% during the first set of aligners. It was necessary to apply refinement set to achieve a good predictability for expansion of about 70%. The expansion in the lower arch was observed to be more predictable than in the upper arch.

ABSTRACT The human gut microbiota possesses the capacity to synthesize vitamins, especially B group vitamins, which are recognized as indispensable for various biological processes both among members of these bacterial communities and host cells. Accordingly, vitamin production by intestinal commensals has attracted significant interest. Nevertheless, our current understanding of bacterial vitamin synthesis is primarily based on individual genomic and monoculture investigations, therefore not providing an overall view of the biosynthetic potential of complex microbial communities. In the current study, we utilized over 100 bacterial genes known to be involved in the biosynthesis of B group and K vitamins to assess the corresponding vitamin biosynthetic potential of approximately 8,000 human gut microbiomes. Our analyses reveal that host-associated factors, such as age and geographical origin, appear to influence the diversity and abundance of vitamin biosynthetic pathways. Furthermore, we identify gut microbiota members that substantially contribute to these biosynthetic functions at each stage of human life. Interestingly, inference of microbial co-associations and network relationships uncovered the apparent key role played by folate and cobalamin in equilibrium establishment of the infant and adult gut microbial communities, respectively.IMPORTANCEOverall, this study expands our understanding of microbe-mediated vitamin biosynthesis in the human gut and may provide potential novel targets to improve availability of these essential micronutrients in the host.

In this review we focus on the role of in-car sound, specifically the artificial engine sounds, on drivers’ speed perception and control, a topic that has received little attention so far. Previous studies indicate that removing or reducing engine sound leads drivers to underestimate speed and, consequently, to drive faster. Furthermore, evidence suggests that specific sound frequencies could play a role in this process, highlighting the importance of in-car sound features. First, we show that the amount of research in the field is scarce and rather outdated, and that this is largely due to the fact that industrial research is subject to very few publications. Then, we examine benefits and limitations of different research paradigms used and we propose a protocol to investigate systematically the phenomenon. In particular, we argue for the benefits of a wider use of psychophysical methods in speed perception, a field that has been typically explored by means of driving simulation. Finally, we highlight some methodological and statistical limitations that might impact the interpretation of the evidence considered. Our methodological considerations could be particularly useful for researchers aiming to investigate the impact of sound on speed perception and control, as well as for those involved in the design of in-car sounds. These are particularly relevant for the design of electric vehicles, which represent a challenge but also the ideal testing ground to advance the knowledge in the field.

Bifidobacteria are well known as common and abundant colonizers of the human gut and are able to exert multiple beneficial effects on their host, although the cooperative and competitive relationships that may occur among bifidobacterial strains are still poorly investigated. Therefore, to dissect possible molecular interactions among bifidobacterial species that typically colonize the human gut, three previously identified bifidobacterial prototypes, i.e., B. bifidum PRL2010, B. breve PRL2012, and B. longum PRL2022 were cultivated individually as well as in bi- and tri-association in a human gut-simulating medium. Transcriptomic analyses of these co-associations revealed up-regulation of genes predicted to be involved in the production of extracellular structures including pili (i.e., flp pilus assembly TadE protein gene), exopolysaccharides (i.e., GtrA family protein gene) and teichoic acids (i.e., ABC transporter permease), along with carbohydrate, amino acid and vitamin metabolism-related genes (i.e., exo-alpha-sialidase; beta-galactosidase and pyridoxamine kinase), suggesting that co-cultivation of bifidobacteria induces a response, in individual bifidobacterial strains, aimed at enhancing their proliferation and survival, as well as their ability to cooperate with their host to promote their persistence. Furthermore, exposure of the selected prototypes to human cell line monolayers unveiled the ability of the bifidobacterial tri-association to communicate with their host by increasing the expression of genes involved in adherence to/interaction with intestinal human cells. Lastly, bifidobacterial tri-association promoted the transcriptional upregulation of genes responsible for maintaining the integrity and homeostasis of the intestinal epithelial barrier.

