Search Results (392)

Background: Osteodysplastic syndromes comprise a very diverse group of clinically and genetically heterogeneous disorders characterized by defects in bone and connective tissue development, as well as in bone density. Here, we report the case of a 48-year-old female with a complex medical history characterized by bone dysplasia, hyperostosis, and partial tooth agenesis. Methods: Genetic testing was performed using WES analysis and Sanger sequencing. Molecular modeling analysis and dynamics simulation explored the impact of detected pathogenic variants. Results: The genetic analysis detected multiple pathogenic variants in genes CREB3L1, SLCO2A1, SFRP4, LRP5, and LRP6, each of which has been associated with rare osteodysplastic syndromes. The patient was homozygous for the same rare alleles associated with three of the identified autosomal recessive disorders osteogenesis imperfecta type XVI, primary hypertrophic osteoarthropathy, and metaphyseal dysplasia Pyle type. She also had a variant linked to autosomal dominant endosteal hyperostosis and a variant previously associated with increased risk of osteoporosis and bone fractures. Two of the detected variants are predicted to cause abnormal splicing, while molecular modeling and dynamics simulations analysis suggest that the other three variants probably confer altered local secondary structure and flexibility that may have functionally devastating consequences. Conclusions: Our case highlights the rare coexistence of multiple osteodysplastic syndromes in a single patient that may complicate differential diagnosis. Furthermore, this case emphasizes the necessity for early genetic investigation of such complex cases with overlying phenotypic traits, followed by genetic counseling, facilitating orchestration of clinical interventions and allowing prevention and/or prompt management of manifestations. Full article

In power grids that integrate renewable energy sources, the virtual synchronous machine (VSM) or synchronverter offers a viable solution to the challenge posed by reduced inertia. This technology employs inverters to transfer power to the electrical network that relies on a control algorithm emulating the dynamic behavior of synchronous machines. Over the past decade, it has been applied in various contexts, leveraging its control structure based on the fundamental equations of synchronous machines. Although several review articles have been published on control strategies for grid-forming inverters, they often lack a specific focus on recent developments related to the synchronverter. Therefore, this paper aims to fill that gap by presenting a detailed review on high-quality research databases to retrieve recent documents published in recent years. These documents were classified according to journals, conferences, and books. A keyword bibliographic analysis was performed to identify the attractive topics related to the synchronverter control strategy. The paper reviews recent improvements in and applications of the synchronverter, identifying emerging trends and new potential use cases to provide a workflow guide for readers and researchers, as the documents are presented in comprehensive tables, streamlining the process of locating specific references. In addition, some advantages and disadvantages of synchronverters are reported. Full article

This study aimed to characterize the time-dependent effects of methane (CH₄) inhalation, initiated at defined intervals following sepsis onset, on organ function, systemic oxygen utilization, and mitochondrial respiration in a rodent model. Adult rats were subjected to abdominal sepsis or sham operation. Septic animals were assigned to groups receiving 2.2% CH₄ in normoxic air at specific post-insult phases (early: 3–6 h; intermediate: 16–19 h; late: 19–22 h), while a control group remained untreated. At 24 h, organ function was evaluated using a Rat-Specific Organ Failure Assessment (ROFA) score, along with measurements of plasma myeloperoxidase (MPO) activity, Complex I–II-linked oxidative phosphorylation in renal and cerebellar tissues, systemic oxygen extraction, and global tissue perfusion (pCO₂-gap). Sepsis induced significant organ dysfunction, impaired hemodynamics, reduced oxygen utilization, and decreased mitochondrial respiration. CH₄ inhalation improved survival when administered early, restored cerebellar mitochondrial respiration during the intermediate phase, and in the late phase reduced ROFA scores and MPO levels, while attenuating mitochondrial dysfunction in renal and cerebellar tissues. All CH₄-treated groups demonstrated improved renal function and enhanced tissue oxygenation. Targeted CH₄ inhalation during sepsis confers protective effects by preserving mitochondrial function, reducing inflammation, and improving oxygen dynamics, suggesting promising therapeutic potential. Full article

