Search Results (1,560)

Characterized by social communication deficits and the presence of restricted and repetitive behaviors, autism spectrum disorder (ASD) is a significant neurodevelopmental condition. Genetic studies have revealed a strong association between ASD and numerous mutations that alter the function of key proteins, either through activation or inactivation. These alterations are widely hypothesized to affect neuronal morphogenesis; however, a comprehensive understanding of the specific molecular cascades driving these cellular and symptomatic changes remains lacking. In this study, we report for the first time that signaling through the atypical Rho family guanine-nucleotide exchange factor (GEF) Dock7 and ErbB2, an activator acting upstream of Dock7, drives the excessive elongation of neuronal processes observed in association with the ASD- and intellectual disability (ID)-linked semaphorin-5A (Sema5A) Arg676Cys variant (p.Arg676Cys). Knockdown of Dock7 using short hairpin RNA or inhibition of ErbB2 kinase signaling with a specific chemical inhibitor reduced this excessive process elongation in primary cortical neurons. Similar results were obtained in the N1E-115 cell line, a neuronal cell model that undergoes neuronal morphological differentiation. Moreover, inhibition of ErbB2-Dock7 signaling specifically decreased the overactivation of the downstream molecules Rac1 and Cdc42. These findings indicate that the ErbB2–Dock7 signaling axis plays a role in mediating the aberrant neuronal morphology associated with the ASD- and ID-linked Sema5A p.Arg676Cys. Targeting this pathway may therefore offer a potential approach to addressing the molecular and cellular developmental challenges observed in ASD. Full article

Background: Cyclosporine (CSA) is a fast-acting systemic immunosuppressant frequently used in moderate-to-severe atopic dermatitis (AD), but its long-term use is limited by toxicity. AD affects as many as 20% of children and nearly 10% of adults worldwide and its chronic, recurrent course often requires several systemic treatment lines, making optimization of sequential therapy a high clinical priority. Tralokinumab, an IL-13–targeting monoclonal antibody, represents a safer alternative with a slower onset of action. This study aimed to compare the effectiveness and safety of tralokinumab initiated as monotherapy versus in overlap with CSA during the transition from conventional to biologic therapy. Methods: We conducted a prospective observational study involving 27 adults with moderate-to-severe AD treated with tralokinumab for at least 16 weeks. Patients were categorized into two groups: tralokinumab monotherapy plus topical agents (TM; n = 23) and tralokinumab initiated with a cyclosporine overlap for up to 12 weeks (TO; n = 4). Disease severity was evaluated using the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), and numerical rating scale (NRS) for pruritus at baseline and weeks 16, 24, and 52. Results: Both TM and TO groups demonstrated significant clinical improvement across all outcomes, with no statistically significant differences between groups (p > 0.05 for EASI, IGA, and NRS). At week 52, TM patients showed mean reductions of 18.66 (EASI), 2.21 (IGA), and 4.49 (NRS), while TO patients showed reductions of 15, 2, and 3.50, respectively. Tralokinumab was discontinued in eight patients (29.6%), most commonly due to lack of efficacy. Discontinuation rates did not differ significantly between groups. However, the very small size of the TO group (n = 4) substantially limits statistical power and any contrasts should be interpreted as exploratory. Conclusions: In this prospective real-world cohort, we observed improvement after initiating tralokinumab, with and without a short cyclosporine bridge. In light of CSA’s risks, TM may be considered a reasonable first-line systemic option. Prospective randomized studies are needed to determine whether overlap confers additional benefit. Full article

Tyrosine (Tyr) degradation is a crucial pathway in animals. However, its role in plants remains to be examined. Fumarylacetoacetate hydrolase (FAH) is the final enzyme involved in Tyr degradation. Studies of a mutant of the SHORT-DAY SENSITIVE CELL DEATH 1 (SSCD1) gene encoding FAH in Arabidopsis have shown that blockage of this pathway results in the accumulation of Tyr metabolites, thereby inducing cell death under short-day conditions. Seed dormancy is a critical trait which is regulated by endogenous and environmental cues, among which abscisic acid (ABA) and gibberellin (GA) are the primary effectors. ABA induces seed dormancy, whereas GA releases seed dormancy. In this study, sscd1 seeds displayed deep dormancy and hypersensitivity to the GA biosynthesis inhibitor paclobutrazol, but not to ABA during germination. However, exogenous GA₃ could not completely recover dormancy or germination of sscd1 seeds. Moreover, GA₃ level was reduced, which was consistent with the decreased expression of GA3-oxidase 1 in imbibed sscd1 seeds. Furthermore, SSCD1 acted upstream of RGA-LIKE 2. Eliminating the accumulation of Tyr metabolites by inhibiting homogentisate dioxygenase, an enzyme upstream of FAH, completely rescued the phenotype of sscd1 seeds. Additionally, germination of sscd1 seeds was hypersensitive to FAH deficiency-induced accumulation of succinylacetone, which is a Tyr metabolite. These findings suggest that FAH deficiency in sscd1 causes accumulation of Tyr metabolites, thereby disrupting GA biosynthesis and signaling. This resulted in deep dormancy and hypersensitivity to paclobutrazol during germination and highlights the important role of the Tyr degradation pathway in GA-mediated seed dormancy and germination. Full article

