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Abstract Objectives to evaluate over a 48-month follow-up period the: 1) long-term effectiveness and safety; 2) drug retention rate (DRR); 3) impact of comorbidities and bDMARDs line on MDA and DAPSA remission/low disease activity (LDA) of secukinumab in a multicenter Italian cohort of PsA patients. Methods Consecutive PsA patients receiving secukinumab were followed prospectively in Italian centers between 2016 and 2023. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were recorded. Treatment response was evaluated at 6 and 12 months after initiation, and every year up to 48 months (T48). DRR was assessed according to clinical and demographic features, comorbidities and bDMARDs line. Adverse events (AE) were recorded. Results Six hundred eighty-five patients [42.5% male] were enrolled; 32.9% naïve received secukinumab; 74.2% had ≥ 1 comorbidity. Overall, secukinumab yielded improved outcomes at T48: naïve maintained lower disease activity vs. non-naïve [DAPSA 4.0 (1.4–8.1) vs. 6.0 (2.2–10.4);p = 0.04]; 76.9% naïve and 66.2% non-naïve achieved MDA; MDA no comorbidities vs. 1–3 comorbidities 78.8% vs. 73.3% (p 3 comorbidities 78.8% vs. 48.7% (p 3 comorbidities. Treatment was discontinued in 233 patients due to loss of effectiveness, and in 41 due to AE. The overall DRR at T48 was 66%, with differences according to bDMARDs line (p

Abstract Chronic idiopathic neutropenia (CIN) is a rare benign condition caused by an immune attack against neutrophils, either primary or in the context of other autoimmune conditions, lymphoproliferative syndromes, and inborn errors of immunity. In this single-center prospective study, 131 adult CIN patients were enrolled (median age 55 years, range: 20–93). At baseline, 56% had anti-neutrophil autoantibodies and 31% had autoimmune comorbidities. Over a median 3-year follow-up, the rate of grade ≥ 2 infections was 42%, with 10% grade ≥ 3, irrespective of neutrophil counts, demographics, and anti-neutrophil antibodies positivity, and G-CSF was used in 6 patients only. No malignant evolution nor deaths were observed. Bone marrow evaluation showed a large granular lymphocyte (LGL) infiltrate in 52%, mostly polyclonal, and hypocellularity in 31% of cases. Immune-histochemistry highlighted deposits of IgG, IgM, and complement fractions C3 and C4d in most cases. Interestingly, 19% of tested patients displayed somatic mutations of myeloid genes with an association with age. In conclusion, adult CIN appears to be a benign condition without life-threatening infections, yet deserving an extensive hematologic evaluation including bone marrow assessment to inform the differential diagnosis.

Abstract Integrating artificial limbs as part of one's body involves complex neuroplastic changes resulting from various sensory inputs. While somatosensory feedback is crucial, plastic processes that enable embodiment remain unknown. We investigated this using somatosensory evoked fields (SEFs) in the primary somatosensory cortex (S1) following the Rubber Hand Illusion (RHI), known to quickly induce artificial limb embodiment. During electrical stimulation of the little finger and thumb, 19 adults underwent neuromagnetic recordings before and after the RHI. We found early SEF displacement, including an illusion-brain correlation between extent of embodiment and specific changes to the first cortical response at 20 ms in Area 3b, within S1. Furthermore, we observed a posteriorly directed displacement at 35 ms towards Area 1, known to be important for visual integration during touch perception. That this second displacement was unrelated to extent of embodiment implies a functional distinction between neuroplastic changes of these components and areas. The earlier shift in Area 3b may shape extent of limb ownership, while subsequent displacement into Area 1 may relate to early visual-tactile integration that initiates embodiment. Here we provide evidence for multiple neuroplastic processes in S1—lasting beyond the illusion—supporting integration of artificial limbs like prostheses within the body representation.

Abstract Inflammatory bowels diseases (IBD) are high risk conditions for colorectal cancer (CRC). The discovery of IBD and CRC noninvasive protein/peptide biomarkers using saliva and feces was the aim of this study involving 20 controls, 25 IBD (12 Crohn’s Disease-CD), 37 CRC. By untargeted proteomic (LTQ-Orbitrap/MS), a total of 152 proteins were identified in saliva. Absent in controls, 73 proteins were present in both IBD and CRC, being mainly related to cell-adhesion, cadherin-binding and enzyme activity regulation (g-Profiler). Among the remaining 79 proteins, 14 were highly expressed in CD and 11 in CRC. These proteins clustered in DNA replication/expression and innate/adaptive immunity. In stool, endogenous peptides from 30 different proteins were identified, two being salivary and CD-associated: Basic Proline-rich Protein 1 (PRBs) and Acidic Proline-rich Phosphoprotein. Biological effects of the PRBs-related peptides GQ-15 and GG-17 found in CD stool were evaluated using CRC cell lines. These peptides induced cell proliferation and activated Erk1/2, Akt and p38 pathways. In conclusion, the salivary proteome unveiled DNA stability and immunity clusters shared between IBD and CRC. Salivary PRB-derived peptides, enriched in CD stool, stimulate CRC cell proliferation and the pro-oncogenic RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways suggesting a potential involvement of PRBs in IBD and cancer pathogenesis.

Abstract The tree‐like morphology of neurons and glia is a key cellular determinant of circuit connectivity and metabolic function in the nervous system of essentially all animals. To elucidate the contribution of specific cell types to both physiological and pathological brain states, it is important to access detailed neuroanatomy data for quantitative analysis and computational modeling. NeuroMorpho.Org is the largest online collection of freely available digital neural reconstructions and related metadata and is continuously updated with new uploads. Earlier in the project, we released multiple datasets together yearly, but this process caused an average delay of several months in making the data public. Moreover, in the past 5 years, >80% of invited authors agreed to share their data with the community via NeuroMorpho.Org, up from

Abstract We study freeze-in production of Higgs portal dark matter (DM) at temperatures far below the dark matter mass. The temperature of the Standard Model (SM) thermal bath may have never been high such that dark matter production via thermal emission has been Boltzmann-suppressed. This allows for a significant coupling between the Higgs field and DM, which is being probed by the direct DM detection experiments and invisible Higgs decay searches at the LHC. We delineate the corresponding parameter space in the Higgs portal framework with dark matter of spin 0, 1/2 and 1.