ObjectiveThe aim of the present retrospective study was to compare the changes resulting from treatment using the MA and the TB with special regard to the oro-and naso-pharyngeal sagittal airway dimensions in subjects with dentoskeletal Class II malocclusions and positive history of Sleep Disorder Breathing (SDB) diagnosed through the Pediatric Sleep Questionnaire (PSQ).Materials and methodsThis retrospective study involved 2 groups of subjects: patients treated with Twin Block (TB group: n = 22, 10 males, 12 females; mean age 12.0 ± 1.3 years) and patients treated with Mandibular Advancement (MA group: n = 23, 11 males, 12 females; mean age 12.2 ± 1.1 years). Pretreatment (T1) and posttreatment (T2) lateral cephalograms were analyzed. All patients underwent the PSQ to diagnose SDB.ResultsIn both treated groups there was an increase in the airways dimensions and an improvement in symptoms related SDB. The statistical comparison of the changes between T1 and T2 in the TB group showed a significant increment in upper airway size (PNS-AD2, +1.50 mm + −3.30; McNamara's upper pharynx dimension, +2.21 + −4.21) after active treatment. The MA group showed similar results during active treatment with a significant increase in both upper (PNS-AD2, +2.72 + −2.65; McNamara's upper pharynx dimension, +2.97 + −3.07) and lower (PNS-AD1, +2.17 mm + −3.54) airway size.ConclusionsDespite the different structure of these two devices and the different advancement protocols, both appliances were valuable as a suitable treatment option for Class II patients with respiratory disorders, inducing an increase of upper and lower airway size and a significant reduction in diurnal symptoms.

BackgroundAlthough telemedicine has been proven to have significant potential for improving care for patients with cardiac problems, there remains a substantial risk of introducing disparities linked to the use of digital technology, especially for older or socially vulnerable subgroups. ObjectiveWe investigated factors influencing adherence to a telemedicine-delivered health education intervention in patients with ischemia, emphasizing demographic and socioeconomic considerations. MethodsWe conducted a descriptive, observational, prospective cohort study in consecutive patients referred to our cardiology center for acute coronary syndrome, from February 2022 to January 2023. Patients were invited to join a web-based health educational meeting (WHEM) after hospital discharge, as part of a secondary prevention program. The WHEM sessions were scheduled monthly and used a teleconference software program for remote synchronous videoconferencing, accessible through a standard computer, tablet, or smartphone based on patient preference or availability. ResultsOut of the 252 patients (median age 70, IQR 61.0-77.3 years; n=189, 75% male), 98 (38.8%) declined the invitation to participate in the WHEM. The reasons for nonacceptance were mainly challenges in handling digital technology (70/98, 71.4%), followed by a lack of confidence in telemedicine as an integrative tool for managing their medical condition (45/98, 45.9%), and a lack of internet-connected devices (43/98, 43.8%). Out of the 154 patients who agreed to participate in the WHEM, 40 (25.9%) were unable to attend. Univariable logistic regression analysis showed that the presence of a caregiver with digital proficiency and a higher education level was associated with an increased likelihood of attendance to the WHEM, while the converse was true for increasing age and female sex. After multivariable adjustment, higher education level (odds ratio [OR] 2.26, 95% CI 1.53-3.32; P

The approach to skeletal dysmorphisms in the maxillofacial area usually requires an orthodontic treatment by means of fixed appliances, both before and after the surgical phase. Since its introduction, Invisalign system has become a popular treatment choice for the clinicians because of the aesthetics and comfort of the removable clear aligners compared with the traditional appliances. Therefore, the aim of the present report was to illustrate the management of a malocclusion by means of clear aligners associated with the traditional surgical technique. The present paper shows a case of a 18-year-old female patient characterized by a Class III malocclusion with lateral deviation of the mandible. Clear aligners were used during the pre- and postsurgical phases rather than fixed appliances. The posttreatment cephalometric analysis emphasized the stability of the dental and skeletal symmetry corrections, occlusion and functional balance, over a 4-year follow-up. The results achieved at the end of the treatment showed how clear aligners can be effective in the management of the orthodontic phases in orthognathic surgery. The follow-up after 4 years emphasizes the stability of the treatment over time.