Grain legume crops are rich in nutritional value and play a crucial role in global food sustainability. Like many other crops, they are affected by various abiotic stresses that reduce yield and seed quality, thereby threatening food security. Several strategies have been proposed to mitigate these effects and enhance yield. Among them, the use of biostimulants offers a sustainable and efficient approach to improving stress tolerance in the short term. However, the molecular mechanisms underlying the effects of individual or combined molecules remain poorly understood and could significantly influence the development of edited crops with enhanced stress tolerance in the long term. Melatonin (MT) has emerged as a versatile biostimulant, providing multiple benefits across different crop species. Given its key role in plant physiological processes, along with endogenous production, receptor identification, and signaling functions, it has been suggested to act as a hormone-like molecule. Nonetheless, the molecular response triggered by its application remains under investigation, particularly in grain legume species. This review explores the current state of MT applications for alleviating abiotic stress in grain legume crops, with emphasis on drought, salinity, metals/metalloids, and heat stress. We integrate biochemical, molecular, and physiological evidence to highlight the main scientific gaps regarding MT function in grain legumes. Finally, we discuss the biotechnological prospects of combining MT with modern breeding tools, as well as strategies for its delivery and sustainable production. Full article

This study investigates the potential role of microplastics in the development of diabetes mellitus and assesses their presence in individuals undergoing insulin therapy. A total of 100 participants were included: 50 insulin-dependent diabetic patients and 50 healthy controls. The diabetic group was divided into two subgroups based on their insulin regimen: those receiving one daily injection of basal insulin and those receiving four injections of basal and short-acting insulin. Blood samples were analysed for microplastic content using chromatographic methods (LC/GC-MSMS and LCTOF MS). The findings revealed that diabetic patients had significantly higher serum microplastic levels (3.14 ± 1.30 µg/mL) than healthy individuals (1.50 ± 0.89 µg/mL, p < 0.05). Within the diabetic group, patients receiving four injections had a longer disease duration (15.14 ± 3.64 years) than those receiving one injection (10.56 ± 5.21 years), with a statistically significant difference (p = 0.001). However, microplastic levels did not differ significantly based on injection frequency. A strong positive correlation was observed between microplastic levels and both HbA1c (%) and fasting glucose levels (p = 0.001). These results imply that microplastics may act as endocrine disruptors that contribute to the development of diabetes, rather than being introduced through insulin treatment itself. Full article

High-performance spun bionanocomposite fibers, composed of high-molecular-weight chitosan (HMW), low-molecular-weight chitosan “oligomers” (LMW), and cellulose nanofibers (CNFs), were successfully fabricated via gel spinning of viscous aqueous chitosan (CHI) based formulations into a NaOH coagulation bath. The X-ray diffraction (XRD) analysis revealed that the incorporation of cellulose nanofibers contributed to enhance crystallinity of chitosan in spun fibers. The spinning process, which comprised sequential acidic solubilization, basic neutralization, stretching, and drying steps, produced chitosan/CNF composite fibers with high crystallinity, further enhanced by the incorporation of low molecular weight chitosan. The cellulose nanofibers seem to promote CHI crystallization, by acting as nucleation sites for the nucleation and growth of chitosan crystals, with those latter of LMW further enhancing crystallization and orientation due to higher mobility of shorter polymer chains. Two-dimensional XRD patterns demonstrated the preferential alignment of both CNFs and chitosan crystals along the fiber axis. Increasing the proportion of short-chain chitosan led to a reduction of the viscosity of collodion, facilitating the spinning of solutions with higher polymer concentrations. The X-ray diffraction (XRD) analysis revealed that the addition of low-molecular-weight chitosan (LMW), with an intermediate molecular weight Mw of ~4.4 × 10⁴ g/mol, produced the most significant improvements in the crystallinity index (CrI) and orientation. This structural enhancement corresponded to superior mechanical properties like Young’s modulus, yield stress σ_y, and stress-at-break σ_b of the processed composite fibers. By incorporating that intermediate molecular weight chitosan, a Young’s modulus as high as 20 GPa was achieved for the spun composite fibers, which was twice higher than the modulus of around 10 GPa obtained by adding the lowest molecular weight chitosan of Mw ~ 2.9 × 10⁴ g/mol in the composite, and largely above the modulus of around 5 GPa obtained for fiber just spun with chitosan without incorporation of cellulose nanofibers. Full article