Abstract Recent studies have shown a growing interest in the so-called “aperiodic” component of the EEG power spectrum, which describes the overall trend of the whole spectrum with a linear or exponential function. In the field of brain aging, this aperiodic component is associated both with age-related changes and performance on cognitive tasks. This study aims to elucidate the potential role of education in moderating the relationship between resting-state EEG features (including aperiodic component) and cognitive performance in aging. N = 179 healthy participants of the “Leipzig Study for Mind–Body-Emotion Interactions” (LEMON) dataset were divided into three groups based on age and education. Older adults exhibited lower exponent, offset (i.e. measures of aperiodic component), and Individual Alpha Peak Frequency (IAPF) as compared to younger adults. Moreover, visual attention and working memory were differently associated with the aperiodic component depending on education: in older adults with high education, higher exponent predicted slower processing speed and less working memory capacity, while an opposite trend was found in those with low education. While further investigation is needed, this study shows the potential modulatory role of education in the relationship between the aperiodic component of the EEG power spectrum and aging cognition.

Abstract Urban areas face increasing pressure due to densification, presenting numerous challenges involving various stakeholders. The impact of densification on human well-being in existing urban areas can be both positive and negative, which requires a comprehensive understanding of its consequences. Computational Urban Design (CUD) emerges as a valuable tool in this context, offering rapid generation and evaluation of design solutions, although it currently lacks consideration for human perception in urban areas. This research addresses the challenge of incorporating human perception into computational urban design in the context of urban densification, and therefore demonstrates a complete process. Using Place Pulse 2.0 data and multinomial logit models, the study first quantifies the relationship between volumetric built elements and human perception (beauty, liveliness, and safety). The findings are then integrated into a Grasshopper-based CUD tool, enabling the optimization of parametric designs based on human perception criteria. The results show the potential of this approach. Finally, future research and development ideas are suggested based on the experiences and insights derived from this study.

Abstract Background Carbon (C) sink and stock are among the most important ecosystem services provided by forests in climate change mitigation policies. In this context, old-growth forests constitute an essential reference point for the development of close-to-nature silviculture, including C management techniques. Despite their small extent in Europe, temperate old-growth forests are assumed to be among the most prominent in terms of biomass and C stored. However, monitoring and reporting of C stocks is still poorly understood. To better understand the C stock amount and distribution in temperate old-growth forests, we estimated the C stock of two old-growth stands in the Dinaric Alps applying different assessment methods, including direct and indirect approaches (e.g., field measurements and allometric equations vs. IPCC standard methods). This paper presents the quantification and the distribution of C across the five main forest C pools (i.e., aboveground, belowground, deadwood, litter and soil) in the study areas and the differences between the applied methods. Results We report a very prominent C stock in both study areas (507 Mg C ha− 1), concentrated in a few large trees (36% of C in 5% of trees). Moreover, we found significant differences in C stock estimation between direct and indirect methods. Indeed, the latter tended to underestimate or overestimate depending on the pool considered. Conclusions Comparison of our results with previous studies and data collected in European forests highlights the prominence of temperate forests, among which the Dinaric Alps old-growth forests are the largest. These findings provide an important benchmark for the development of future approaches to the management of the European temperate forests. However, further and deeper research on C stock and fluxes in old-growth stands is of prime importance to understand the potential and limits of the climate mitigation role of forests.

Glioblastoma (GBM) is a primary tumor in the central nervous system with poor prognosis. It exhibits elevated glucose uptake and lactate production. This metabolic state of aerobic glycolysis is known as the Warburg effect. N6‐isopentenyladenosine (iPA), a natural cytokine modified with an isopentenyl moiety derived from the mevalonate pathway, has well‐established anti‐tumor activity. It inhibits cell proliferation in glioma cells, inducing cell death by apoptosis and/or necroptosis. In the present study, we found that iPA inhibits aerobic glycolysis in unmodified U87MG cells and in the same cell line engineered to over‐express wild‐type epidermal growth factor receptor (EGFR) or EGFR variant III (vIII), as well as in a primary GBM4 patient‐derived cell line. The detection of glycolysis showed that iPA treatment suppressed ATP and lactate production. We also evaluated the response of iPA treatment in normal human astrocyte primary cells, healthy counterpart cells of the brain. Aerobic glycolysis in treated normal human astrocyte cells did not show significant changes compared to GBM cells. To determine the mechanism of iPA action on aerobic glycolysis, we investigated the expression of certain enzymes involved in this metabolic pathway. We observed that iPA reduced the expression of pyruvate kinase M2 (PKM2), which plays a key role in the regulation of aerobic glycolysis, promoting tumor cell proliferation. The reduction of PKM2 expression is a result of the inhibition of the inhibitor of nuclear factor kappa‐B kinase subunit, beta/nuclear factor‐kappa B pathway upon iPA treatment. In conclusion, these experimental results show that iPA may inhibit aerobic glycolysis of GBM in stabilized cell lines and primary GBM cells by targeting the expression and activity of PKM2.

Objective: Auditory-driven gamma synchrony (GS) is linked to the function of a specific cortical circuit based on a parvalbumin+ and pyramidal neuron loop. This circuit is impaired in neuropsychiatric conditions (i.e. schizophrenia, Alzheimer's disease, stroke etc.) and its relevance in clinical practice is increasingly being recognized. Auditory stimulation at a typical gamma frequency of 40 Hz can be applied as a ‘stress test’ of excitation/inhibition (E/I) of the entire cerebral cortex, to drive GS and record it with magnetoencephalography (MEG) or high-density electroencephalography (EEG). However, these two techniques are costly and not widely available. Therefore, we assessed whether a single EEG electrode is sufficient to provide an accurate estimate of the auditory-driven GS level of the entire cortical surface while expecting the highest correspondence in the auditory and somatosensory cortices. Methods: We measured simultaneous EEG-MEG in 29 healthy subjects, utilizing 3 EEG electrodes (C4, F4, O2) and a full MEG setup. Recordings were performed during binaural exposure to auditory gamma stimulation and during silence. We compared GS measurement of each of the three EEG electrodes separately against full MEG mapping. Time-resolved phase locking value (PLVt) was computed between EEG signals and cortex reconstructed MEG signals. Results: During auditory stimulation, but not at rest, EEG captures a significant amount of GS, especially from both auditory cortices and motor-premotor regions. This was especially true for frontal (C4) and central electrodes (F4). Discussion and Conclusions: While hd-EEG and MEG are necessary for accurate spatial mapping of GS at rest and during auditory stimulation, a single EEG channel is sufficient to detect the global level of GS. These results have great translational potential for mapping GS in standard clinical settings.

Diabetic foot ulcer (DFU), one of the most significant complications of diabetes, is a condition that causes anatomical and functional alterations of the foot resulting in an important social and economic impact, related to disability and health care costs. Recently, three-dimensional bioprinting - which allows the fabrication of complex and biocompatible structures - has been identified as a promising approach in the field of regenerative medicine to promote the healing of chronic wounds, such as DFU. In this concise review we highlight the most relevant and recent attempts of using 3D bioprinted constructs in vivo - both on animals and people - in order to treat non-healing diabetic ulcers and prevent their worsening. Finally, we briefly focus on the future implications of bioprinting, suggesting its forthcoming importance not only for DFU treatment but also for other areas of clinical care.