During the 28th Conference of the Parties (COP28), organized under the United Nations Framework Convention on Climate Change and hosted by the United Arab Emirates, member nations reached a global agreement to begin transitioning away from fossil fuel dependence, forcing the Gulf Cooperation Council (GCC) countries to balance their commitment to a green transition with the need to secure short-term energy supplies. This study highlights the challenges facing the GCC’s efforts to expand renewable energy, even as the region continues to have a significant influence over international energy markets. This study utilizes dynamic panel estimation over the period 2003 to 2022, focusing on the core pillars of the Energy Transition Index to analyze the evolving renewable energy use in the GCC. The results present a clear and optimistic perspective on the region’s renewable energy prospects. Despite the continued dependence on fossil fuels, the findings indicate that, if effectively managed, oil and gas revenues can serve as strategic instruments to support the transition toward cleaner energy sources. These insights offer policymakers robust guidance for long-term energy planning and highlight the critical importance of international collaboration in advancing the GCC’s sustainable energy transition. Full article

Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder affecting a large number of individuals in Europe. The disease arises from mutations in the CFTR gene encoding the cystic fibrosis transmembrane conductance regulator, a chloride ion channel crucial for maintaining epithelial ion and fluid homeostasis. Dysfunctional CFTR disrupts mucociliary clearance, particularly in the respiratory tract, resulting in persistent bacterial colonization, chronic inflammation, and progressive pulmonary damage—ultimately leading to respiratory failure, the principal cause of mortality in CF patients. Early diagnosis and advances in therapy have substantially improved both survival and quality of life. A hallmark of CF pathology is the establishment of polymicrobial infections within the thickened airway mucus. Pseudomonas aeruginosa is the dominant pathogen in chronic CF lung infections and demonstrates a remarkable capacity for adaptation via biofilm formation, metabolic reprogramming, and immune evasion. Biofilms confer increased tolerance to antimicrobial agents and facilitate long-term persistence in hypoxic, nutrient-limited microenvironments. P. aeruginosa exhibits a wide range of virulence factors, including exotoxins (e.g., ExoU, ExoS), pigments (pyoverdine, pyochelin), and motility structures (flagella and pili), which contribute to tissue invasion, immune modulation, and host damage. During chronic colonization, P. aeruginosa undergoes significant genotypic and phenotypic changes, such as mucoid conversion, downregulation of acute virulence pathways, and emergence of hypermutator phenotypes that facilitate rapid adaptation. Persistent cells, a specialized subpopulation characterized by metabolic dormancy and antibiotic tolerance, further complicate eradication efforts. The dynamic interplay between host environment and microbial evolution underlies the heterogeneity of CF lung infections and presents significant challenges for treatment. Elucidating the molecular mechanisms driving persistence, hypermutability, and biofilm resilience is critical for the development of effective therapeutic strategies targeting chronic P. aeruginosa infections in CF. Full article

The resistance of breast cancer cells to therapeutic antibodies such as anti-HER2 trastuzumab can be overcome by engaging natural killer (NK) cells for killing antibody-binding tumor cells via antibody-dependent cellular cytotoxicity (ADCC). Here, we investigated how autophagy modulation affects trastuzumab-mediated ADCC in HER2-positive JIMT1 breast cancer cells and NK cells. Autophagy inducers (rapamycin and resveratrol) had no significant impact, but the inhibitor bafilomycin nearly abolished ADCC. Protection occurred when either cancer or NK cells were pretreated, indicating dual effects. Bafilomycin reduced phosphatidylserine externalization, the loss of plasma membrane integrity, caspase-3/7 activity, and DNA fragmentation. It downregulated pro-apoptotic BAK1 and BAX without altering BCL-2. Additionally, bafilomycin decreased HER2 surface expression, impairing trastuzumab binding, and modulated immune regulators (STAT1, CD95, and PD-L1) in NK and/or in the cancer cells. Bafilomycin disrupted HER2 trafficking and induced HER2 internalization, leading to its accumulation in cytoplasmic vesicles. These findings show that autophagy inhibition by bafilomycin confers ADCC resistance by altering apoptosis, immune signaling, and HER2 dynamics. The study underscores autophagy’s role in antibody-based cancer therapy efficacy. Full article