Gamified recommender systems, which mix game design with recommendation frameworks, are a new way to increase user involvement and satisfaction. Even though they have a lot of potential, there has not been any systematic research on how their design affects how people use them. This study introduces a fuzzy DEMATEL-based framework for the assessment and enhancement of gamified recommender systems. Four theoretically grounded gamified recommender system prototypes were developed as a novel contribution, as no readily available systems exist for these designs. The assessment utilized nine user-centric criteria—Effectiveness, Transparency, Persuasiveness, Satisfaction, Trust, Usefulness, Ease of Use, Efficiency, and Education—systematically derived from a PRISMA-guided literature review. This study integrates gamification theory, systematic review, and fuzzy decision-making to formulate a comprehensive framework for identifying the key factors influencing adoption. The fuzzy DEMATEL was applied to evaluate feedback from 25 end-users, and it was found that usefulness and ease of use were the most essential factors for satisfaction and system effectiveness. Analysis of design showed that competition in Points, Badges, and Leaderboards (PBL) design boosts short-term motivation, Acknowledgments, Objectives, and Progression (AOP) boosts progress and openness, Acknowledgments, Competition, and Time Pressure (ACT) boosts efficiency in competitive situations but might lower satisfaction, and Acknowledgments, Objectives, and Social Pressure (AOS) depends on social influence and accountability. Full article

Agriculture significantly contributes to greenhouse gas (GHG) emissions, yet fluxes from irrigated semi-arid systems remain poorly quantified. This study investigates CO₂, CH₄, N₂O, and NH₃ fluxes in a short-term lettuce experiment under semi-arid conditions. The objective was to quantify flux variability and identify key environmental and management drivers. High-frequency soil gas flux measurements were conducted under three treatments: irrigated soil (I), irrigated soil with plants (IP), and irrigated soil with plants plus NH₄NO₃ fertilizer (IPF). Environmental factors, including solar radiation, soil temperature, water-filled pore space, and relative projected leaf area, were monitored. A Random Forest model identified main flux determinants. Fluxes varied with plant function, growth, and fertilization. IP exhibited net CO₂ uptake through photosynthesis, whereas I and IPF showed net CO₂ emissions from soil respiration and fertilizer-induced disruption of plant function, respectively. CH₄ uptake occurred across treatments but decreased with plant presence. Fertilization in IPF triggered episodic N₂O (EF = 0.1%) and NH₃ emissions (EF = 0.97%) linked to nitrogen input. Vegetated semi-arid soils can act as CO₂ sinks when nitrogen is optimally managed. Excess or poorly timed nitrogen delays CO₂ uptake and increases reactive nitrogen losses. Methanotrophic activity drives CH₄ dynamics and is influenced by plants and fertilization. Maintaining crop vigor and applying precision nitrogen management are essential to optimize productivity while mitigating GHG and NH₃ emissions in semi-arid lettuce cultivation. Full article

In this study, we apply machine learning to model the spatiotemporal dynamics of gene expression during early Drosophila embryogenesis. By optimizing model architecture, feature selection, and spatial grid resolution, we developed a predictive pipeline capable of accurately classifying active nuclei and forecasting their future distribution in time. We evaluated the model on two reporter constructs for the short gastrulation (sog) gene, sogD and sogD_∆Su(H), allowing us to assess its performance across distinct genetic contexts. The model achieved high accuracy on the wild-type sogD dataset, particularly along the dorsal–ventral (DV) axis during nuclear cycle 14 (NC14), and accurately predicted expression in the central regions of both wild-type and Suppressor of Hairless (Su(H)) mutant enhancers, sogD_∆Su(H). Bootstrap analysis confirmed that the model performed better in the central region than at the edges, where prediction accuracy dropped. Our previous work showed that Su(H) can act both as a repressor at the borders and as a stabilizer of transcriptional bursts in the center of the sog expression domain. This dual function is not unique to Su(H); other broadly expressed transcription factors also exhibit context-dependent regulatory roles, functioning as activators in some regions and repressors in others. These results highlight the importance of spatial context in transcriptional regulation and demonstrate the ability of machine learning to capture such nuanced behavior. Looking ahead, incorporating mechanistic features such as transcriptional bursting parameters into predictive models could enable simulations that forecast not just where genes are expressed but also how their dynamics unfold over time. This form of in silico enhancer mutagenesis would make it possible to predict the effects of specific binding site changes on both spatial expression patterns and underlying transcriptional activity, offering a powerful framework for studying cis-regulatory logic and modeling early developmental processes across diverse genetic backgrounds. Full article