Abstract Background Activation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies. Methods This study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads. Results We show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival. Conclusions Altogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.

Dual-energy CT (DECT) is an innovative technology that is increasingly widespread in clinical practice. DECT allows for tissue characterization beyond that of conventional CT as imaging is performed using different energy spectra that can help differentiate tissues based on their specific attenuation properties at different X-ray energies. The most employed post-processing applications of DECT include virtual monoenergetic images (VMIs), iodine density maps, virtual non-contrast images (VNC), and virtual non-calcium (VNCa) for bone marrow edema (BME) detection. The diverse array of images obtained through DECT acquisitions offers numerous benefits, including enhanced lesion detection and characterization, precise determination of material composition, decreased iodine dose, and reduced artifacts. These versatile applications play an increasingly significant role in tumor assessment and oncologic imaging, encompassing the diagnosis of primary tumors, local and metastatic staging, post-therapy evaluation, and complication management. This article provides a comprehensive review of the principal applications and post-processing techniques of DECT, with a specific focus on its utility in managing oncologic patients.

Abstract We present a quantitative strategy to identify all projection neuron types from a given region with statistically different patterns of anatomical targeting. We first validate the technique with mouse primary motor cortex layer 6 data, yielding two clusters consistent with cortico-thalamic and intra-telencephalic neurons. We next analyze the presubiculum, a less-explored region, identifying five classes of projecting neurons with unique patterns of divergence, convergence, and specificity. We report several findings: individual classes target multiple subregions along defined functions; all hypothalamic regions are exclusively targeted by the same class also invading midbrain and agranular retrosplenial cortex; Cornu Ammonis receives input from a single class of presubicular axons also projecting to granular retrosplenial cortex; path distances from the presubiculum to the same targets differ significantly between classes, as do the path distances to distinct targets within most classes; the identified classes have highly non-uniform abundances; and presubicular somata are topographically segregated among classes. This study thus demonstrates that statistically distinct projections shed light on the functional organization of their circuit.

Coastal environments are complex systems that are influenced by a combination of natural processes and human activities. Scientific interest in the effects of coastal erosion/accretion and climatic change-related processes has greatly increased in recent decades due to the growing human development along coastal areas. This paper investigates the state and evolution of beach–dune systems for the 1977–2001 and 2001–2019 periods of the Mediterranean coast of Andalusia (Spain) using two different proxies: the dune toe line, which was used to track foredunes evolution, and the high-water line, which was used to assess shoreline evolution. Results showed a general erosional behavior of the studied beach–dune systems and identified cases where the main trend was altered through human interventions. During the 1977–2001 period, foredunes essentially showed erosion (54%), accretion (24%), and stability (22%) and shorelines showed accretion (40%) and erosion and stability (34% each). During the 2001–2019 period, foredunes essentially showed erosion (42%), stability (30%), and accretion (28%), and shorelines showed erosion (40%), accretion (34%), and stability (26%). Combining the evolution classes of each proxy (dune toe/shoreline) allows the behavior of both shoreline proxies to be assessed together and provides insights additional to those derived from the use of a single proxy. In this regard, Erosion/erosion (EE) and Accretion/accretion (AA) were the most frequent behaviors in the first and second periods. The results obtained provide additional insights on the nature and drivers of coastal change that aid local coastal managers and administrations in understanding erosion processes. The method can be applied to other areas around the world where a similar database is available.

We provide a short review of some aspects of dark matter (DM) production in non-standard cosmology. Considering the simplest Higgs portal model as a definite particle physics setup, we consider the impact on the parameter space corresponding to the correct relic density and the complementary experimental constraints of the presence, during thermal production, of an exotic component dominating the energy density of the universe. In the second part of the work, we will focus on the case that such an exotic component satisfies the equation of state of matter and can produce DM non-thermally.

Abstract Background During the last decade, there has been a growing number of cases of children born from pregnancy-associated cancer (PAC), however there are currently insufficient data on the follow up to be observed in this category of newborns. Objective of the study was to evaluate the neonatal outcomes of infants born to mother with PAC, the potential adverse effect of chemotherapy during pregnancy and the risk of metastasis to the fetus. Methods Maternal clinical data and neonatal outcomes of child born to mothers diagnosed with PAC were collected; infants were divided into those were and were not exposed to chemotherapy during fetal life and their outcomes were compered. Results A total of 37 newborn infants from 36 women with PAC were analyzed. Preterm delivery occurred in 83.8% of the cases. No significant differences in neonatal outcomes were found between infants who were and were not exposed to chemotherapy during pregnancy. The median follow-up period was 12 months. Conclusions PAC treatment during the second or third trimester does not seem to be dangerous for the fetus, however infants born from PAC must be carefully evaluated for to rule out the consequences of chemotherapy and exclude the presence of metastasis. Long-term follow-up, especially in children exposed to chemotherapy, should be encouraged to obtain relevant data on long-term toxicity.

Abstract Purpose To assess the prevalence of alterations in anthropometric parameters predictive of metabolic syndrome and cardiovascular risk among childhood brain tumor survivors. Methods Anthropometric parameters predictive of metabolic syndrome and cardiovascular risk were analyzed [height, weight, BMI, waist circumference, hip circumference, waist-height ratio (WHtR), waist-hip ratio (WHR, blood pressure] of 25 patients who survived childhood brain tumors. Results 21 patients (84%) showed alteration of at least one predictive anthropometric parameter. 11 patients (44%) showed a BMI > 75th percentile and 19 patients (76%) showed a pathological WHR value. A pathological WHtR (> 0.5), was identified in 17 patients (68%); the average WHtR observed was 0.53. 9 patients (36%) showed an alteration of all three anthropometric parameters considered. Comparing this subpopulation with the subpopulation with less than three altered parameters, a greater prevalence of the combined alteration was observed in the female sex compared to the male sex (67% vs. 26%). No significant differences were observed regarding the age of diagnosis and end of treatment nor the treatments carried out (chemotherapy, radiotherapy, steroid therapy) between the two groups. Conclusion These results suggest that this population is at high risk of presenting pathological values of BMI, WHR and WHtR with consequent high risk of developing metabolic syndrome and cardiovascular diseases.