Background/Objectives: Isocitrate dehydrogenase (IDH) mutations are hallmark features in subsets of gliomas, producing the oncometabolite D-2-hydroxyglutarate (2HG). Although IDH mutations are associated with better clinical outcomes, their relationship with tumor progression is complex. This study aimed to investigate, in vitro and in vivo, the phenotypic consequences of IDH mutation and 2HG exposure in glioblastoma (GBM) under normoxic and hypoxic conditions and under temozolomide (TMZ) and radiation exposure. Methods: Experiments were conducted using IDH-wildtype (IDH-wt) and IDH-mutant (IDH-mut) glioma cell lines under controlled oxygen conditions. Functional assays included cell viability, cell cycle analysis, apoptosis profiling, migration, and surface marker expression via flow cytometry. Orthotopic xenografts were established in immunocompromised mice to assess in vivo tumor growth and morphology, followed by MRI and histological analysis. Treatments included TMZ, radiation, and 2HG at varying concentrations. Statistical analyses were performed using SPSS and RStudio. Results:IDH-wt cells exhibited faster proliferation and greater adaptability under hypoxia, while IDH-mut cells showed cell cycle arrest and limited growth. 2HG recapitulated IDH-mut features in IDH-wt cells, including increased apoptosis under TMZ, reduced proliferation, and altered CD24/CD44 expression. In vivo, IDH-wt tumors were larger and more infiltrative, while 2HG administration reduced tumor volume and promoted compact morphology. Notably, migration was initially similar across genotypes but increased in IDH-mut and 2HG-treated IDH-wt cells over time, though suppressed under therapeutic stress. Conclusions: IDH mutation and 2HG modulate glioma cell biology, including cell cycle dynamics, proliferation rates, migration, and apoptosis. While the IDH mutation and its metabolic product confer initial growth advantages, they enhance treatment sensitivity and reduce invasiveness, highlighting potential vulnerabilities for targeted therapy. Full article

Bone metabolism is a dynamic process involving continuous bone formation and resorption, orchestrated by the interplay between osteoblasts and osteoclasts. Osteoporosis (Op), the most prevalent osteo-metabolic disorder globally, results from an imbalance in this remodeling cycle. Hashimoto’s thyroiditis (HT), a chronic autoimmune thyroid disorder, has been increasingly recognized as a contributor to bone loss, even in euthyroid individuals. HT is marked by immune dysregulation, autoantibody production, and chronic inflammation, factors that can alter bone remodeling. Furthermore, both thyroid-stimulating hormone (TSH) and thyroid hormones (THs) independently influence bone health. Low TSH and elevated TH levels, including in subclinical states, have been linked to reduced bone mineral density (BMD) and increased fracture risk. Nutritional factors, particularly selenium and iodine intake, modulate both thyroid and bone function, and can be considered as a link between HT and Op. In particular, antioxidant-rich diets such as the Mediterranean diet may confer protective effects. This review integrates current clinical and experimental evidence linking HT with bone metabolism disorders, emphasizing the multifactorial nature of bone fragility in autoimmune thyroid disease and the potential role of diet in mitigating its impact. Full article

Polymer electrolytes (PEs) provide enhanced safety for high–energy–density lithium metal batteries (LMBs), yet their practical application is hampered by intrinsically low ionic conductivity and insufficient electrochemical stability, primarily stemming from suboptimal Li⁺ solvation environments and transport pathways coupled with slow polymer dynamics. Herein, we demonstrate a molecular design strategy to overcome these limitations by regulating the Li⁺ solvation structure through the synergistic interplay of conventional Lewis acid–base coordination and engineered hydrogen bond (H–bond) networks, achieved by incorporating specific H–bond donor functionalities (N,N′–methylenebis(acrylamide), MBA) into the polymer architecture. Computational modeling confirms that the introduced H–bonds effectively modulate the Li⁺ coordination environment, promote salt dissociation, and create favorable pathways for faster ion transport decoupled from polymer chain motion. Experimentally, the resultant polymer electrolyte (MFE, based on MBA) enables exceptionally stable Li metal cycling in symmetric cells (>4000 h at 0.1 mA cm⁻²), endows LFP|MFE|Li cells with long–term stability, achieving 81.0% capacity retention after 1400 cycles, and confers NCM622|MFE|Li cells with cycling endurance, maintaining 81.0% capacity retention after 800 cycles under a high voltage of 4.3 V at room temperature. This study underscores a potent molecular engineering strategy, leveraging synergistic hydrogen bonding and Lewis acid–base interactions to rationally tailor the Li⁺ solvation structure and unlock efficient ion transport in polymer electrolytes, paving a promising path towards high–performance solid–state lithium metal batteries. Full article

