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We proposed and analyzed the fractional simultaneous technique for approximating all the roots of nonlinear equations in this research study. The newly developed fractional Caputo-type simultaneous scheme’s order of convergence is 3ς+5, according to convergence analysis. Engineering-related numerical test problems are taken into consideration to demonstrate the efficiency and stability of fractional numerical schemes when compared to previously published numerical iterative methods. The newly developed fractional simultaneous approach converges on random starting guess values at random times, demonstrating its global convergence behavior. Although the newly developed method shows global convergent behavior when all starting guess values are distinct, the method diverges otherwise. The total computational time, number of iterations, error graphs and maximum residual error all clearly illustrate the stability and consistency of the developed scheme. The rate of convergence increases as the fractional parameter’s value rises from 0.1 to 1.0.

This paper presents an efficient two-step hybrid block method (ETHBM) to obtain an approximate solution to the FitzHugh–Nagumo problem. The considered partial differential equation model problems are semi-discretized, reducing them to equivalent ordinary differential equations using the method of lines. In order to evaluate the effectiveness of the proposed ETHBM, three numerical examples are presented and compared with the results obtained through existing methods. The results demonstrate that the proposed ETHBM produces more efficient results than some other numerical approaches in the literature.

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

Abstract This study proposes a Geographic Information Systems-based methodology to measure accessibility to urban services from the elderly perspective to support urban planning processes. Specifically, it seeks to understand and clarify how the urban environment can influence the quality of life for older adults, mostly through pedestrian and public transport networks, locations of essential urban services, and the organisation of their resources. In light of a significant demographic change, policymakers will have to promote age-friendly urban planning approaches to guarantee equal access to services and activities. We propose a methodology to measure accessibility to healthcare provision services that considers land-use and mobility features and older adults' behavioural traits. The method belongs to the family of 2SFCA—2 steps floating catchment area—which evaluate accessibility as the combination of both supply and demand of urban services. Therefore, we have introduced innovative elements to shape actual mobility opportunities for the elderly and their travel choices. The methodology was applied to Milan's city to measure accessibility to the Health Protection Agency (ATS) services, which is responsible for healthcare assistance to the elderly dwelling in the city. The outputs show that a significant share of older people (almost 40%) suffer from poor accessibility to primary health services and that they mostly live in the city periphery. Moreover, the application to a case study has shown that the methodology could identify the critical aspects needed to aid urban planning to achieve a high quality of life for elderly people.

Abstract In this study, orodispersible films formed from hydroxypropyl methylcellulose (HPMC) E6 (2, 2.5, and 3%) and plasticizers ((glycerin (Gly), propylene glycol (PP), or polyethylene glycol (PEG)), containing doxazosin mesylate, were prepared by the solvent casting method and characterized. Design of experiments (DoE) was used as a statistical tool to facilitate the interpretation of the experimental data and allow the identification of optimal levels of factors for maximum formulation performance. Differential scanning calorimetry (DSC) curves and X-ray powder diffraction (XRPD) diffractograms showed doxazosin mesylate amorphization, probably due to complexation with the polymer (HPMC E6), and the glass transition temperature of the polymer was reduced by adding a plasticizer. Fourier transformed infrared (FTIR) spectroscopy results showed that the chemical structure of doxazosin mesylate was preserved when introduced into the polymer matrix, and the plasticizers, glycerin and PEG, affected the polymer matrix with high intensity. The addition of plasticizers increased the elongation at break and adhesiveness (Gly > PEG > PP), confirming the greater plasticizer effect of Gly observed in DSC and FTIR studies. Greater transparency was observed for the orodispersible films prepared using PP. The addition of citric acid as a pH modifier was fundamental for the release of doxazosin mesylate, and the desirability formulation had a release profile similar to that of the reference product.