(Series Information) European Papers - A Journal on Law and Integration, 2023 8(2), 853-878 | Article | (Table of Contents) I. Dual-track proceedings and the current scope of protection. – II. The need for a clear notion of “idem”. – III. The “sufficiently close connection in substance and time”: ECtHR case-law post A and B v Norway. – IV. The “sufficiently close connection in substance and time”: the unspoken balancing act engaged in by the ECtHR and an alternative criterion to assess whether there was a duplication of proceedings. – V. Lis pendens and ne bis in idem. – VI. Conclusion. | (Abstract) This Article analyses the issue of the compatibility with the ne bis in idem principle of the double-track sanctioning systems present in various European legal orders in the light of the case-law of the European Court of Human Rights and the Court of Justice of the European Union. In particular, after a reconstruction of the most significant case-law after the famous ruling A and B v. Norway, three main critical points are brought into focus: the divergences between the national and European case-law on the interpretation of the notion of idem factum, the difficult practical application of the close connection test between proceedings developed by the European Court of Human Rights, which can be seen as the precipitate of an unsatisfactory balancing act of opposing interests, and the possible extension of the ne bis in idem principle also to cases of lis pendens.

Abstract Comprehensive quantification of neuronal architectures underlying anatomical brain connectivity remains challenging. We introduce a method to identify distinct axonal projection patterns from a source to a set of target regions and the count of neurons with each pattern. A source region projecting to n targets could have 2 n -1 theoretically possible projection types, although only a subset of these types typically exists. By injecting uniquely labeled retrograde tracers in k target regions (k

Abstract Digital reconstructions provide an accurate and reliable way to store, share, model, quantify, and analyze neural morphology. Continuous advances in cellular labeling, tissue processing, microscopic imaging, and automated tracing catalyzed a proliferation of software applications to reconstruct neural morphology. These computer programs typically encode the data in custom file formats. The resulting format heterogeneity severely hampers the interoperability and reusability of these valuable data. Among these many alternatives, the SWC file format has emerged as a popular community choice, coalescing a rich ecosystem of related neuroinformatics resources for tracing, visualization, analysis, and simulation. This report presents a standardized specification of the SWC file format. In addition, we introduce xyz2swc, a free online service that converts all 26 reconstruction formats (and 72 variations) described in the scientific literature into the SWC standard. The xyz2swc service is available open source through a user-friendly browser interface ( https://neuromorpho.org/xyz2swc/ui/ ) and an Application Programming Interface (API).

Background: A knee injury in an athlete leads to periods of forced exercise interruption. Myocardial work (MW) assessed by echocardiographic and cardiopulmonary exercise testing (CPET) are two essential methods for evaluating athletes during the period following injury. However, compared to pre-surgery evaluations, the variations in cardiovascular parameters and functional capacity assessed by these methods after surgery remain unclear. Methods: We evaluated 22 non-professional athletes aged 18–52, involved in prevalently aerobic or alternate aerobic/anaerobic sports activities, who were affected by a knee pathology requiring surgical treatment. The evaluation was performed at rest using transthoracic echocardiography, including MW assessment, and during exercise using CPET. Each athlete underwent the following two evaluations: the first before surgery and the second after surgery (specifically at the end of the deconditioning period). Results: Resting heart rate (HR) increased significantly (from 63.3 ± 10.85 to 71.2 ± 12.52 beats per minute, p = 0.041), while resting diastolic and systolic blood pressure, forced vital capacity, and forced expiratory volume in the first second did not show significant changes. Regarding the echocardiographic data, global longitudinal strain decreased from −18.9 ± 1.8 to −19.3 ± 1.75; however, this reduction was not statistically significant (p = 0.161). However, the global work efficiency (GWE) increased significantly (from 93.0% ± 2.9 to 94.8% ± 2.6, p = 0.006) and global wasted work (GWW) reduced significantly (from 141.4 ± 74.07 to 98.0 ± 50.9, p = 0.007). Additionally, the patients were able to perform maximal CPET at both pre- and post-surgery evaluations, as demonstrated by the peak respiratory exchange ratio and HR. However, the improved myocardial contractility (increased GWE and decreased GWW) observed at rest did not translate into significant changes in exercise parameters, such as peak oxygen consumption and the mean ventilation/carbon dioxide slope. Conclusions: After surgery, the athletes were more deconditioned (as indicated by a higher resting HR) but exhibited better resting myocardial contractility (increased GWE and reduced GWW). Interestingly, no significant changes in exercise capacity parameters, as evaluated by CPET, were found after surgery, suggesting that the improved myocardial contractility was offset by a greater degree of muscular deconditioning.

This paper deals with beach litter presence on the Ionian coast of Albania, i.e., at Vlora Bay and the Albanian Riviera, which is the most famous coastal tourist destination in the country. Along 16 beaches surveyed in November–December 2022 was found a total amount of 6621 litter items (or 416 kg) belonging to 114 categories of the EU J−code list. Most of these were plastic fragments and items (82%), mainly linked to local tourist activities. Wastewaters were responsible for bringing different litter items to the urban beaches of Vlora Bay. The most commonly observed litter items were cigarette butts, plastic caps/lids, and medium-sized plastic fragments of non-foamed plastic. The cleanest beaches, quite often, were the ones where beach clubs implemented clean-up programs during and at the end of the summer season. The results of this paper constitute a baseline of the beach litter amount and content along the study coast, which has never been investigated before. Municipalities and beach clubs have to implement more frequent and efficient clean-up activities and educational initiatives to reduce beach pollution, with special attention paid to the presence of cigarette butts and other small plastic items.

Over the last several years, a growing body of evidence from anatomical, physiological, and functional neuroimaging studies has increasingly indicated that the cerebellum is actively involved in managing higher order cognitive functions and regulating emotional responses. It has become clear that when children experience congenital or acquired cerebellar lesions, these injuries can lead to a variety of cognitive and emotional disorders, manifesting in different combinations. This underscores the cerebellum’s essential role not only throughout developmental stages but particularly in facilitating learning processes, highlighting its critical importance beyond its traditional association with motor control. Furthermore, the intricate neural circuits within the cerebellum are believed to contribute to the fine-tuning of motor actions and coordination but are also increasingly recognized for their involvement in cognitive processes such as attention, language, and problem solving. Recent research has highlighted the importance of cerebellar health and integrity for optimal functioning across various domains of the human experience.

The role of forests in providing multiple goods and services has been recognized worldwide. In such a context, reliable spatial predictions of forest attributes such as tree volume and current increment are fundamental for conducting forest monitoring, improving restoration programs, and supporting decision-making processes. This article presents the methodology and the results of the wall-to-wall spatialization of the growing stock volume and the current annual increment measured in 273 plots of data of the Italian National Forest Inventory over an area of more than 3260 km2 in the Friuli Venezia Giulia region (Northeast Italy). To this aim, a random forest model was tested using as predictors 4 spectral indices from Sentinel-2, a high-resolution Canopy Height Model derived from LiDAR, and geo-morphological data. According to the Leave One Out cross-validation procedure, the model for the growing stock shows an R2 and an RMSE% of 0.67 and 41%, respectively. Instead, an R2 of 0.47 and an RMSE% of 57% were obtained for the current annual increment. The validation with an independent dataset further improved the models’ performances, yielding significantly higher R2 values of 0.84 and 0.83 for volume and for increment, respectively. Our results underline a relatively higher importance of LiDAR-derived metrics compared to other covariates in estimating both attributes, as they were even twice as important as vegetation indices for growing stock. Therefore, these metrics are promising for the development of a national LiDAR-based model.