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory illness in infants, young children, as well as elderly and immunocompromised patients worldwide. RSV is classified into two major subtypes, RSV-A and RSV-B, and remains the most frequently detected pathogen in infants hospitalized with acute respiratory infections. Recent advances have brought both passive and active immunization strategies, including FDA-approved vaccines for older adults and pregnant women and new monoclonal antibodies (mAbs) for infant protection. Although significant progress has been made, the need remains for improved antiviral treatments, particularly for vulnerable infants and immunocompromised patients. Recent studies have identified multiple RSV mutations that confer resistance to current treatments. These mutations, detected in both in vitro studies and clinical isolates, often complicate therapeutic outcomes, underscoring the need for updated and effective management strategies. In this context, evaluating protein flexibility through tools like DisoMine provides insight into how specific mutations impact structural dynamics at binding sites, thus affecting ligand affinity. This review aims to synthesize these aspects, offering a comprehensive insight into ongoing efforts to counteract RSV and address the evolving challenge of drug resistance. Full article

Amid accelerating population aging and the rapid evolution of digital technologies, the digital transformation of rural elderly care services has become a pivotal strategy for restructuring the rural elderly care system. This study identified the local government, rural elderly care service centers, and the elderly population as the principal stakeholders, and developed a tripartite evolutionary game-theory model to examine the dynamic strategic interactions among these actors under the influence of digital technologies. The model further investigated the evolutionary trajectories and equilibrium conditions of their behavioral strategies. Numerical simulations conducted via MATLAB were employed to validate and visualize the model outcomes. The findings revealed the following. (1) The evolutionary equilibrium of digital elderly care service development in rural areas is jointly determined by the strategic choices of the three parties, with its stability shaped by a complex interplay of cost structures, incentive mechanisms, and utility outcomes. (2) Cost factors exhibit heterogeneous effects across stakeholders. Specifically, excessive regulatory costs diminish the performance incentives of local governments, digital infrastructure and operational expenditures influence service centers’ capacity for precision-oriented service delivery, and the participation of the elderly is constrained by affordability thresholds. (3) Local government behavior demonstrates a pronounced sensitivity to incentives. In particular, rewards and social reputation conferred by higher-level governmental bodies exert a significantly stronger influence than punitive measures. (4) Government subsidies for digital transformation enhance cross-stakeholder synergy through dual transmission channels. Nonetheless, excessive subsidies may escalate fiscal risk, while moderately calibrated penalty mechanisms effectively curb moral hazard within service centers. This study advances theoretical understanding of multi-stakeholder coordination in the context of digitally enabled rural elderly care and provides actionable insights for policymakers aiming to formulate interest-aligned strategies and construct resilient, intelligent governance systems for elderly care. Full article

The study of bacteriocins has significantly enhanced our understanding of microbial interactions, notably within the genus Streptococcus. Among the most functionally diverse and clinically relevant bacteriocins are those belonging to the lantibiotic class, which exhibit potent antimicrobial properties and are central to the competitive dynamics of streptococcal species. This review focuses on the discovery and characterization of bacteriocins produced by Streptococcus pyogenes and Streptococcus salivarius, emphasizing their biological significance within their exclusive human host. A cornerstone of these studies has been the development and application of the pioneer agar culture-based bacteriocin detection methodology, known as streptococcal bacteriocin fingerprinting. This approach has proven invaluable for the initial detection and differentiation of a wide array of bacteriocin-like inhibitory substances (BLIS) in streptococcal populations. A central theme of this review is the diverse biological roles of lantibiotics in S. pyogenes and S. salivarius, particularly in relation to microbial competition, colonization dynamics, and host interactions. The expression of lantibiotic determinants provides distinct advantages to the producing strain, including enhanced niche establishment and the ability to suppress competing microbes. Furthermore, the presence of specific lantibiotic immunity mechanisms safeguards the producer from self-inhibition and potential antagonism from closely related competitors. In S. pyogenes, lantibiotic production has been implicated in virulence modulation, raising important questions about its role in pathogenicity and host immune evasion. Conversely, S. salivarius, a prominent commensal and probiotic candidate species, utilizes its lantibiotic arsenal to confer colonization benefits and mediate beneficial interactions, especially within the oral and upper respiratory tract microbiomes. The implications of in situ lantibiotic expression extend beyond microbial ecology, presenting opportunities for innovative probiotic and therapeutic applications. The potential for harnessing bacteriocin-producing streptococci in antimicrobial interventions, particularly in combating antibiotic-resistant pathogens, underscores the translational relevance of these findings. This review integrates historical and contemporary perspectives on streptococcal bacteriocin research, providing insights into future avenues for leveraging these bioactive peptides in clinical and biotechnological contexts. Full article

