Search Results (309)

Reptiles with diving capabilities have evolved physiological adaptations as well as conformational changes to temporarily sustain life underwater. Despite the importance of both respiratory and cardiovascular systems during diving, most studies have focused on respiratory adaptations. Thus, characterisation of previously undescribed cardiovascular anatomical variations in diving vertebrates is of broad interest. Thirteen clinically healthy, free-ranging adult female Murray River turtles (Chelidae: Emydura macquarii) were collected for research purposes, euthanised and autopsied. Prominent, valve-like structures, comprised exclusively of smooth muscle myocytes, were identified in medium- and large-calibre muscular arteries of all individuals. Additionally, multiple intramural vascular channels, mimicking post-thrombotic recanalization, were observed within medium-calibre muscular arteries. Further, we confirmed the presence of alpha-smooth-muscle actin-positive cells lining the cardiac atria in E. macquarii. Quantitative morphometric analyses demonstrated that the valve-like structures frequently occupied a substantial proportion of the vascular lumen, in some cases exceeding 90% luminal narrowing. Their consistent presence across multiple individuals and organ systems supports the interpretation that these are physiological vascular structures rather than artefacts. This study examines the potential physiological and evolutionary roles of these vascular structures, providing a basis for further research into cardiovascular adaptations in vertebrates subjected to postural changes and diving-related haemodynamic challenges. Full article

To improve the flavor quality and antioxidant activity of walnut gluten peptides, gluten was extracted from defatted walnut meal by alkaline solubilization and acid precipitation, hydrolyzed with alkaline protease to prepare antioxidant peptides, and further modified by the Maillard reaction. The optimal sugar source was selected by single-factor experiments, and reaction conditions were optimized by response surface methodology. Peptide conformational changes were characterized by UV, fluorescence, DSC, FTIR, and SEM, while changes in amino acid composition, flavor properties, and antioxidant activity were systematically evaluated. Fructose was identified as the optimal sugar source. The optimal reaction conditions were a peptide-to-sugar ratio of 1:1.2, 78.5 °C, initial pH 7.6, and 2 h reaction time, under which the sensory score reached 8.5 and DPPH radical scavenging activity reached 66.92%. Maillard modification markedly altered peptide conformation, as shown by increased UV absorbance, decreased intrinsic fluorescence intensity with a red shift, an increase in denaturation temperature from 80 °C to 100 °C, reduced α-helix content, increased β-sheet content, and transformation of the microstructure from a loose porous morphology to dense block-like aggregates. Free amino acid content increased initially and then decreased, whereas total essential amino acids were largely retained, indicating that the overall nutritional composition was preserved. However, further evaluation of digestibility and bioavailability is required to confirm nutritional value. These findings provide a feasible strategy for improving the flavor and functional properties of walnut gluten peptides and support their high-value utilization. Full article

G protein-coupled receptor kinase 5 (GRK5) is an important therapeutic target involving cardiovascular diseases, cancer, and inflammatory disorders. However, the features of its activation as an essential function regulation process have been poorly understood, limiting related drug development. The work utilizes a molecular dynamics simulation coupled with an interpretable machine learning model to identify key structure and dynamics determinants distinguishing the active and inactive states of GRK5. Benefiting from the unbiased and data-driven framework, the work reveals that the active site tether (AST) is a dominant activation-associated feature, acting as a conformational switch that regulates kinase domain movements. Beyond this canonical element, we also uncover two previously underappreciated structure modules contributing to GRK5 activation, such as the coupling interaction between the α10/α11 helix interface with the N-terminal lipid-binding domain (NLBD) in the active state, and the α5 helix region that facilitates large-scale RH domain reorientation. Conformation dynamics analyses further indicate that GRK5 activation involves disruption of the interdomain interactions and interaction coupling between AST, αN-helix, kinase domain N-lobe, NLBD, and α10/α11 hinge. These observations provide valuable insights into understanding the GPK5 activation mechanism and also highlight the power of machine learning in capturing functionally conformational changes, and in turn offering a methodological guideline for the studying of the protein function mechanism. Full article