INTRODUCTION: The postnatal activation of the hypothalamic-pituitary-gonadal (HPG) axis is usually known as 'minipuberty'. There are still open questions about its biological function and significance depending on sex, gestational age (GA) and birth weight (BW) with few available longitudinal data. METHODS: A single-centre, longitudinal study to quantify urinary follicle stimulating hormone (uFSH), luteinizing hormone (uLH) and testosterone (uTs) in male neonates. Neonates were enrolled and stratified into three subgroups: full-term boys appropriate for GA (FT AGA); FT boys with BW ≤3rd centile [FT small for gestational age (SGA)]; and preterm (PT) boys ≤33 weeks of GA. Urinary hormones were correlated to simultaneous auxological parameters, linear growth and external genitalia at scheduled time-points. RESULTS: Forty-six boys were recruited, with subgroup sizes FT AGA n=23, FT SGA n=11 and PT n=12. PT boys display a pulsatile pattern of urinary gonadotropins (uGns) with higher levels of uLH and a gradual increase of uTs. Testicular descent started from 29-32 weeks with the peak of uTs. During the first 12-months post-term age (PTA), FT AGA boys displayed a better linear growth (p

In the last year a new virus (SARS-CoV-2) and the disease caused by it (COVID-19) has quickly spread around the world, leading the World Health Organization to declare a public health emergency and, then, a global pandemic status. The strategies adopted by many countries to reduce the impact of the pandemic were mainly based on social distancing rules and on stay-at-home measures or lockdowns. These strategies had severe disruptive consequences on many sectors, including all levels of education. While the "traditional" (face-to-face) Higher Education (HE) system was unprepared for the lockdown (e.g., no plans for a massive shift to online teaching were available/ready), it reacted in an extremely quick and effective way, replacing face-to-face teaching with online teaching. While COVID-19 has been extremely challenging for education, the experience has undoubtedly provided positive inputs for the digitalization of the HE system. The question is however, if whether after the COVID-19 emergency everything will go back to the previous situation or instead if the pandemic has irreversibly changed HE. While we are still in the middle of the crisis, it is in our view beneficial to start to reflect on the challenges and open issues that emerged during this period and the lessons learned for the "new normal" (as it is often referred to). In this conceptual paper we seek to start this discussion by focusing on the following relevant aspects that should be considered to succeed in the digital transformation: broadband network infrastructure and hardware devices; e-learning software; organization of teaching activities; pedagogical issues; diversity and inclusivity; and a number of other issues. We conclude that the COVID-19 pandemic will irreversibly change HE and probably for the better.

Foodborne diseases can be prevented by implementing a food safety system that manages food chain risks from producer to end-user, from a One Health perspective. In 2017, the European Parliament and the European Council adopted Regulation No. 625 on official food controls and other official activities performed to ensure the application of food and feed laws and rules on animal health and welfare, plant health, and plant protection products. Italy issued a national law, Legislative Decree No. 27/2021, to adapt and adhere to European standards. We aim to describe the adoption and implementation of the new Legislative Decree by an Italian Food Hygiene and Nutrition Service, specifically focusing on the amendments introduced by Articles 7 and 8, namely the establishment of the second expert opinion and dispute procedures, and their integration with the promulgation of Article 70 of Legislative Decree No. 150/2022. These modifications aim to reduce the number of minor offenses that proceed to trial.

Summary: Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that may overlap with Langerhans Cell Histiocytosis (LCH). This “mixed” entity is poorly characterized. We here investigated the clinical phenotype, outcome, and prognostic factors of a large cohort of patients with mixed ECD-LCH. Methods: This retrospective study was performed at two referral centers in France and Italy (Pitié-Salpêtrière Hospital, Paris; Meyer Children’s Hospital, Florence). We included children and adults with ECD diagnosed in 2000–2022 who had biopsy-proven LCH, available data on clinical presentation, treatment and outcome, and a minimum follow-up of one year. Outcomes included differences in clinical presentation and survival between mixed ECD-LCH and isolated ECD; we also investigated response to treatments and predictors of survival in the mixed cohort. Survival was analyzed using the Kaplan-Maier method and differences in survival with the long-rank test. Cox regression models were used to evaluate the potential impact of age and gender on survival and to identify predictors of non-response and survival. Findings: Out of a cohort of 502 ECD patients, 69 (14%) had mixed ECD-LCH. Compared to isolated ECD, mixed ECD-LCH occurred more frequently in females (51 vs. 26%, p