A misalignment between the legislation and the effectiveness of Mediterranean fisheries management has emerged due to the status of the stocks (still largely in overfishing) and the discontent of stakeholders regarding management plans and tools that are not always recognized as appropriate to the characteristics of the concerned fisheries. Stakeholders’ involvement in management processes is one of the main pillars of the Common Fisheries Policy revision. The literature underlines, in an increasingly urgent manner, the importance of stakeholders fully understanding the contents of management plans and, vice versa, necessary for the successful implementation of policies. Focusing on the path towards sustainability endorsed by the BluFish project, the paper tries to provide an answer about the sustainability of some selected Southern Italian fisheries, by adopting the assessment approach of the Marine Stewardship Council. The assessment approach, based on a set of Performance Indicators and on a well-defined scoring scheme, focuses on three dimensions of sustainability. In addition to the classic assessment of the state of the stocks, there is an extensive screening of the impact of anthropic activity such as fishing on the entire ecosystem, including both the impact on accessory species and on vulnerable habitats and species. The evaluation adopted goes even further, with an approach that also includes the management and governance sphere, also trying to evaluate the level of involvement of the operators in the decision-making process. The paper illustrates that the selected fisheries are not fully sustainable but some of them have excellent potential for improvement even in the short term by identifying and implementing the appropriate action. The most relevant weaknesses identified refer to the low scores obtained for sustainability of stocks, mainly around the Harvest Control Rules (HCR) and the Harvest Strategy indicators, highlighting the importance of improving the management of the assessed stocks. The paper highlights how data and scientific knowledge availability is essential for a detailed mapping and evaluation of fishing activities but also that the path towards more sustainable and responsible fisheries does not work without a strong participation of all the key stakeholders.

BackgroundThe application of Pulsed electric fields as a mild and easily scalable electrotechnology represents an effective approach to selectively intensify the extractability of bioactive compounds from grape pomace, one of the most abundant residues generated during the winemaking process.ObjectiveThis study addressed the optimization of the pulsed electric fields (PEF)-assisted extraction to enhance the extraction yields of bioactive compounds from red grape pomace using response surface methodology (RSM).MethodsThe cell disintegration index (Zp) was identified as response variable to determine the optimal PEF processing conditions in terms of field strength (E = 0.5–5 kV/cm) and energy input (WT = 1–20 kJ/kg). For the solid-liquid extraction (SLE) process the effects of temperature (20–50°C), time (30–300min), and solvent concentration (0–50% ethanol in water) on total phenolic content (TPC), flavonoid content (FC), total anthocyanin content (TAC), tannin content (TC), and antioxidant activity (FRAP) of the extracts from untreated and PEF-treated plant tissues were assessed. The phenolic composition of the obtained extracts was determined via HPLC-PDA.ResultsResults demonstrated that the application of PEF at the optimal processing conditions (E = 4.6 kV/cm, WT = 20 kJ/kg) significantly enhanced the permeabilization degree of cell membrane of grape pomace tissues, thus intensifying the subsequent extractability of TPC (15%), FC (60%), TAC (23%), TC (42%), and FRAP values (31%) concerning the control extraction. HPLC-PDA analyses showed that, regardless of the application of PEF, the most abundant phenolic compounds were epicatechin, p-coumaric acid, and peonidin 3-O-glucoside, and no degradation of the specific compounds occurred upon PEF application.ConclusionThe optimization of the PEF-assisted extraction process allowed to significantly enhance the extraction yields of high-value-added compounds from red grape pomace, supporting further investigations of this process at a larger scale.