For a protein to perform its biological functions, it must adopt a specific three-dimensional conformation. In addition, many proteins require the assistance of other protein complexes known as chaperonins to fold —i.e., to acquire such a specific conformation—, although the exact mechanisms whereby the chaperonins act and assist the folding process have not been completely determined. In this work, we characterize the physical environment at the interior of the chaperonin HSP60/HSP10 via Molecular Dynamics Simulations. We found that, inside the cavity of the chaperonin (within a region covering much of the cavity’s volume), the long-range electrostatic potential presents a structured pattern that, except for small fluctuations, does not change in time. The electrostatic potential generates an electric field that can be modeled, as a first approximation, as constant and unidirectional $(\mathit{E}/\left(\mathrm{V}·{\AA }^{-1}\right)\approx -0.0054\widehat{𝚤}+0.010\widehat{\mathit{𝚥}}-0.162\widehat{k}$, here the chaperonin’s main axis is aligned along $\widehat{k})$, which can produce large deformations in the structure of a heated protein (Rhodanese); the long-range approximated $\mathit{E}\left(\mathit{r}\right)$ can in fact unfold the Rhodanese, when applied as an external field. Finally, we discuss the possible implications of such an electric field for the protein folding problem, within the context of proteins whose folding is assisted by chaperones. The existence and effects of the electric field are consistent with several theories and experimental observations related to the protein folding problem, in particular with the foldon view. Full article

This paper evaluates the advantages of overlapping microwave ablation (OMWA) for the personalized treatment of large tumors, providing quantitative and technical references for conformal tumor eradication. A three-dimensional numerical model coupled with electromagnetic fields and Pennes’ biological heat transfer equation was constructed, comprehensively considering the nonlinear behavior of tissue electrical and thermal parameters with temperature changes. A simulation model was developed to predict temperature distribution and the formation of the coagulation zone under single-needle multiple-point and multiple-needle multiple-point OMWA strategies. The LiTS2017 public dataset of liver tumor cases and real clinical cases was selected for verification. The results showed that OMWA could achieve faster thermal accumulation, higher central temperature, and more conformal tumor coverage. Compared with the single-needle strategy, OMWA significantly reduces thermal damage to surrounding healthy tissues while achieving complete tumor coverage. Therefore, OMWA is more efficient and safer than the single-needle strategy in the personalized treatment of large tumors and can provide important references for clinical preoperative planning and parameter optimization. Full article

Non-covalent molecular self-assembly serves as a distinctive strategy for enhancing the mechanical performance of lignin-based composite hydrogels. Nevertheless, the self-assembly process can be significantly influenced, leading to alterations in the nanostructure of the hydrogel, because of the diverse conformational reorganizations of lignin in different solvents. In this research, a solvent exchange process was employed to generate a phase-separated structure comprising hydrophobic lignin domains and hydrophilic poly(N,N-dimethylacrylamide) (PDMA) domains through the aggregation of lignin, thereby forming tough lignin/PDMA hydrogels. By adjusting the solvent composition, the hydrogels exhibit distinct nanostructural transformations that are precisely correlated with the changes in Hansen Solubility Parameters (HSPs) of the solvent mixtures. Balanced HSPs facilitates the formation of small-scale lignin domains with high-domain density, which act as crosslinking points for the establishment of a reinforced network. Remarkably, lignin/PDMA hydrogels prepared at a boundary solvation condition unexpectedly induced the formation of large and highly condensed lignin domains, which displayed a radius of gyration (Rg) of 7.7 nm and an inter-domain distance (d-spacing) of 98.1 nm within the hydrogel network. These unique nanostructural features further contribute to its superior mechanical performance, including excellent tensile strength of 3.2 MPa, Young’s modulus of 5.7 MPa, and fracture energy of 41.2 kJ m⁻², which outperforms most reported lignin hydrogels. Additionally, it offers a strong adhesion and rapid drying approach, rendering the hydrogel more suitable for applications as hydrogel coatings. Full article