It has been shown that vertical transmission of the SARS-CoV-2 strain is relatively rare, and there is still limited information on the specific impact of maternal SARS-CoV-2 infection on vertical transmission. The current study focuses on a transcriptomics analysis aimed at examining differences in gene expression between placentas from mother–newborn pairs affected by COVID-19 and those from unaffected controls. Additionally, it investigates the in situ expression of molecules involved in placental inflammation. The Papa Giovanni XXIII Hospital in Bergamo, Italy, has recorded three instances of intrauterine transmission of SARS-CoV-2. The first two cases occurred early in the pandemic and involved pregnant women in their third trimester who were diagnosed with SARS-CoV-2. The third case involved an asymptomatic woman in her second trimester with a twin pregnancy, who unfortunately delivered two stillborn fetuses due to the premature rupture of membranes. Transcriptomic analysis revealed significant differences in gene expression between the placentae of COVID-19-affected mother/newborn pairs and two matched controls. The infected and control placentae were matched for gestational age. According to the Benjamani–Hochberg method, 305 genes met the criterion of an adjusted p-value of less than 0.05, and 219 genes met the criterion of less than 0.01. Up-regulated genes involved in cell signaling (e.g., CCL20, C3, MARCO) and immune response (e.g., LILRA3, CXCL10, CD48, CD86, IL1RN, IL-18R1) suggest their potential role in the inflammatory response to SARS-CoV-2. RNAscope® technology, coupled with image analysis, was utilized to quantify the surface area covered by SARS-CoV-2, ACE2, IL-1β, IL-6, IL-8, IL-10, and TNF-α on both the maternal and fetal sides of the placenta. A non-statistically significant gradient for SARS-CoV-2 was observed, with a higher surface coverage on the fetal side (2.42 ± 3.71%) compared to the maternal side (0.74 ± 1.19%) of the placenta. Although not statistically significant, the surface area covered by ACE2 mRNA was higher on the maternal side (0.02 ± 0.04%) compared to the fetal side (0.01 ± 0.01%) of the placenta. IL-6 and IL-8 were more prevalent on the fetal side (0.03 ± 0.04% and 0.06 ± 0.08%, respectively) compared to the maternal side (0.02 ± 0.01% and 0.02 ± 0.02%, respectively). The mean surface areas of IL-1β and IL-10 were found to be equal on both the fetal (0.04 ± 0.04% and 0.01 ± 0.01%, respectively) and maternal sides of the placenta (0.04 ± 0.05% and 0.01 ± 0.01%, respectively). The mean surface area of TNF-α was found to be equal on both the fetal and maternal sides of the placenta (0.02 ± 0.02% and 0.02 ± 0.02%, respectively). On the maternal side, ACE-2 and all examined interleukins, but not TNF-α, exhibited an inverse mRNA amount compared to SARS-CoV-2. On the fetal side, ACE-2, IL-6 and IL-8 were inversely correlated with SARS-CoV-2 (r = −0.3, r = −0.1 and r = −0.4, respectively), while IL-1β and IL-10 showed positive correlations (r = 0.9, p = 0.005 and r = 0.5, respectively). TNF-α exhibited a positive correlation with SARS-CoV-2 on both maternal (r = 0.4) and fetal sides (r = 0.9) of the placenta. Further research is needed to evaluate the correlation between cell signaling and immune response genes in the placenta and the vertical transmission of SARS-CoV-2. Nonetheless, the current study extends our comprehension of the molecular and immunological factors involved in SARS-CoV-2 placental infection underlying maternal–fetal transmission.

Blau syndrome (BS) is a rare autoinflammatory granulomatosis characterized by granulomatous arthritis, uveitis, and dermatitis. Ocular complications are particularly severe in BS, significantly contributing to morbidity. This study aims to identify potential biomarkers for BS ocular degeneration through proteomic profiling of tear samples from affected patients. Seven subjects from the same family, including four carriers of the BS-associated NOD2 mutation (p.E383K), were recruited alongside healthy controls. Tear samples were collected using Schirmer strips and analyzed via mass spectrometry. A total of 387 proteins were identified, with significant differences in protein expression between BS patients, healthy familial subjects, and healthy controls. Key findings include the overexpression of alpha-2-macroglobulin (A2M) and immunoglobulin heavy constant gamma 4 (IGHG4) in BS patients. Bioinformatic analysis revealed that differentially expressed proteins are involved in acute-phase response, extracellular exosome formation, and protein binding. Notably, neutrophils’ azurophilic granule components, as azurocidin (AZU1), myeloperoxidases (MPO), and defensins (DEFA3), were highly expressed in the most severely affected subject, suggesting a potential role of neutrophils in BS ocular severity. These proteins might be promising biomarkers for ocular involvement in BS, facilitating early detection and tailored treatment strategies.

IntroductionAccording to various censuses, Europe has less than 1.5 million ha of old-growth forests (OGF). Most of them are in the boreal zone, while their presence in the temperate zone is residual and fragmented.In the framework of the EU biodiversity strategy, it has been adopted a broad definition of OGF which includes late-seral forests and forests with some management legacies. However, research purposes need to identify strictly defined OGFs characterized by structure, disturbance history, and processes typical and exclusive of the last stage of the forest dynamic.MethodsThe present paper wants to contribute to this debate by presenting a research network of four mixed (Fagus-Abies-Picea) montane OGFs in the Dinaric Alps (Lom, BiH; Janj, BiH; Perućica, BiH; Biogradska Gora, MNE), summarizing 20 years of multidisciplinary research by focusing on the structural characteristics and the disturbance history of the whole network and their coherency with strict OGF indicators. These sites were selected in relatively structurally uniform study areas, where 142 permanent plots have been established since 2002.Results and discussionThe study sites have a high living (747–1,201 m3 ha−1) and coarse woody debris (CWD) biomass (304–410 m3 ha−1), resulting in the highest forest carbon sink at the continental level (398–484 Mg C ha−1). The presence of large and old trees is one of the critical characteristics of the old-growth stage: in Lom and Perućica, there are 19 trees and 14 ha−1 larger than 1 m at breast height, respectively, and 14 trees and 15 trees ha−1 older than 400 years. In the last three centuries, continuous small-scale disturbances have driven forest dynamics, developing stands characterized by gap-phase dynamics and quasi-equilibrium structure. The Dinaric OGF network presents robust indicators of old-growthness, similar structural characteristics, and dynamic processes across all four sites. Identifying this sub-set of OGF using strict criteria is critical for recognizing conservation priorities and for quantifying, along an old-growthness chronosequence, the current structural differences of managed or recently abandoned forests. Besides, only OGF selected with rigorous criteria can act as a reliable reference for ecological restoration and sustainable forest management as a benchmark for carbon sink and for quantifying the impact of climate change on forests.