Alpha oscillations play a vital role in managing the brain's resources, inhibiting neural activity as a function of their phase and amplitude, and are changed in many brain disorders. Developing minimally invasive tools to modulate alpha activity and identifying the parameters that determine its response to exogenous modulators is essential for the implementation of focussed interventions. We introduce Alpha Closed-Loop Auditory Stimulation (αCLAS) as an EEG-based method to modulate and investigate these brain rhythms in humans with specificity and selectivity, using targeted auditory stimulation. Across a series of independent experiments, we demonstrate that αCLAS alters alpha power, frequency, and connectivity in a phase, amplitude, and topography-dependent manner. Using single-pulse-αCLAS, we show that the effects of auditory stimuli on alpha oscillations can be explained within the theoretical framework of oscillator theory and a phase-reset mechanism. Finally, we demonstrate the functional relevance of our approach by showing that αCLAS can interfere with sleep onset dynamics in a phase-dependent manner.

Phosphorus (P) is recognized as an important driver of terrestrial primary productivity across biomes. Several recent developments in process-based vegetation models aim at the concomitant representation of the carbon (C), nitrogen (N), and P cycles in terrestrial ecosystems, building upon the ecological stoichiometry and the processes that govern nutrient availability in soils. Thus, understanding the spatial distribution of P forms in soil is fundamental to initializing and/or evaluating process-based models that include the biogeochemical cycle of P. One of the major constraints for the large-scale application of these models is the lack of data related to the spatial patterns of the various forms of P present in soils, given the sparse nature of in situ observations. We applied a model selection approach based on random forest regression models trained and tested for the prediction of different P forms (total, available, organic, inorganic, and occluded P) – obtained by the Hedley sequential extraction method. As input for the models, reference soil group and textural properties, geolocation, N and C contents, terrain elevation and slope, soil pH, and mean annual precipitation and temperature from 108 sites of the RAINFOR network were used. The selected models were then applied to predict the target P forms using several spatially explicit datasets containing contiguous estimated values across the area of interest. Here, we present a set of maps depicting the distribution of total, available, organic, inorganic, and occluded P forms in the topsoil profile (0–30 cm) of the pan-Amazon region in the spatial resolution of 5 arcmin. The random forest regression models presented a good level of mean accuracy for the total, available, organic, inorganic, and occluded P forms (77.37 %, 76,86 %, 75.14 %, 68.23 %, and 64.62% respectively). Our results confirm that the mapped area generally has very low total P concentration status, with a clear gradient of soil development and nutrient content. Total N was the most important variable for the prediction of all target P forms and the analysis of partial dependence indicates several features that are also related with soil concentration of all target P forms. We observed that gaps in the data used to train and test the random forest models, especially in the most elevated areas, constitute a problem to the methods applied here. However, most of the area could be mapped with a good level of accuracy. Also, the biases of gridded data used for model prediction are introduced in the P maps. Nonetheless, the final map of total P resembles the expected geographical patterns. Our maps may be useful for the parametrization and evaluation of process-based terrestrial ecosystem models as well as other types of models. Also, they can promote the testing of new hypotheses about the gradient and status of P availability and soil-vegetation feedback in the pan-Amazon region. The reference maps can be downloaded from https://doi.org/10.25824/redu/FROESE (Darela-Filho and Lapola, 2023).

Abstract In vitro simulators of the human gastrointestinal (GI) tract are remarkable technological platforms for studying the impact of food on the gut microbiota, enabling continuous and real-time monitoring of key biomarkers. However, comprehensive real-time monitoring of gaseous biomarkers in these systems is required with a cost-effective approach, which has been challenging to perform experimentally to date. In this work, we demonstrate the integration and in-line use of carbon nanotube (CNT)-based chemiresitive gas sensors coated with a thin polydimethylsiloxane (PDMS) membrane for the continuous monitoring of gases within the Simulator of the Human Microbial Ecosystem (SHIME). The findings demonstrate the ability of the gas sensor to continuously monitor the different phases of gas production in this harsh, anaerobic, highly humid, and acidic environment for a long exposure time (16 h) without saturation. This establishes our sensor platform as an effective tool for real-time monitoring of gaseous biomarkers in in vitro systems like SHIME.