Background/Objectives: Management of bipolar disorder is marked by variability in lithium response, with responders constituting a distinct clinical subgroup. Although pharmacogenetic studies implicate polymorphisms in neuroplasticity-related genes (BDNF) and hypothalamic–pituitary–adrenal (HPA) axis regulators (NR3C1), the underlying biophysical mechanisms remain poorly characterized. This study aims to bridge this structural–mechanistic gap by quantifying the atomic-level effects of key lithium-response polymorphisms on protein–protein interaction stability and conformational dynamics. Methods: Variant sequences for BDNF rs6265 and NR3C1 rs56149945 were generated and structurally modeled with SWISS-MODEL. Protein–protein interaction analyses focused on the BDNF–TrkB and NR3C1–FKBP5 systems. Structural alignment and conformational comparisons were performed with ChimeraX and US-align, while interaction energetics were evaluated with PRODIGY and HawkDock. Conformational flexibility was assessed using CABS-flex through RMSF analysis. Results: Structural validation showed acceptable model quality. Binding analyses indicated stronger interactions in the variant complexes. In the BDNF–TrkB complex, binding affinity shifted from −13.8 to −15.1 kcal/mol with an ~8.5-fold lower dissociation constant, while the NR3C1–FKBP5 variant complex shifted from −16.3 to −18.8 kcal/mol with an ~65-fold lower dissociation constant. MM/GBSA calculations supported increased stability, with binding energies changing from −61.98 to −83.91 kcal/mol (BDNF–TrkB) and from −18.88 to −31.25 kcal/mol (NR3C1–FKBP5). Structural superposition showed high conservation of global folds (pruned RMSD 0.779 Å and 0.310 Å; TM-scores 0.753 and 0.967). RMSF profiles were largely overlapping, indicating localized interface adjustments rather than global conformational changes. Conclusions: These findings suggest that lithium-response polymorphisms may modulate protein–protein interaction stability while preserving overall structure, providing a structural framework for exploring genetic influences on lithium treatment response. Full article

Dietary fiber (DF) has a profound influence on human health mainly by modulating the gut microbiota. This review provides an overview of DF derived from cereals, legumes, fruits, vegetables, fungi, and seaweeds, specifically addressing the relationship between microbial utilization and source-specific structural characteristics (such as linking patterns, conformation, solubility, and fermentability). Due to these structural properties, different DFs display selective microbial responses that favor fermentation and the production of short-chain fatty acids (SCFAs). These microbial responses and fermentation-derived metabolites associated with DF intake may contribute to reduced risk of obesity, diabetes, inflammatory bowel disease, and other chronic disorders. This review does not address the trial heterogeneity, dose response, safety, and conflicting evidence, and much of the available evidence is largely observational and heterogeneous. Future studies should focus on dose–response trials of defined DF structures with standardized microbiome and metabolomic endpoints, including validation in human interventions. This review summarizes the DF source and structure, selective changes in the microbiota across various study types, including in vitro, animal models, and human studies, and how these relate to overall health. Full article

Metamaterials possess unique and desirable multiphysical behaviors derived from deliberately arranging conventional materials into designed structural topologies. Multifunctional mechanical metamaterials that can both carry load and provide in situ state awareness are increasingly needed for applications such as structural health monitoring and soft robotic systems. To address the demand for multifunctional metamaterials, this study reports a scalable fabrication strategy for self-sensing lattice metamaterials by conformally dip-coating 3D-printed flexible cells with a carbon nanotube (CNT)–styrene–ethylene–butylene–styrene (SEBS) nanocomposite. Scanning electron microscopy shows that the coating conforms closely to the printed struts with well-dispersed CNT networks. The electromechanical behavior of coated Octet, Kelvin, and auxetic unit cells was characterized under quasi-static cyclic uniaxial compression (0–40% strain). All the coated structures exhibited highly stable, reversible, and repeatable piezoresistive response, with a near-linear relationship between resistance change and strain. Among the tested geometries, the auxetic unit cell achieved the highest strain sensitivity that was approximately four times that of the Octet cell and six times that of the Kelvin cell. To evaluate scalability, auxetic lattices containing eight scaled auxetic unit cells were shown to retain high sensitivity and remained statistically similar to the unit cell. This study demonstrates that the strain sensing performance of nanocomposites can be engineered through lattice topology using a simple dip-coating functionalization approach, enabling scalable self-sensing metamaterials for large-scale and conformal sensing applications. Full article