Armando Ruinelli’s forty-year architectural experience, as documented in the recent publication Leggere il tempo, is characterised by its sensitivity and attention to context. Devoid of excess and extravagance, his work establishes a polite dialogue with its surroundings, reflecting the discreet personality of the author. At the core of Ruinelli’s practice lies a profound ethical consideration, extending beyond the design phase to encompass the entire spectrum of operational intricacies. His perspective on time translates into an acceptance of material aging, emphasising the importance of allowing buildings to follow their natural course. Rooted in context, his architecture seeks not only continuity but harmonious integration within the Alpine landscapes they inhabit. In dialogue with the interviewer, Ruinelli emphasises his preference for artisanal work, highlighting the significance of precision in execution and the centrality of humans over materials. His poetic exploration is manifested in creating atmospheres and carefully balancing the dynamic components of a project. Reflecting on the role of the architect, he envisions them as craftsmen endowed with both technical acumen and creative vision. Finally, Ruinelli shares a meaningful project – the fountains in the Soglio cemetery – a creation laden with delicacy and symbolism that underscores the spiritual depth of his work.

Hippocampome.org is a mature open-access knowledge base of the rodent hippocampal formation focusing on neuron types and their properties. Previously, Hippocampome.org v1.0 established a foundational classification system identifying 122 hippocampal neuron types based on their axonal and dendritic morphologies, main neurotransmitter, membrane biophysics, and molecular expression (Wheeler et al., 2015). Releases v1.1 through v1.12 furthered the aggregation of literature-mined data, including among others neuron counts, spiking patterns, synaptic physiology, in vivo firing phases, and connection probabilities. Those additional properties increased the online information content of this public resource over 100-fold, enabling numerous independent discoveries by the scientific community. Hippocampome.org v2.0, introduced here, besides incorporating over 50 new neuron types, now recenters its focus on extending the functionality to build real-scale, biologically detailed, data-driven computational simulations. In all cases, the freely downloadable model parameters are directly linked to the specific peer-reviewed empirical evidence from which they were derived. Possible research applications include quantitative, multiscale analyses of circuit connectivity and spiking neural network simulations of activity dynamics. These advances can help generate precise, experimentally testable hypotheses and shed light on the neural mechanisms underlying associative memory and spatial navigation.

Abstract The posterior superior temporal sulcus (pSTS) is a critical node in a network specialized for perceiving emotional facial expressions that is reciprocally connected with early visual cortices (V1/V2). Current models of perceptual decision-making increasingly assign relevance to recursive processing for visual recognition. However, it is unknown whether inducing plasticity into reentrant connections from pSTS to V1/V2 impacts emotion perception. Using a combination of electrophysiological and neurostimulation methods, we demonstrate that strengthening the connectivity from pSTS to V1/V2 selectively increases the ability to perceive facial expressions associated with emotions. This behavior is associated with increased electrophysiological activity in both these brain regions, particularly in V1/V2, and depends on specific temporal parameters of stimulation that follow Hebbian principles. Therefore, we provide evidence that pSTS-to-V1/V2 back-projections are instrumental to perception of emotion from facial stimuli and functionally malleable via manipulation of associative plasticity.

Abstract The increasing number of peer-reviewed publications constitutes a challenge for biocuration. For example, NeuroMorpho.Org, a sharing platform for digital reconstructions of neural morphology, must evaluate more than 6000 potentially relevant articles per year to identify data of interest. Here, we describe a tool that uses natural language processing and deep learning to assess the likelihood of a publication to be relevant for the project. The tool automatically identifies articles describing digitally reconstructed neural morphologies with high accuracy. Its processing rate of 900 publications per hour is not only amply sufficient to autonomously track new research, but also allowed the successful evaluation of older publications backlogged due to limited human resources. The number of bio-entities found since launching the tool almost doubled while greatly reducing manual labor. The classification tool is open source, configurable, and simple to use, making it extensible to other biocuration projects.

Abstract In this paper, a resonant converter model is proposed that takes into account the thermal and electrical dynamics of the main components. With respect to state‐of‐art, where model‐based design approaches are often implemented off‐line, the proposed model has a low computational complexity such that it can be simulated in real‐time. This real‐time electro‐thermal model enables also the design of a predictive control algorithm, that is proposed to optimize the current control of a SiC‐based resonant converter by handling both thermal and electrical operating limits of its components. To validate the interaction between the converter model and the predictive control algorithm, validation is proposed via real‐time processor‐in‐the‐loop, with application to the on‐board charger for high‐voltage Li‐ion battery pack, typical of modern fully electrified vehicles.

We present a statistical study of some physical properties of medium-scale traveling ionospheric disturbances (MSTIDs) registered over the Mexican territory during 2018 and 2019 (solar minimum). The analysis is based on total electron content (TEC) approximations using data from the ground-based Global Navigation Satellite System (GNSS) receivers at different locations, divided into three regions according to geographic longitudes: west, center, and east. The MSTIDs were classified into day and night events, and only geomagnetically quiet days were considered to reduce the solar influence. We explored fundamental aspects of the MSTIDs, such as differences between day and night events, occurrence patterns, and geographical differences. Our results show some similarities with the occurrence periods of gravity waves, exhibiting high activity during summer and winter. For this period, however, most events occurred between 20:00 and 04:00 AM UT. The most energetic events, i.e., large amplitudes and power, occurred around the sunset terminator. This suggests that the density gradient generated when the sunlight falls benefits MSTID formation.

Machine learning and computer vision have proven to be valuable tools for farmers to streamline their resource utilization to lead to more sustainable and efficient agricultural production. These techniques have been applied to strawberry cultivation in the past with limited success. To build on this past work, in this study, two separate sets of strawberry images, along with their associated diseases, were collected and subjected to resizing and augmentation. Subsequently, a combined dataset consisting of nine classes was utilized to fine-tune three distinct pretrained models: vision transformer (ViT), MobileNetV2, and ResNet18. To address the imbalanced class distribution in the dataset, each class was assigned weights to ensure nearly equal impact during the training process. To enhance the outcomes, new images were generated by removing backgrounds, reducing noise, and flipping them. The performances of ViT, MobileNetV2, and ResNet18 were compared after being selected. Customization specific to the task was applied to all three algorithms, and their performances were assessed. Throughout this experiment, none of the layers were frozen, ensuring all layers remained active during training. Attention heads were incorporated into the first five and last five layers of MobileNetV2 and ResNet18, while the architecture of ViT was modified. The results indicated accuracy factors of 98.4%, 98.1%, and 97.9% for ViT, MobileNetV2, and ResNet18, respectively. Despite the data being imbalanced, the precision, which indicates the proportion of correctly identified positive instances among all predicted positive instances, approached nearly 99% with the ViT. MobileNetV2 and ResNet18 demonstrated similar results. Overall, the analysis revealed that the vision transformer model exhibited superior performance in strawberry ripeness and disease classification. The inclusion of attention heads in the early layers of ResNet18 and MobileNet18, along with the inherent attention mechanism in ViT, improved the accuracy of image identification. These findings offer the potential for farmers to enhance strawberry cultivation through passive camera monitoring alone, promoting the health and well-being of the population.