Abstract The sex profile estimation of pre-historic communities is often complicated by the commingled and scattered nature of skeletal assemblages. Demographic profiles are usually lacking and provide very truncated representations of these populations but proteomic analysis of sex-specific amelogenin peptides in tooth enamel brings new promise to these studies. The main objective was to obtain the sex profile of the human assemblage recovered from the Neolithic cave-necropolis of Escoural (Montemor-o-Novo, southern Portugal) through liquid chromatography-mass spectrometry. The secondary objective was to analyse sex-specific linear enamel hypoplasias (LEH), and to test the reliability of canine odontometric sex estimation. Sex estimation through peptide analysis was carried out in 36 left permanent canines which were macroscopically examined for the presence of LEH. The canine buccolingual diameter was used for odontometric sex estimation. The obtained sex ratio (0.5:1, M:F) is biased to female individuals, probably due to cultural factors since the natural sex ratio of the human population falls between 0.95:1 and 1.02:1 (M:F). A high frequency of LEH was observed, but with no significant sexual differences (p = 0.554). The mean LEH age of onset occurred at 3 years of age, with no significant differences between the sexes (p = 0.116), and was possibly related to the weaning process. Odontometric sex estimation revealed a correct classification of 80%, with a high number of males mistakenly attributed to females. This study is one of the largest samples subjected to peptide analysis, and thus demonstrates its usefulness on the research of commingled and scattered skeletal assemblages.

Background: Umbilical venous catheters (UVCs) are the standard of care in neonatal intensive care units (NICUs) to administer fluids, parenteral nutrition and medications, although complications may occur, including central line-associated blood stream infections (CLABSIs). However, the dwell time to reduce CLABSI risk remains an open issue. Methods: We performed a single-center retrospective study of newborns hospitalized in the Modena NICU with at least one UVC inserted over a 6-year period (period 1: January 2011–December 2013; period 2: January 2019–December 2021). We selected a non-consecutive 6-year period to emphasize the differences in UVC management practices that have occurred over time in our NICU. The UVC dwell time and catheter-related complications during the first 4 weeks of life were examined. Results: The UVC dwell time was shorter in period 2 (median 4 days vs. 5 days, p < 0.00001). Between the two periods, the incidence of CLABSIs remained unchanged (p = 0.5425). However, in period 2, there was an increased need for peripherally inserted central catheters (PICCs) after UVC removal, with a rise in PICC infections after UVC removal (p = 0.0239). Conclusions: In our NICU, shortening UVC dwell time from 5 to 4 days did not decrease the UVC-related complications. Instead, the earlier removal of UVCs led to a higher number of PICCs inserted, possibly increasing the overall infectious risk.

Background: The purpose of this study was to compare the accuracy of three different intraoral scanners (IOSs) and to evaluate the patients’ experience. Methods: Thirty subjects were scanned with three different IOSs (TRIOS Color®, iTero Element 5D®, and iTero Lumina®): a sample of 90 maxillary casts was collected. The inclusion criteria were permanent dentition, absence of defects during the dental impression, and complete record of the palatal vault. After the scanning procedure, patients were asked to answer a questionnaire (10 answers, scale from 1 to 10) to compare their experiences with iTero Element and iTero Lumina in the scanning procedure. Results: Differences were recorded in the upper central incisor region (f-ratio of 4.186 for Mesiodistal 1.1 and f-ratio of 4.222 for Mesiodistal 2.1, p < 0.05), while intercanine width Upper 13–23 showed the smallest f-ratio (0.226) when compared to the other results, followed by Mesiodistal 1.4 (0.433). Patients reported more comfort, less pain, decreased duration, and a better technology visualization of the impression with iTero Lumina. No significant differences concerning dryness of the mouth and gag reflex were found. Conclusions: The examined IOSs offer comparable accuracy in capturing dental arch dimensions. The interviewed patients expressed an overall preference for digital impressions performed with iTero Lumina, linked to increased comfort, painless practice, and a better technology visualization of the impression.

