Search Results (696)

Protein–polyelectrolyte nanostructures assembled via electrostatic interactions offer versatile applications in biomedicine, tissue engineering, and food science. However, several open questions remain regarding their intermolecular interactions and the influence of external conditions—such as temperature and pH—on their assembly, stability, and responsiveness. This study explores the formation and stability of networks between poly(acrylic acid) (PAA) and lysozyme (LYZ) at the nanoscale upon thermal treatment, using a combination of experimental and simulation measures. Experimental techniques of static and dynamic light scattering (SLS and DLS), Fourier transform infrared spectroscopy (FTIR), and circular dichroism (CD) are combined with all-atom molecular dynamics simulations. Model systems consisting of multiple PAA and LYZ molecules explore collective assembly and complexation in aqueous solution. Experimental results indicate that electrostatic complexation occurs between PAA and LYZ at pH values below LYZ’s isoelectric point. This leads to the formation of nanoparticles (NPs) with radii ranging from 100 to 200 nm, most pronounced at a PAA/LYZ mass ratio of 0.1. These complexes disassemble at pH 12, where both LYZ and PAA are negatively charged. However, when complexes are thermally treated (TT), they remain stable, which is consistent with earlier findings. Atomistic simulations demonstrate that thermal treatment induces partially reversible structural changes, revealing key microscopic features involved in the stabilization of the formed network. Although electrostatic interactions dominate under all pH and temperature conditions, thermally induced conformational changes reorganize the binding pattern, resulting in an increased number of contacts between LYZ and PAA upon thermal treatment. The altered hydration associated with conformational rearrangements emerges as a key contributor to the stability of the thermally treated complexes, particularly under conditions of strong electrostatic repulsion at pH 12. Moreover, enhanced polymer chain associations within the network are observed, which play a crucial role in complex stabilization. These insights contribute to the rational design of protein–polyelectrolyte materials, revealing the origins of association under thermally induced structural rearrangements. Full article

The management of adult spinal deformity (ASD) has evolved dramatically over the past century, transitioning from external bracing and in situ fusion to complex, technology-driven surgical interventions. This review traces the historical development of spinal deformity correction and highlights contemporary enabling technologies that are redefining the surgical landscape. Advances in stereoradiographic imaging now allow for precise, low-dose three-dimensional assessment of spinopelvic parameters and segmental bone density, facilitating individualized surgical planning. Robotic assistance and intraoperative navigation improve the accuracy and safety of instrumentation, while patient-specific rods and interbody implants enhance biomechanical conformity and alignment precision. Machine learning and predictive modeling tools have emerged as valuable adjuncts for risk stratification, surgical planning, and outcome forecasting. Minimally invasive deformity correction strategies, including anterior column realignment and circumferential minimally invasive surgery (cMIS), have demonstrated equivalent clinical and radiographic outcomes to traditional open surgery with reduced perioperative morbidity in select patients. Despite these advancements, complications such as proximal junctional kyphosis and failure remain prevalent. Adjunctive strategies—including ligamentous tethering, modified proximal fixation, and vertebral cement augmentation—offer promising preventive potential. Collectively, these innovations signal a paradigm shift toward precision spine surgery, characterized by data-informed decision-making, individualized construct design, and improved patient-centered outcomes in spinal deformity care. Full article

Flexibility in phased antenna arrays open the world of new applications. Such arrays can conform to different shapes while ensuring performance in harsh conditions. The purpose of this study is to perform a detailed comparative analysis of numerous studies of flexible phased antenna arrays. This work summarizes the main manufacturing techniques and the commonly used materials with their properties. It also outlines the key challenges and future trends in the development of flexible phased antenna arrays. The paper concludes with research recommendations to address the identified technical issues. Full article

The renin–angiotensin system (RAS) plays a central role in cardiovascular regulation and has gained prominence in the pathogenesis of Coronavirus Disease 2019 (COVID-19) due to the critical function of angiotensin-converting enzyme 2 (ACE2) as the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin IV, but not angiotensin II, has recently been reported to enhance the binding between the viral spike protein and ACE2. To investigate the virological significance of this effect, we developed a single-round infection assay using SARS-CoV-2 viral-like particles expressing the spike protein. Our results demonstrate that while angiotensin II does not affect viral infectivity across concentrations ranging from 40 nM to 400 nM, angiotensin IV enhances viral entry at a low concentration but exhibits dose-dependent inhibition at higher concentrations. These findings highlight the unique dual role of angiotensin IV in modulating SARS-CoV-2 entry. In silico molecular docking simulations indicate that angiotensin IV was predicted to associate with the S1 domain near the receptor-binding domain in the open spike conformation. Given that reported plasma concentrations of angiotensin IV range widely from 17 pM to 81 nM, these levels may be sufficient to promote, rather than inhibit, SARS-CoV-2 infection. This study identifies a novel link between RAS-derived peptides and SARS-CoV-2 infectivity, offering new insights into COVID-19 pathophysiology and informing potential therapeutic strategies. Full article