Abstract Gene vectors to treat cystic fibrosis lung disease should be targeted to the conducting airways, as peripheral lung transduction does not offer therapeutic benefit. Viral transduction efficiency is directly related to the vector residence time. However, delivered fluids such as gene vectors naturally spread to the alveoli during inspiration, and therapeutic particles of any form are rapidly cleared via mucociliary transit. Extending gene vector residence time within the conducting airways is important, but hard to achieve. Gene vector conjugated magnetic particles that can be guided to the conducting airway surfaces could improve regional targeting. Due to the challenges of in-vivo visualisation, the behaviour of such small magnetic particles on the airway surface in the presence of an applied magnetic field is poorly understood. The aim of this study was to use synchrotron imaging to visualise the in-vivo motion of a range of magnetic particles in the trachea of anaesthetised rats to examine the dynamics and patterns of individual and bulk particle behaviour in-vivo. We also then assessed whether lentiviral-magnetic particle delivery in the presence of a magnetic field increases transduction efficiency in the rat trachea. Synchrotron X-ray imaging revealed the behaviour of magnetic particles in stationary and moving magnetic fields, both in-vitro and in-vivo. Particles could not easily be dragged along the live airway surface with the magnet, but during delivery deposition was focussed within the field of view where the magnetic field was the strongest. Transduction efficiency was also improved six-fold when the lentiviral-magnetic particles were delivered in the presence of a magnetic field. Together these results show that lentiviral-magnetic particles and magnetic fields may be a valuable approach for improving gene vector targeting and increasing transduction levels in the conducting airways in-vivo.

Abstract Intrauterine growth restriction (IUGR) is associated with a higher incidence of perinatal complications as well as cardiovascular and renal diseases later on. A better insight into the disease mechanisms underlying these sequalae is important in order to identify which IUGR infants are at a higher risk and find strategies to improve their outcome. In this prospective case–control study we examined whether IUGR had any effect on renal and cerebral perfusion and oxygen saturation in term neonates. We integrated near-infrared spectroscopy (NIRS), echocardiographic, Doppler and renal function data of 105 IUGR infants and 105 age/gender-matched controls. Cerebral and renal regional oxygen saturation values were measured by NIRS during the first 12 h after birth. Echocardiography alongside Doppler assessment of renal and anterior cerebral arteries were performed at 6, 24, 48 and 72 h of age. Glomerular and tubular functions were also assessed. We found a left ventricular dysfunction together with a higher cerebral oxygen saturation and perfusion values in the IUGR group. IUGR term infants showed a higher renal oxygen saturation and a reduced oxygen extraction together with a subclinical renal damage, as indicated by higher values of urinary neutrophil gelatinase-associated lipocalin and microalbumin. These data suggest that some of the haemodynamic changes present in growth-restricted foetuses may persist postnatally. The increased cerebral oxygenation may suggest an impaired transition to normal autoregulation as a consequence of intra-uterine chronic hypoxia. The higher renal oxygenation may reflect a reduced renal oxygen consumption due to a subclinical kidney damage.

Here we revise all the paleontological sample of Notarchirico, including historical collections and new findings collected during 2016–2023 excavations. Notarchirico is one of the most significant sites for the study of human evolution and terrestrial ecosystem dynamics during the Early-Middle Pleistocene Transition, preserving nearly 100.000 years of environmental and climatic changes constrained between 695 ± 6 ka and 614 ± 12 ka. The deposit yielded the oldest human fossil of the Italian Peninsula, and one of the oldest European evidence of Homo heidelbergensis, as well as one of the earliest evidence of bifacial tools in western Europe, commonly associated with the Acheulean techno-complex. Our paleontological results revealed the presence of three different mammal complexes, documenting faunal dynamics in response of climatic driven-changes recognized during the early Middle Pleistocene. The lower complex (levels I2-G) indicates the dominance of wooded spaces, sparse steppes, and the existence of water bodies (lakes or ponds), indicating a deterioration of the fully interglacial conditions recorded during the end of MIS 17; the middle complex (levels G-C) with a low number of mammal remains can be attributed to the glacial conditions of MIS 16; the upper complex (levels B-above α) indicates an improvement in climate, transitioning towards the full interglacial conditions of the of MIS 15. The faunal sample of Notarchirico, based on its firm chronological setting, offers important data for the Biochronological Scheme of European Land Mammals, including one of the oldest records of Palaeoloxodon antiquus and Cervus elaphus in Europe, Panthera spelaea in southwestern Europe, Dama cf. roberti in Italian Peninsula, and one of the latest occurrences of Bison schoetensacki in Europe. [ABSTRACT FROM AUTHOR]