Computational simulations with data-driven physiological detail can foster a deeper understanding of the neural mechanisms involved in cognition. Here, we utilize the wealth of cellular properties from Hippocampome.org to study neural mechanisms of spatial coding with a spiking continuous attractor network model of medial entorhinal cortex circuit activity. The primary goal is to investigate if adding such realistic constraints could produce firing patterns similar to those measured in real neurons. Biological characteristics included in the work are excitability, connectivity, and synaptic signaling of neuron types defined primarily by their axonal and dendritic morphologies. We investigate the spiking dynamics in specific neuron types and the synaptic activities between groups of neurons. Modeling the rodent hippocampal formation keeps the simulations to a computationally reasonable scale while also anchoring the parameters and results to experimental measurements. Our model generates grid cell activity that well matches the spacing, size, and firing rates of grid fields recorded in live behaving animals from both published datasets and new experiments performed for this study. Our simulations also recreate different scales of those properties, e.g., small and large, as found along the dorsoventral axis of the medial entorhinal cortex. Computational exploration of neuronal and synaptic model parameters reveals that a broad range of neural properties produce grid fields in the simulation. These results demonstrate that the continuous attractor network model of grid cells is compatible with a spiking neural network implementation sourcing data-driven biophysical and anatomical parameters from Hippocampome.org. The software (version 1.0) is released as open source to enable broad community reuse and encourage novel applications.

Abstract The hMSSM is a special parameterization of the minimal supersymmetric extension of the Standard Model (MSSM) in which the mass of the lightest Higgs boson is automatically set to the LHC measured value, M h =125 GeV, by adjusting the supersymmetric particle spectrum such that it provides the required amount of radiative corrections to the Higgs boson masses. The latter spectrum was in general assumed to be very heavy, as indicated by the present exclusion limits of the LHC, not to affect the phenomenology of the Higgs sector. In this work, we investigate the impact on the hMSSM by a light gaugino and higgsino sector, that is allowed by the present LHC data. In particular, we discuss the radiative corrections due to charginos and neutralinos to the Higgs boson masses and couplings and show that an hMSSM can still be realized in this context. We first describe how this scenario is implemented in the package SuSpect that generates the MSSM Higgs and supersymmetric spectra. We then analyze the possible impact of Higgs boson decays into these new states, as well as the reverse cascade channels with Higgs bosons in the final states, for the constraints on the MSSM Higgs sector at the LHC. We further explore the cosmological constraints on the hMSSM with a light gaugino-higgsino spectrum. We analyze the relic abundance of the lightest neutralino as a candidate of the dark matter in the Universe and the constraints on its mass and couplings by the present and future astroparticle physics experiments.

We assess the complementarity between colliders, direct detection searches, and gravitational wave interferometry in probing a scenario of dark matter in the early universe. The model under consideration contains a B−L gauge symmetry and a vector-like fermion which acts as the dark matter candidate. The fermion induces significant a large dark matter-nucleon scattering rate, and the Z′ field produces clear dilepton events at colliders. Thus, direct detection experiments and colliders severely constrain the parameter space in which the correct relic density is found in agreement with the data. Nevertheless, little is known about the new scalar responsible for breaking the B-L symmetry. If this breaking occurs via a first-order phase transition at a TeV scale, it could lead to gravitational waves in the mHz frequency range detectable by LISA, DECIGO, and BBO instruments. The spectrum is highly sensitive to properties of the scalar sector and gauge coupling. We show that a possible GW detection, together with information from colliders and direct detection experiments, can simultaneously pinpoint the scalar self-coupling, and narrow down the dark matter mass where a thermal relic is viable.

Introduction: The term "atypical melanocytic nevus" (AMN) is used as a synonym for dysplastic nevus (DN) in clinical practice. Although the criteria for diagnosis of AMN/DN by the Agency for Research on Cancer helps to differentiate AMN/DN from common acquired nevi, they do not have high degrees of specificity, as they are similar to those used for the diagnosis of melanoma. Objectives: In this retrospective study we evaluated the correlation and diagnostic concordance of dermoscopy, confocal microscopy, and histological examination in 50 AMN. Methods: A graded scale was used to compare histological examination with dermoscopy and confocal microscopy. Low magnification histological images of only the central part of lesions were examined. This allowed histological diagnoses based almost exclusively on architectural criteria instead of simultaneously architectural and cytological, as in the global histological examination. Results: Our data demonstrate that the diagnostic accuracy of dermoscopy and confocal microscopy diagnosis of the clinical aspects of AMN/DN as nevi or melanomas tends to be equivalent, being fair for nevi and excellent for melanomas. The total percentage of AMN suggested that the accuracy of confocal microscopy in the diagnosis of melanoma (86.7%) is greater than that of dermoscopy (73.3%). Conclusions: This study demonstrated that diagnostic assessments of AMN/DN by dermoscopy and confocal microscopy are accurate and often coincide with those of histological examination and that their combined use helps to better manage and monitor these patients by facilitating early detection of melanomas and reducing unnecessary excisions of benign melanocytic lesions.

IntroductionThis study aimed to investigate profiles of personality evaluated by temperament and character dimensions (TCI) in 638 adult and older adult patients (CP) who had recently been diagnosed with breast, colon, lung, and other kinds of cancer (female and male subjects were assessed). Tests: Temperament and Character Inventory (TCI). Statistical analysis: cluster K-means analysis for personality traits.ResultsTwo different personality profiles emerged: “Low self-determination and pessimism” (Profile 1) and “Self-determination and self-caring (medium)” (Profile 2). The following significant differences were observed in the TCI dimensions between the two profiles: Temperament-Novelty-Seeking (NS) (p < 0.001); Harm-Avoidance (HA) (p < 0.001); Reward-Dependence (RD) (p < 0.001); Persistence (PS) (p < 0.001); Character-Self-Directness (SD) (p < 0.001); Cooperativeness (C) (p > 0.001); Self-Transcendence (ST) (p < 0.001). No differences in the two profiles were found between adult and elderly patients. Profile 1 - “Low self-determination and pessimism”: Patients with this profile present low resistance to frustration, poor search for novelty and solutions (NS), anxiety and pessimism (medium HA), high social attachment and dependence on the approval of others (medium-high RD), and low self-determination (PS) as temperament dimensions; and medium-low self-direction, low autonomy and ability to adapt (SD-medium-low), medium cooperativeness (C), and low self-transcendence (ST) as character dimensions. Profile 2 - “Self-determination and self-caring (medium)”: Patients with this profile have resistance to frustration, ability to search for novelty and solutions (medium-NS), low anxiety and pessimism (HA), low social attachment and dependence on approval (medium-low-RD), and determination (medium-high PS) as dimensions of temperament; and autonomy and capacity for adaptation and self-direction (SD), capacity for cooperation (high-CO), and self-transcendence (medium-high-ST) as character dimensions.ConclusionPersonality screening allows a better understanding of the difficulties of the individual patient and the planning of targeted psychotherapeutic interventions that promote quality of life and good adaptation to the disease course.