Autophagy and apoptosis are two essential mechanisms regulating cell fate. Although distinct, their signaling pathways are closely interconnected through various crosstalk mechanisms. Lipid rafts are described to act as both physical and functional platforms during the early stages of autophagic and apoptotic processes. Only recently has a role for lipid raft-associated molecules in regulating EV biogenesis and release begun to emerge. In particular, lipids of EV membranes are essential components in conferring stability to these vesicles in different extracellular environments and/or to facilitate binding or uptake into recipient cells. In this review we highlight these aspects, focusing on the role of lipid molecules during apoptosis and secretory autophagy pathways. We describe the molecular machinery that connects autophagy and apoptosis with vesicular trafficking and lipid metabolism during the release of EVs, and how their alterations contribute to the development of various diseases, including autoimmune disorders and cancer. Overall, these findings emphasize the complexity of autophagy/apoptosis crosstalk and its key role in cellular dynamics, supporting the role of lipid rafts as new therapeutic targets. Full article

In this piece, we approach graffiti from the perspective of the ‘circuits of valorization’ that qualify as well as quantify it. We understand a valorization circuit as an assemblage of cultural, legal, economic and geographic dynamics surrounding a given artefact, which eventually confer a certain ‘value’ to it. Here, we look at examples of global graffiti, with attention to how cities and administrations juggle with its controversial valorization, implementing various policies to rein it in, but also to exploit it. Typically, graffiti appears and lives in ill-defined, metamorphic urban spaces: as an urban artefact, graffiti occupies loose, interstitial places and rhymes with an aesthetic of defacement and infestation. The ‘in place/out of place’ dialectic is thus central for claims to legitimacy, legality, and, ultimately, also the ‘quality’ of graffiti. Through the lens of radical legal pluralism, we argue that graffiti can insert a distinctive dynamism into the lawscape, rather than be a sheer inert object of urban policies. Graffiti itself actively participates, not simply in populating the lawscape, but in its actual crafting. Full article

The global dissemination of plasmid-mediated mcr genes, which confer resistance to the last-resort antibiotic colistin, represents a critical public health challenge driven by the interplay of clinical, agricultural, and environmental factors. This review examines the genetic and ecological dynamics of mcr-bearing plasmids, focusing on their role in disseminating colistin resistance across diverse bacterial hosts and ecosystems. Key plasmid families demonstrate distinct evolutionary strategies, including IncI2, IncHI2, and IncX4. IncI2 plasmids favor stability in livestock and clinical settings. IncHI2 plasmids, on the other hand, leverage transposons to co-select for multidrug resistance, while IncX4 plasmids achieve global dissemination through streamlined, conjugation-efficient architectures. The pervasive spread of mcr genes is exacerbated by their integration into chromosomes via mobile genetic elements and co-selection with resistance to other antibiotic classes, amplifying multidrug-resistant phenotypes. Environmental reservoirs, food chains, and anthropogenic practices further facilitate cross-niche transmission, underscoring the interconnectedness of resistance under the One Health framework. Addressing this crisis requires coordinated strategies, including reducing colistin misuse in agriculture, enhancing surveillance of high-risk plasmid types, and fostering international collaboration to preserve antimicrobial efficacy and mitigate the threat of untreatable infections. Full article