Background: Neonatal cerebral stroke includes a range of focal and multifocal ischemic and hemorrhagic brain lesions, occurring in about one of 3000 live births. More than 50% of children with neonatal stroke develop adverse outcomes, mainly unilateral cerebral palsy. Asymmetries in segmental movements at three months have been proven to be an early sign of CP in infants with unilateral brain damage. Recognition of additional early signs could enhance prognostic assessment and enable an early and targeted intervention. Aim: The aim of the study was to assess early signs of CP in infants with arterial cerebral stroke through the General Movements Assessment and the Motor Optimality Score—Revised (MOS-R). Method: Twenty-four infants born at term (12 females and 12 males) diagnosed with ACS, and 24 healthy infants (16 females and 8 males) were assessed. The GMs (fidgety movements) and MOS-R were assessed from videos recorded at 11–14 weeks of post-term age. Cognitive and motor outcomes were assessed at 24 months using the Griffiths III developmental quotient and Amiel-Tison neurological examination. The gross motor function classification system expanded and revised (GMFCS-E&R) was adopted to categorize CP. Results: Among infants with ACS, 21 (87.5%) developed unilateral CP. Most of them showed non-disabling CP (14 had GMFCS-E&R grade 1 [66.6%], 6 grade 2 [28.6%], and 1 grade 5 [4.8%]). Fidgety movements (FMs) were absent in 17 (70.8%), sporadic in 4 (16.7%) infants, and normal in 3 (12.5%). Segmental movement asymmetry was found in 22/24 (91.7%). According to the MOS-R, motor items (kicking, mouth movements), postural patterns (midline centered head, finger posture variability), and movement character (monotonous and stiff) were statistically different among infants with ACS and healthy infants. The MOS-R median global score was lower in the group with ACS compared to the control group (6 vs 26; p < 0.01). FMs, segmental movement asymmetry, and MOS-R global score were significantly correlated with abnormal outcome. MOS-R global scores less than or equal to 13 had 100% specificity and sensitivity in predicting GMFCS-E&R grade ≥ 2 CP in infants with ACS. Conclusions: The rate of CP was high among infants with ACS, but in most cases it showed low GMFCS-E&R grades. The study highlighted a significant correlation between MOS-R, together with absent FMs and unilateral CP in infants with ACS. Moreover, the MOS-R showed high sensitivity and specificity in the prediction of CP. Combined assessment of FMs and MOS-R could help to better identify infants at high risk of developing UCP in a population of infants with ACS. Early identification of precocious signs of unilateral CP is fundamental to providing an early individualized intervention.

Quantum cellular automaton (QCA) is a model for universal quantum computation and a natural candidate for digital quantum simulation of relativistic quantum fields. Here we introduce the first photonic platform for implementing QCA simulation of a free relativistic Dirac quantum field in 1+1 dimension, through a Dirac quantum cellular automaton (DQCA). Encoding the field position degree of freedom in the orbital angular momentum (OAM) of single photons, our state-of-the-art setup experimentally realizes eight steps of a DQCA, with the possibility of having complete control over the input OAM state preparation and the output measurement making use of two spatial light modulators. Therefore, studying the distribution in the OAM space at each step, we were able to reproduce the time evolution of the free Dirac field observing the Zitterbewegung, an oscillatory movement extremely difficult to see in a real-case experimental scenario that is a signature of the interference of particle and antiparticle states. The accordance between the expected and measured Zitterbewegung oscillations certifies the simulator performances, paving the way towards the application of photonic platforms to the simulation of more complex relativistic effects.

Abstract Flow cytometry (FCM) can investigate dozens of parameters from millions of cells and hundreds of specimens in a short time and at a reasonable cost, but the amount of data that is generated is considerable. Computational approaches are useful to identify novel subpopulations and molecular biomarkers, but generally require deep expertize in bioinformatics and the use of different platforms. To overcome these limitations, we introduce CRUSTY, an interactive, user-friendly webtool incorporating the most popular algorithms for FCM data analysis, and capable of visualizing graphical and tabular results and automatically generating publication-quality figures within minutes. CRUSTY also hosts an interactive interface for the exploration of results in real time. Thus, CRUSTY enables a large number of users to mine complex datasets and reduce the time required for data exploration and interpretation. CRUSTY is accessible at https://crusty.humanitas.it/ .