We conducted experimental investigations on the effect of stable thermal conditions on rough-wall boundary layers, with a specific focus on their response to abrupt increases in surface roughness. For stably stratified boundary layers, a new analytical relation between the skin-friction coefficient, $C_f$ , and the displacement thickness was proposed. Following the sharp roughness change, the overshoot in $C_f$ is slightly enhanced in stably stratified layers when compared with that of neutral boundary layers. Regarding the velocity defect law, we found that the displacement thickness multiplied by $\sqrt{2/C_f}$ , performs better than the boundary layer thickness alone when describing the similarity within internal boundary layers for both neutral and stable cases. A non-adjusted region located just beneath the upper edge of the internal boundary layer was observed, with large magnitudes of skewness and kurtosis of streamwise and wall-normal velocity fluctuations for both neutral and stable cases. At a fixed wall-normal location, the greater the thermal stratification, the greater the magnitudes of skewness and kurtosis. Quadrant analysis revealed that the non-adjusted region is characterised by an enhancement/reduction of ejection/sweep events, particularly for stably stratified boundary layers. Spatially, these ejections correspond well with peaks of kurtosis, exhibit stronger intensity and occur more frequently following the abrupt change in surface conditions. [ABSTRACT FROM AUTHOR]

Nonlinear problems, which often arise in various scientific and engineering disciplines, typically involve nonlinear equations or functions with multiple solutions. Analytical solutions to these problems are often impossible to obtain, necessitating the use of numerical techniques. This research proposes an efficient and stable Caputo-type inverse numerical fractional scheme for simultaneously approximating all roots of nonlinear equations, with a convergence order of 2 ψ + 2 . The scheme is applied to various nonlinear problems, utilizing dynamical analysis to determine efficient initial values for a single root-finding Caputo-type fractional scheme, which is further employed in inverse fractional parallel schemes to accelerate convergence rates. Several sets of random initial vectors demonstrate the global convergence behavior of the proposed method. The newly developed scheme outperforms existing methods in terms of accuracy, consistency, validation, computational CPU time, residual error, and stability. [ABSTRACT FROM AUTHOR]

Introduction: Organised by the 'Qualitative Long Covid Network', a workshop for qualitative Long COVID (LC) researchers, LC charity representatives and people with LC took place in June 2023, where research on the intersectional inequalities affecting LC prevalence, recognition and care was shared and discussed. Methods: Five key themes were drawn up from presentations, discussions and reflections during the workshop, which are presented in this study. Results: The following five themes are discussed: the unfairness of LC, difficulties in accessing care, mistrust of the healthcare system, a lack of understanding of LC and experiences of stigma and discrimination. Factors that widen or narrow inequalities related to LC were identified. Conclusion: A call to action is proposed to investigate and address inequalities through a robust LC research agenda that speaks with conviction to policy and decision‐makers. We argue that there needs to be a strong investment in research and evidence‐based policy and practice to mitigate the worst effects of the condition and address the inequalities in experience, treatment and support, which are experienced more often and more acutely by some of society's most vulnerable and disadvantaged individuals. Patient and Public (PPI) Contribution: Projects included in this article had PPI ongoing activity to inform their research. A member of the CONVALESCENCE PPI group presented at the QLC Network 'Long Covid and Health Inequalities' workshop, as did members of Long COVID Kids, Long COVID Support and Long COVID SOS charities. They were all invited to be co‐authors of this article. [ABSTRACT FROM AUTHOR]

This article discusses a new interdisciplinary, mixed-methods approach to using data from the first British Birth Cohort Study, the National Survey of Health and Development (NSHD, 1946). It emerges from a collaboration between two historians of postwar Britain and a mixed-methods life course studies researcher. Our approach brings together cohort-level quantitative data with less well-known qualitative data from a sample of 150 participants' original NSHD interview questionnaires to generate new perspectives on how macro processes of social change were experienced at an individual level and varied across the life course. The NSHD school-age and early adulthood sweeps included a series of open-ended questions relating to education, work, and social identities, which offer a sense of how participants responded to and understood the social transformations of the postwar decades within their everyday lives. This article explains our methodological rationale, before focussing on the wider analytical possibilities of our approach in relation to social mobility. [ABSTRACT FROM AUTHOR]