Designing UHPC beams for shear is challenging because many factors—geometry, concrete strength, fibers, and stirrups—act together. In this study, we compile a large, curated database of laboratory tests and develop machine learning models to predict shear capacity. The best models provide accurate point predictions and, importantly, a 95% prediction band that tells how much uncertainty to expect; in tests, about 95% of results fall inside this band. For day-to-day design, we also offer a short, design-oriented formula with explicit coefficients and variables that can be used in a spreadsheet. Together, these tools let engineers screen options quickly, check designs with an uncertainty margin, and choose a conservative value when needed. The approach is transparent, easy to implement, and aligned with common code variables, so it can support preliminary sizing, verification, and assessment of UHPC members. Full article

Background: Saharan dust intrusions (SDIs) are associated with poor air quality and adverse respiratory outcomes. However, their impact on real-world inhaler utilization remains insufficiently characterized. We aimed to examine the association between SDI and the dispensing of short-acting beta-agonists (SABA) and inhaled corticosteroid–long-acting beta-agonist (ICS–LABA) combinations in the Canary Islands, Spain. Methods: Pharmaceutical sales data for SABA and ICS–LABA were collected from 60 pharmacies in Santa Cruz de Tenerife (TF) and Las Palmas de Gran Canaria (GC) between June 2017 and May 2022. SDI days were identified based on daily PM₁₀ concentrations > 40 µg/m³ from the regional air quality monitoring network. Linear regression models evaluated associations between drug dispensations and SDI presence, frequency, and intensity, adjusting for seasonality (winter vs. summer). Results: Over 60 months, SABA sales were 14.8% lower in TF compared with GC, while ICS–LABA sales were 10.9% higher. SDI presence was associated with significantly higher ICS–LABA dispensations in both provinces (+5.7% in TF, +10.2% in GC), whereas no association was found for SABA. ICS–LABA sales correlated weakly but significantly with both SDI frequency and PM₁₀ levels. Seasonal analysis revealed stronger effects in winter, with ICS–LABA dispensations increasing by 14.3% (TF) and 9.6% (GC) during SDI months. For SABA, seasonal differences were independent of SDI exposure. Conclusions: SDIs in the Canary Islands are independently associated with increased dispensing of ICS–LABA maintenance therapy, particularly during winter months. Dispensing data offer a valuable population-level indicator of respiratory impact from natural airborne pollution and support the integration of environmental alerts into preventive respiratory care strategies. Full article

This study unpacks how supply chain management, knowledge management, and green innovations act as critical levers in driving energy transition while safeguarding environmental sustainability in an era of escalating climate challenges. Focusing on the G7 nations and using data from 2000 to 2022, this study addresses two central research questions: (i) What are the key determinants of energy transition (ET)? And (ii) what are the key determinants of environmental degradation (ED)? To answer these questions, the study applied Lewbel IV-2SLS and FGLS estimators, revealing that in G7 economies, supply chain performance reduces environmental degradation but slows energy transition. Digital transformation also hinders transition in the short run, though at higher maturity it helps curb degradation. Trade openness supports transition but increases degradation, while urbanization promotes transition. Knowledge management and green innovation follow an inverted-U pattern, and control of corruption shows mixed effects. Energy transition itself strongly reduces environmental degradation, whereas economic growth generally increases it. Based on these results, the study formulates a set of policy recommendations to align economic growth with long-term sustainability goals. Full article