Phage display has advanced the discovery of peptides that selectively bind to a wide variety of cell surface molecules, offering new modalities to modulate disease-related protein–protein interactions (PPIs). These cell-binding peptides occupy a unique pharmaceutical space between small molecules and large biologics, and their growing popularity has opened up new avenues for targeting cell surface proteins that were previously considered undruggable. This work provides an overview of methods for identifying cell-selective peptides using phage display combinatorial libraries, covering in vitro, ex vivo, and in vivo biopanning approaches. It addresses key considerations in library design, including the peptide conformation (linear vs. cyclic) and length, and highlights examples of clinically approved peptides developed through phage display. It also discusses the on-phage chemical cyclization of peptides to overcome the limitations of genetically encoded disulfide bridges and emphasizes advances in combining next-generation sequencing (NGS) with phage display to improve peptide selection and analysis workflows. Furthermore, due to the often suboptimal binding affinity of peptides identified in phage display selections, this article discusses affinity maturation techniques, including random mutagenesis and rational design through structure–activity relationship (SAR) studies to optimize initial peptide candidates. By integrating these developments, this review outlines practical strategies and future directions for harnessing phage display in targeting challenging cell surface proteins. Full article

In this paper we examine the OpenJDK library implementation of the ConcurrentLinkedQueue. We use model checking to verify that it behaves according to the algorithm it is based on: Michael and Scott’s fast and practical non-blocking concurrent queue algorithm. In addition, we develop a simple concurrent queue specification in CSP and verify that Michael and Scott’s algorithm satisfies it. We conclude that both the algorithm and the implementation are correct and both conform to our simpler concurrent queue specification, which we can use in place of either implementation in future verification tasks. The complete code is available on GitHub. Full article

Aqueous solutions are not homogeneous and could be considered supramolecular systems. They can emit electromagnetic waves. Electromagnetic emission from one supramolecular system (“source”) can be received by another supramolecular system (“receiver”) without direct contact (distantly). This process represents a transfer of a “molecular signal” and causes changes in conformation and symmetry of the “receiver”. The aim of the current work is to theoretically describe such changes primarily using a solution of the chiral protein interferon-gamma (IFNγ) as an example. We provide theoretical evidence that supramolecular systems of highly diluted (HD) aqueous solutions formed by self-assembly after mechanical activation generate a stronger molecular signal compared to non-activated solutions, due to their higher energy-saturated state. Additionally, molecular signals cause supramolecular systems with complex (including chiral) structures to undergo easier changes in conformation and symmetry compared to simpler systems, enhancing their biological activity. Using statistical physics, we obtained the parameter Ic, characterizing the magnitude of conformational and symmetry changes in supramolecular (including chiral) systems caused by molecular signals. In quantum information science, there is an analogue of the parameter Ic, which characterizes the entanglement depth of quantum systems. This study contributes to the understanding of the physico-chemical basis of distant molecular interactions and opens up new possibilities for controlling the properties of complex biological and chemical systems. Full article

The evolution of a flame front in a channel was considered in a two-dimensional approximation. In the approximation of the potential flow of combustion products and unburned mixture, the formation of a finger-shaped flame was considered after ignition at the closed end of the channel, on the channel axis, and on the side wall of the channel. The prerequisites for the formation of a tulip-shaped flame were considered in a potential approximation. The method of conformal mapping was used. Simple analytical functions were used that allowed equipotential lines and streamlines to be transformed. The shape of the flame front was obtained. The analytical results were compared with the experimentally obtained results of the flame front evolution and with numerical results obtained by other authors. The conditions for the applicability of the conformal mapping to a reacting gas mixture were given. Full article