Fisheries discards in the Moroccan Mediterranean Sea present a significant challenge at the intersection of marine resource management and societal concerns. Bottom trawl fisheries, which involve dragging nets along the seabed, capture a wide array of marine species, many of which are subsequently discarded. This study offers the first comprehensive analysis of discard composition from Moroccan trawl fleets, drawing on data collected from 2019 to 2022 through an onboard sampling program. Among the 103 species from 59 families discarded, 16 were elasmobranchs and 88 were bony fishes. Discarded biomass showed significant variation based on season, fishing areas, and their interaction, with discard ratios ranging from 1.06% to 43.7%. Teleostei made up the predominant fraction of discarded biomass, followed by Elasmobranchii, Thaliacea, and Holocephali. The study found significant variations in mean biomass values across different ports and seasons, highlighting dynamic patterns in biomass distribution among marine classes. However, the number of species recorded in discards remained stable across ports and seasons, indicating consistent environmental conditions. The findings underscore the need for targeted fishery management measures to minimize the ecological impacts of discards, tailored to specific times and locations. [ABSTRACT FROM AUTHOR]

Simple Summary: Adjuvant therapy with targeted therapy or immunotherapy has become the standard of care for fully resected stage III–IV melanoma. In this scenario, real-world data are needed to relate the actual effectiveness and safety of these regimens with the evidence provided in the clinical trials. This study provides clinicians and researchers with the results of an Italian single-center real-world experience on the use of adjuvant therapy in resected stage III–IV melanoma patients. Our findings confirm the real-world effectiveness and safety of adjuvant regimens, yet underscores the need for further research to explore biomarker-based predictors for relapse and to assess the translation of improved relapse-free survival into long-term overall survival benefit. This study was carried out at the Dermatologic Clinic of the University of Turin, Italy, to assess the effectiveness and safety of adjuvant therapy in patients who received either targeted therapy (TT: dabrafenib + trametinib) or immunotherapy (IT: nivolumab or pembrolizumab) for up to 12 months. A total of 163 patients participated, including 147 with stage III and 19 with stage IV with no evidence of disease. The primary outcomes were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). At 48 months, both TT and IT approaches yielded comparable outcomes in terms of RFS (55.6–55.4%, p = 0.532), DMFS (58.2–59.8%, p = 0.761), and OS (62.4–69.5%, p = 0.889). Whilst temporary therapy suspension was more common among TT-treated patients compared to IT-treated individuals, therapy discontinuation due to adverse events occurred at comparable rates in both groups. Predictors of relapse included mitoses, lymphovascular invasion, ulceration, and positive sentinel lymph nodes. Overall, the proportion of BRAF-mutated patients receiving IT stood at 7.4%, lower than what was observed in clinical trials. [ABSTRACT FROM AUTHOR]

Finding all the roots of a nonlinear equation is an important and difficult task that arises naturally in numerous scientific and engineering applications. Sequential iterative algorithms frequently use a deflating strategy to compute all the roots of the nonlinear equation, as rounding errors have the potential to produce inaccurate results. On the other hand, simultaneous iterative parallel techniques require an accurate initial estimation of the roots to converge effectively. In this paper, we propose a new class of global neural network-based root-finding algorithms for locating real and complex polynomial roots, which exploits the ability of machine learning techniques to learn from data and make accurate predictions. The approximations computed by the neural network are used to initialize two efficient fractional Caputo-inverse simultaneous algorithms of convergence orders ς+2 and 2ς+4, respectively. The results of our numerical experiments on selected engineering applications show that the new inverse parallel fractional schemes have the potential to outperform other state-of-the-art nonlinear root-finding methods in terms of both accuracy and elapsed solution time.