Background: Adolescence is a vulnerable period for the onset of severe psychiatric conditions, such as psychotic spectrum disorders. Non-adherence to antipsychotics is a common problem in young people with these conditions and paves the way for relapse, rehospitalization, and functional impairment. Co-occurring substance use disorders (SUDs) further undermine adherence and worsen outcomes. Long-acting injectable antipsychotics (LAIs) improve adherence and outcomes in adults, but none are licensed for use in individuals under 18. This review seeks to distill the available evidence on LAIs’ use in adolescents, from efficacy to safety, and to outline clinical practice recommendations. Methods: A narrative review was conducted. The evidence was organized by drug class: risperidone, paliperidone, aripiprazole, and other antipsychotics (olanzapine, haloperidol, first-generation depots). Results: Evidence in adolescents remains sparse and heterogeneous. Risperidone LAI has shown improvements in symptom severity, functioning, and behavioral control in bipolar disorder and schizophrenia, though commonly associated with side effects. Paliperidone palmitate demonstrated benefit in first-episode schizophrenia and autism spectrum disorder with intellectual disability, reducing hospital use but carrying risks of EPS and hyperprolactinemia. Aripiprazole LAI showed functional gains, short-term tolerability, and encouraging acceptance in case reports. Other LAIs were used in highly resistant cases with some clinical benefit, though extrapyramidal adverse events were common. Conclusions: The current literature provides limited data, and no clinical guidelines exist for the use of LAI in adolescents. Nonetheless, off-label use is reported in selected cases in clinical practice. Best practice is to start with oral stabilization, then use the lowest effective LAI with psychosocial support and close monitoring. When SUD co-occurs, LAIs may also help mitigate risks related to misuse/diversion of oral medication, provided that care includes systematic SUD screening and early intervention. Prospective controlled studies are urgently needed to establish long-term efficacy and safety in this vulnerable population. Full article

Agricultural land management is a major determinant of terrestrial carbon (C) fluxes and has substantial implications for greenhouse gas (GHG) mitigation strategies. This study evaluated the net ecosystem carbon balance (NECB) of an agricultural field in an organic integrated crop–livestock system (ICLS) with a ley-arable rotation in northern Germany over two years (2021–2023). Carbon dioxide (CO₂) fluxes were measured using the eddy covariance (EC) method to derive net ecosystem exchange (NEE), gross primary production (GPP), and ecosystem respiration (RECO). This approach facilitated an assessment of the temporal dynamics of CO₂ exchange, alongside detailed monitoring of field-based C imports, exports, and management activities, of a crop sequence including grass-clover (GC) ley, spring wheat (SW), and a cover crop (CC). The GC ley acted as a consistent C sink (NECB: −1386 kg C ha⁻¹), driven by prolonged photosynthetic activity and moderate biomass removal. In contrast, the SW, despite high GPP, became a net source of C (NECB: 120 kg C ha⁻¹) due to substantial export via harvest. The CC contributed to C uptake during the winter period. However, cumulatively, it acted as a net CO₂ source, likely due to drought conditions following soil cultivation and CC sowing. Soil cultivation events contributed to short-term CO₂ pulses, with their magnitude modulated by soil water content (SWC) and soil temperature (TS). Overall, the site functioned as a net C sink, with an average NECB of −702 kg C ha⁻¹ yr⁻¹. This underscores the climate mitigation potential of management practices such as GC ley systems under moderate grazing, spring soil cultivation, and the application of organic fertilizers. To optimize CC benefits, their use should be combined with reduced soil disturbance during sowing or establishment as an understory. Additionally, C exports via harvests could be offset by retaining greater amounts of harvest residues onsite. Full article

Late pregnancy represents a critical period for the onset of eating disorder symptoms, particularly in the presence of psychological and relational vulnerabilities. Among these, the quality of the romantic relationship has received limited empirical attention, despite its potential role in shaping women’s psychological adjustment, influencing both mood and body image. The present study examined the association between romantic relationship quality and eating disorder symptoms during the third trimester of pregnancy, considering the mediating roles of depressive symptoms and body dissatisfaction. A sample of 231 Italian pregnant women (Mage = 32.3 years) completed four self-report measures: the Dyadic Adjustment Scale-7, the Edinburgh Postnatal Depression Scale, the Body Image in Pregnancy Scale, and the Eating Disorder Examination Questionnaire-Short. A serial mediation model was tested, including pre-pregnancy body mass index as a covariate. Results indicated that lower romantic relationship quality was associated with greater eating disorder symptoms through higher depressive symptoms and body dissatisfaction, which acted both independently and sequentially. These findings highlight the complex interplay between relational and psychological factors in the development of disordered eating during pregnancy, emphasizing the need for early screening and integrated interventions addressing both interpersonal and intrapersonal domains. Full article