The present research aims to the evaluation of the deformation capacity of existing reinforced concrete shear walls designed with past non-conforming seismic regulations. A refined analytical model (referred to as the Proposed Model) is presented for generating Load–displacement (P-d) curves for RC shear walls. The model is applicable to medium-rise walls designed with or without modern seismic provisions and incorporates shear effects in both deformation and strength capacity. The application of the Proposed Model is assessed through comparison with numerical models implemented in the widely accepted OpenSees platform. Specifically, two types of elements are examined: the widely used flexural element Force-Based Beam-Column Element (FBE) and the Flexure-Shear Interaction Displacement-Based Beam-Column Element (FSI), which accounts for the interaction between flexure and shear. The results of both analytical and numerical approaches are compared with experimental data from four RC shear wall specimens reported in previous studies. Full article

ABCG2 is a crucial ATP-binding cassette (ABC) transporter involved in multidrug resistance and essential physiological and pharmacological processes. In recent years, multiple ABCG2 structures have been resolved using cryo-electron microscopy (cryo-EM), providing significant insights into its conformational states during its transport cycle. However, even more than 25 years after its description, a high-resolution X-ray crystallographic structure is still unavailable, limiting the understanding of its dynamic transitions, as well as leaving aspects of the transport cycle unresolved and open to discussion. Given the complexity of ABCG2, a multidisciplinary approach is essential in order to fully elucidate its mechanism. This review compiles recent advances in ABCG2 structural biology, highlights unresolved controversies, and explores future directions to bridge the gap between structure and function. Moving forward, integrating multiple structural and functional approaches will be key to uncovering the intricate workings of this enigmatic transporter. In particular, detailed structural insights will be crucial to identifying new ABCG2 substrates and designing selective inhibitors, with important implications for therapeutic development. Full article

Acetone carboxylase (AC) from Xanthobacter autotrophicus is a 360 KDa α₂β₂γ₂ heterohexamer that catalyzes the ATP-dependent formation of phosphorylated acetone and bicarbonate intermediates that react at Mn(II) metal active sites to form acetoacetate. Structural models of X. autotrophicus AC (XaAC) with and without nucleotides reveal that the binding and phosphorylation of the two substrates occurs ~40 Å from the Mn(II) active sites where acetoacetate is formed. Based on the crystal structures, a significant conformational change was proposed to open and close a tunnel that facilitates the passage of reaction intermediates between the sites for nucleotide binding and phosphorylation of substrates and Mn(II) sites of acetoacetate formation. We have employed electron paramagnetic resonance (EPR), kinetic assays, and hydrogen/deuterium exchange mass spectrometry (HDX-MS) of poised ligand-bound states and site-specific amino acid variants to complete an in-depth analysis of Mn(II) coordination and allosteric communication throughout the catalytic cycle. In contrast with the established paradigms for carboxylation, our analyses of XaAC suggested a carboxylate shift that couples both local and long-range structural transitions. Shifts in the coordination mode of a single carboxylic acid residue (αE89) mediate both catalysis proximal to a Mn(II) center and communication with an ATP active site in a separate subunit of a 180 kDa α₂β₂γ₂ complex at a distance of 40 Å. This work demonstrates the power of combining structural models from X-ray crystallography with solution-phase spectroscopy and biophysical techniques to elucidate functional aspects of a multi-subunit enzyme. Full article

The enzyme transglutaminase 2 (TG2) has an open conformation with transamidase activity which crosslinks matrix proteins contributing to fibrosis development. LDN-27219 promotes the closed conformation of TG2, which can enhance vasodilation, but its effects in renal tissue are unknown. We investigated whether LDN-27219 treatment affects albuminuria and markers of renal fibrosis as well as ex vivo vasodilatation. Male C57BL/6 mice (n = 48) underwent unilateral nephrectomy plus insertion of a deoxycorticosterone acetate pellet (DOCA group) or nephrectomy only (sham group). Both groups were randomized to intraperitoneal treatment with either LDN-27219 (8 mg/kg twice daily) or vehicle for 2 weeks. Urine albumin excretion was evaluated by metabolic cages. Kidney tissue fibrosis markers were assessed by qPCR and Western blotting, while the TG2 conformational state was evaluated using native gel electrophoresis. Collagen staining was performed using Picrosirius red and quantified under circularly polarized light. Mesenteric arteries were mounted in wire myographs for evaluation of vasorelaxation. DOCA mouse developed significant albuminuria (p < 0.001 vs. sham), but neither TG2 mRNA nor protein expression was upregulated in the kidney. However, the relative amount of TG2 in the closed conformation was higher in DOCA mice. LDN-27219 did not affect albuminuria, but LDN-27219-treated DOCA mice showed less urine production and less collagen staining than vehicle-treated DOCA mice. LDN-27219 did not affect TG2 mRNA or TG2 protein expression or mRNA of fibrosis markers. LDN-27219-treated mice had enhanced vasorelaxation to the nitric oxide donor sodium nitroprusside. In conclusion, LDN-27219 treatment in the one-kidney DOCA–salt model did not affect renal TG2 mRNA and protein expression or albuminuria but still exerted beneficial effects in terms of reduced kidney fibrosis and urine production in addition to enhanced vasodilatation. Full article