Magnetoencephalography and electroencephalography (M/EEG) seed-based connectivity analysis typically requires regions of interest (ROI)-based extraction of measures. M/EEG ROI-derived source activity can be treated in different ways. For instance, it is possible to average each ROI's time series prior to calculating connectivity measures. Alternatively one can compute connectivity maps for each element of the ROI, prior to dimensionality reduction to obtain a single map. The impact of these different strategies on connectivity estimation is still unclear.Here, we address this question within a large MEG resting state cohort (N=113) and simulated data. We consider 68 ROIs (Desikan-Kiliany atlas), two measures of connectivity (phase locking value-PLV, and its imaginary counterpart- ciPLV), and three frequency bands (theta 4-8 Hz, alpha 9-12 Hz, beta 15-30 Hz). We consider four extraction methods: (i) mean, or (ii) PCA of the activity within the ROI before computing connectivity, (iii) average, or (iv) maximum connectivity after computing connectivity for each element of the seed. Connectivity outputs from these extraction strategies are then compared with hierarchical clustering, followed by direct contrasts across extraction methods. Finally, the results are validated by using a set of realistic simulations.We show that ROI-based connectivity maps vary remarkably across strategies in both connectivity magnitude and spatial distribution. Dimensionality reduction procedures conducted after computing connectivity are more similar to each-other, while PCA before approach is the most dissimilar to other approaches. Although differences across methods are consistent across frequency bands, they are influenced by the connectivity metric and ROI size. Greater differences were observed for ciPLV than PLV, and in larger ROIs. Realistic simulations confirmed that after aggregation procedures are generally more accurate but have lower specificity (higher rate of false positive connections). Although computationally demanding, after dimensionality reduction strategies should be preferred when higher sensitivity is desired. Given the remarkable differences across aggregation procedures, caution is warranted in comparing results across studies applying different extraction methods.

Introduction: To date, tissue biopsy represents the gold standard for characterizing non-small-cell lung cancer (NSCLC), however, the complex architecture of the disease has introduced the need for new investigative approaches, such as liquid biopsy. Indeed, DNA analyzed in liquid biopsy is much more representative of tumour heterogeneity.Materials and methods: We performed a meta-analysis of 17 selected papers, to attest to the diagnostic performance of liquid biopsy in identifying EGFR mutations in NSCLC.Results: In the overall studies, we found a sensitivity of 0.59, specificity of 0.96 and diagnostic odds ratio of 24,69. Since we noticed a high heterogeneity among different papers, we also performed the meta-analysis in separate subsets of papers, divided by 1) stage of disease, 2) experimental design and 3) method of mutation detection. Liquid biopsy has the highest sensitivity/specificity in high-stage tumours, and prospective studies are more reliable than retrospective ones in terms of sensitivity and specificity, both NGS and PCR-based techniques can be used to detect tumour DNA in liquid biopsy.Discussion: Overall, liquid biopsy has the potential to help the management of NSCLC, but at present the non-homogeneous literature data, lack of optimal detection methods, together with relatively high costs make its applicability in routine diagnostics still challenging.

Abstract In human cells BRAF oncogene is invariably expressed as a mix of two coding transcripts: BRAF-ref and BRAF-X1. These two mRNA isoforms, remarkably different in the sequence and length of their 3′UTRs, are potentially involved in distinct post-transcriptional regulatory circuits. Herein, we identify PARP1 among the mRNA Binding Proteins that specifically target the X1 3′UTR in melanoma cells. Mechanistically, PARP1 Zinc Finger domain down-regulates BRAF expression at the translational level. As a consequence, it exerts a negative impact on MAPK pathway, and sensitizes melanoma cells to BRAF and MEK inhibitors, both in vitro and in vivo. In summary, our study unveils PARP1 as a negative regulator of the highly oncogenic MAPK pathway in melanoma, through the modulation of BRAF-X1 expression.

Topological lasers often suffer from low directionality, and/or complex design requirements hindering operation at small wavelengths. Here, by using a few monolayers of perovskite quantum dots, the authors demonstrate a lithography-free, vertical-emitting, single-mode laser emitting in the green.

This research work approaches the prediction of the ultimate transverse strength behavior of unidirectional composite laminas (Yt) using mixed artificial neural network (ANN) models. Thereby, two empirical relations, presented by Teanu and Barbero, were used for comparison purposes and to construct the mixed ANNs. These equations differ in the mechanical properties used to obtain Yt. For the ANN training, a dataset with 85 laminas was used, all obtained from the literature and manufactured with different types of fibers (aramid, glass and carbon) and polymer matrices. The best model obtained was the one based on the relation presented by Barbero, where the void fraction volume (Vv) and the transverse modulus of the fiber (Eft) are input parameters. Another aspect was the discovery of a region in the dataset that drastically changes its behavior, forming a valley in the prediction curves with values far lower than those forecast by empirical equations. This approach can be seen as a new methodology to estimate Yt using the same variables encountered in the classical equations but obtaining values closer to experimental ones.

Abstract We present a simple extension of the Standard Model with three right-handed neutrinos in a SUSY framework, with an additional $$\hbox {U}(1)_\text {F}$$ U ( 1 ) F abelian flavor symmetry with a non standard leptonic charge $$L_e-L_\mu -L_\tau $$ L e - L μ - L τ for lepton doublets and arbitrary right-handed charges. Our model predicts an inverted neutrino mass hierarchy and it is able to reproduce the experimental values of the mixing angles of the PMNS matrix and of the $$r=\Delta m_\text {sun}^2/\Delta m_\text {atm}^2$$ r = Δ m sun 2 / Δ m atm 2 ratio, with only a moderate fine tuning of the Lagrangian free parameters. The baryon asymmetry of the Universe is generated via thermal leptogenesis through CP-violating decays of the heavy right-handed neutrinos. We present a detailed numerical solution of the relevant Boltzmann equation, accounting for the impact of the distribution of the asymmetry in the various lepton flavors.