Abstract The lower female reproductive tract is notoriously dominated by Lactobacillus species, among which Lactobacillus crispatus emerges for its protective and health‐promoting activities. Although previous comparative genome analyses highlighted genetic and phenotypic diversity within the L. crispatus species, most studies have focused on the presence/absence of accessory genes. Here, we investigated the variation at the single nucleotide level within protein‐encoding genes shared across a human‐derived L. crispatus strain selection, which includes 200 currently available human‐derived L. crispatus genomes as well as 41 chromosome sequences of such taxon that have been decoded in the framework of this study. Such data clearly pointed out the presence of intra‐species micro‐diversities that could have evolutionary significance contributing to phenotypical diversification by affecting protein domains. Specifically, two single nucleotide variations in the type II pullulanase gene sequence led to specific amino acid substitutions, possibly explaining the substantial differences in the growth performances and competition abilities observed in a multi‐strain bioreactor culture simulating the vaginal environment. Accordingly, L. crispatus strains display different growth performances, suggesting that the colonisation and stable persistence in the female reproductive tract between the members of this taxon is highly variable.

ABSTRACTThe human gut microbiota is a dynamic community of microorganisms that undergo variable changes over the entire life span. To thoroughly investigate the possible fluctuations of the microbiota throughout human life, we performed a pooled analysis of healthy fecal samples across different age groups covering the entire human life span. Our study integrated data from 79 publicly available studies and new stool samples from an Italian cohort, i.e., the Parma Microbiota project, resulting in 6,653 samples processed through the shotgun metagenomic approach. This approach has allowed species-level taxonomic reconstruction of the gut microbiota and investigation of its metabolic potential across the human life span. From a taxonomic point of view, our findings confirmed and detailed at species-level accuracy that the microbial richness of the gut microbiota gradually increases in the first stage of life, becoming relatively stable during adolescence. Moreover, the analysis identified the potential core microbiota representative of distinct age groups, revealing age-related bacterial patterns and the continuous rearrangement of the microbiota in terms of relative abundances across the life span rather than the acquisition and loss of taxa. Furthermore, the shotgun approach provided insights into the functional contribution of the human gut microbiome. The metagenomic analysis revealed functional age-related differences, particularly in carbohydrate and fiber metabolism, suggesting a co-evolution of the microbiome assembly with diet. Additionally, we identified correlations between vitamin synthesis, such as thiamine and niacin, and early life, suggesting a potential role of the microbiome in human physiology, in particular in the functions of the host’s nervous and immune systems.IMPORTANCEIn this study, we provided comprehensive insights into the dynamic nature of the human gut microbiota across the human life span. In detail, we analyzed a large data set based on a shotgun metagenomic approach, combining public data sets and new samples from the Parma Microbiota project and obtaining a detailed overview of the possible relationship between gut microbiota development and aging. Our findings confirmed the main stages in microbial richness development and revealed specific core microbiota associated with different age stages. Moreover, the shotgun metagenomic approach allowed the disentangling of the functional changes in the microbiome across the human life span, particularly in diet-related metabolism, which is probably correlated to bacterial co-evolution with dietary habits. Notably, our study also uncovered positive correlations with vitamin synthesis in early life, suggesting a possible impact of the microbiota on human physiology.

Abstract Bifidobacteria are commensal microorganisms that typically inhabit the mammalian gut, including that of humans. As they may be vertically transmitted, they commonly colonize the human intestine from the very first day following birth and may persist until adulthood and old age, although generally at a reduced relative abundance and prevalence compared to infancy. The ability of bifidobacteria to persist in the human intestinal environment has been attributed to genes involved in adhesion to epithelial cells and the encoding of complex carbohydrate‐degrading enzymes. Recently, a putative mucin‐degrading glycosyl hydrolase belonging to the GH136 family and encoded by the perB gene has been implicated in gut persistence of certain bifidobacterial strains. In the current study, to better characterize the function of this gene, a comparative genomic analysis was performed, revealing the presence of perB homologues in just eight bifidobacterial species known to colonize the human gut, including Bifidobacterium bifidum and Bifidobacterium longum subsp. longum strains, or in non‐human primates. Mucin‐mediated growth and adhesion to human intestinal cells, in addition to a rodent model colonization assay, were performed using B. bifidum PRL2010 as a perB prototype and its isogenic perB‐insertion mutant. These results demonstrate that perB inactivation reduces the ability of B. bifidum PRL2010 to grow on and adhere to mucin, as well as to persist in the rodent gut niche. These results corroborate the notion that the perB gene is one of the genetic determinants involved in the persistence of B. bifidum PRL2010 in the human gut.