Understanding the evolution of societal values is crucial amidst globalization and migration. This study aimed to (1) map Portugal’s basic human values (BHVs) profile in 2020 through comparison with six European countries (Bulgaria, France, United Kingdom, Hungary, Italy, and Norway) and (2) analyze Portugal’s BHVs trajectory from 2002 to 2020. Drawing on Schwartz’s theory and European Social Survey (ESS) data, we applied descriptive statistics, similarity indices, post-stratification weighting, and trend analysis after extensive data cleaning. Results indicate that in 2020, Portugal displayed high self-transcendence and relatively high openness to change, aligning most closely with the United Kingdom and Hungary. Longitudinal analysis revealed a shift after 2012, marked by rising hedonism, stimulation, and self-direction, and declining conformity. These value dynamics offer insights into future societal demands and potential tensions. Moreover, Portugal’s emerging value configuration—balancing self-transcendence with growing openness—may foster economic opportunities by enhancing attractiveness for innovation ecosystems (linked to self-direction and stimulation), experience-driven tourism (hedonism), and investments aligned with sustainable and social goals (universalism and benevolence). Monitoring value changes remains essential to anticipate societal transformations and inform policy design. Full article

Transitioning to sustainable systems often faces significant challenges. People from different backgrounds often have different views on sustainability, which may lead to group polarisation. To promote collective participation in the transition to sustainability, it is critical to understand the drivers of polarisation and promote inclusiveness in decision-making. We developed a Dialogue Tool based on the HUMAT framework to explore opinion dynamics such as polarisation in the community and find potential pathways to reconcile when division occurs. By simulating dissatisfaction, division, and reconciliation in the community, we studied how individual characteristics (such as openness to change and assertiveness) affect collective decisions. Furthermore, the Dialogue Tool can be used to test possible interventions to reduce polarisation and increase community satisfaction. Visual representations of community dynamics under different scenarios within the Dialogue Tool have the potential to foster meaningful dialogues among stakeholders, which may promote a deeper reflection on community collaboration. While limitations such as simplifications and lack of empirical calibration limit the predictive accuracy of the Dialogue Tool (although this is not its goal), it still shows strong potential for educational and policy applications. It offers insights into social influences, conformity, and polarisation in community settings, making it a promising tool for fostering inclusive, informed decision-making and strengthening community participation in sustainable development transitions. Full article

Current αIIbβ3 antagonists are potent antithrombotic agents, their clinical use is limited by the risk of life-threatening bleeding. Emerging evidence has highlighted key mechanistic differences between thrombosis and hemostasis, opening avenues for safer antithrombotic strategies. Targeting integrin αIIbβ3 outside-in signaling has been proposed to mitigate bleeding risk; however, the short half-life of peptide-based therapeutics remains a major challenge. In this study, we developed an optimized αIIbβ3 antagonist, KGDRR—a recombinant mutant protein derived from snake venom disintegrin, incorporating an Arg55 residue within the KGD loop—through systematic structure–activity relationship (SAR) analysis. Molecular docking revealed a critical cation–π interaction between Arg55 of KGDRR and Tyr122 of the β3 subunit, stabilizing integrin αIIbβ3 in an unliganded-closed conformation. Functionally, KGDRR selectively inhibited thrombus propagation by blocking ligand binding and downstream Gα13-mediated outside-in signaling while preserving initial thrombus core formation, which is a limitation of current αIIbβ3 inhibitors. Unlike conventional antagonists, KGDRR maintained αIIbβ3 in an unliganded-closed conformation without inducing the integrin activation and conformational change that lead to immune-mediated platelet clearance and thrombocytopenia. In animal models, KGDRR effectively suppressed thrombus growth without causing thrombocytopenia or prolonging bleeding time. Furthermore, intramuscular administration of KGDRR achieved a functional half-life 3.5 times longer than that of the clinically used antithrombotic eptifibatide at equivalent antithrombotic efficacy. In conclusion, KGDRR exhibits potent antithrombotic activity with a favorable safety profile and enhanced pharmacokinetic stability. These findings position KGDRR as a promising next generation αIIbβ3 antagonist with the potential to improve clinical outcomes in antithrombotic therapy. Full article