The principles of industrial ecology have emerged as pivotal drivers of eco-innovation, aiming to realize a “zero-waste” society where waste materials are repurposed as valuable resources. In this context, High-Pressure Homogenization (HPH) presents a promising, easily scalable micronization technology, capable of enhancing the extractability and bioaccessibility of bioactive compounds found in tomato processing by-products, which are notably abundant waste streams in the Mediterranean region. This study focuses on optimizing HPH treatment parameters to intensify the recovery of bioactive compounds from tomato pomace. Additionally, it investigates the multifaceted impacts of HPH on various aspects, including color, particle size distribution, microscopic characteristics, surface properties, bioactivity, and lycopene bioaccessibility through in vitro digestion simulations. The results demonstrate that the application of HPH under optimized conditions (80 MPa, 25 °C, 10 passes) induces a remarkable 8-fold reduction in mean particle size, reduced surface tension, improved physical stability, uniform color, increased total phenolic content (+31%), antioxidant activity (+30%), dietary fiber content (+9%), and lycopene bioaccessibility during the intestinal digestion phase compared to untreated samples. These encouraging outcomes support the proposition of integrating HPH technology into an environmentally friendly industrial process for the full valorization of tomato processing residues. By utilizing water as the sole solvent, this approach aims to yield a functional ingredient characterized by greater nutritional and health-promoting values.

This paper presents a new hybrid block method formulated in variable stepsize mode to solve some first-order initial value problems of ODEs and time-dependent partial differential equations in applied sciences and engineering. The proposed method is implemented considering an adaptive stepsize strategy to maintain the estimated error in each step within a specified tolerance. In order to evaluate the performance and usefulness of the proposed technique in real-world applications, several differential problems from applied sciences and engineering, such as the SIR model, Jacobi elliptic function problem, and chemical reactions problems, are solved numerically. The results of numerical simulations in this work demonstrate that the proposed method is more efficient than other existing numerical methods used for comparisons.

Epigenetic modifications, such as changes in DNA methylation, have been linked to several diseases in recent years. The purpose of our study was to search for biomarkers that (using non-invasive techniques) could assist the clinician in the prognosis of infant/adolescent psychopathology. We previously showed that changes in methylation of the 5’-UTR in the DAT1/SLC6A3 gene can be used as a biomarker for the prognosis of initial severe ADHD: treatment-resistant severe ADHD children were characterized by methylated CpG 1 in particular, while methylated CpGs 2 and 6 were then found in children who improved after the therapy. Further, we confirmed these outcomes and provided the hypothesis that symptomatology might be influenced by the children’s genotype and family environment. In particular, levels of CpG 3 methylation in the heterozygous ADHD children were associated with high paternal own risk or stress. Eventually, we found that the same biomarkers are more broadly useful in the field of internalizing or externalizing symptoms (when a certain vulnerability is already present in the child). In particular, it was seen how inheriting specific 9-repeat or 10-repeat VNTR alleles from the mother or from the father could modify the pattern of methylation at the 5′-UTR of the DAT1 gene. A specific pattern of methylations (with CpG 2 following either CpGs 1 + 3 or CpG 6 at the DAT1 5′-UTR) has been associated, therefore, with the likelihood of an internalizing or externalizing developmental trajectory entailing ADHD-like psycho-pathological characteristics. Since each individual responds differently to a specific treatment, we suggest that these methylation patterns may be used as biomarkers to monitor the outcome and/or predict the success of a given therapy (personalized medicine).

This paper introduces an efficient approach for solving Lane–Emden–Fowler problems. Our method utilizes two Nyström schemes to perform the integration. To overcome the singularity at the left end of the interval, we combine an optimized scheme of Nyström type with a set of Nyström formulas that are used at the fist subinterval. The optimized technique is obtained after imposing the vanishing of some of the local truncation errors, which results in a set of symmetric hybrid points. By solving an algebraic system of equations, our proposed approach generates simultaneous approximations at all grid points, resulting in a highly effective technique that outperforms several existing numerical methods in the literature. To assess the efficiency and accuracy of our approach, we perform some numerical tests on diverse real-world problems, including singular boundary value problems (SBVPs) from chemical kinetics.