Thrombosis remains a leading cause of cardiovascular morbidity and mortality. During thrombosis, activated platelets and endothelial cells expose phosphatidylserine (PS) on their outer membranes, creating a surface that accelerates clot formation. Current antithrombotic therapies, such as heparin and warfarin, carry significant bleeding risks, highlighting the need for safer alternatives. In response, we developed a PS-targeting liposomal formulation composed of Zn-dipicolylamine (DPA)-cyanine-3[22,22] and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (molar ratio 3:97). This DPA-harboring liposome (DPAL) binds selectively to PS-rich surfaces such as activated platelets and has demonstrated efficacy in reducing thrombosis in mouse models, with minimal bleeding. In the present study, we examined the interaction of DPAL with albumin, the most abundant plasma protein and a key transporter in the bloodstream, to assess the potential for harmful protein aggregation or structural disruption. Using dynamic light scattering and intrinsic protein fluorescence, we found that, unlike warfarin and heparin, DPAL does not induce any large protein aggregates or cause significant conformational changes near the tryptophan residue when mixed with human serum albumin, suggesting a favorable interaction profile. In addition, we used transwell permeability assays and CyQUANT cell proliferation assays to assess the cytotoxicity of DPAL in cultured human umbilical vein endothelial cells (HUVECs). Our results showed that DPAL does not compromise endothelial barrier integrity in HUVEC monolayers nor the cells’ viability. Our current and previous findings together suggest that DPAL could offer a promising approach to modulate harmful coagulation pathways and provide a new targeted therapeutic strategy for managing thrombotic disorders. Full article

Although powder metallurgy (PM) is known as a near-net-shape fabrication process, a large number of PM parts need to be machined for dimensional conformance or to produce complex geometrical features that cannot be achieved through compaction. However, due mainly to the presence of porosity, the machinability of PM steels is difficult compared to that of wrought steels and can add 20% or more to the overall fabrication cost of PM parts. Among the various measures known to improve the machinability of PM steels, the addition of machining aids, either as admixed or pre-alloyed constituents, is the most popular. Manganese sulfide (MnS) is by far the most common machinability-enhancing additive used in the PM steel industry. Although it is extremely efficient in improving the machining response of PM steels, MnS is known to have detrimental effects on mechanical properties and corrosion resistance. Thus, the use of MnS involves a compromise between obtaining good machinability at the expense of lower mechanical properties and corrosion resistance. In this study, free graphite particles are introduced as a new additive that not only noticeably improves the machinability of PM steel components but also does not affect their mechanical properties or corrosion resistance. It was found that it is possible to obtain free graphite particles in press-and-sintered PM steel components by coating graphite particles with a metallic layer. This coating prevents graphite from diffusing into the iron matrix while creating metallurgical bonds with the surrounding steel matrix during sintering. In this research, graphite particles were coated with nickel and copper through a cementation process. A heat treatment was then performed on this newly developed material to obtain a more uniform single-layer coating and achieve dimensional changes during sintering that are similar to those measured when MnS is used as a machinability enhancer. The results showed that the tensile properties as well as the fatigue resistance of components made of FC-0208-type PM steel containing admixed copper/nickel-coated graphite particles are not affected by the presence of the latter. Moreover, the corrosion resistance of the samples containing copper/nickel-coated graphite was found to be the same as that of samples without the additive, which is a significant improvement on the case where MnS is used. The performance of the newly developed additive in terms of machinability was also characterized in drilling. It was found that this new additive has an identical machinability-enhancing performance to admixed MnS. Full article

Recent advances in sequencing technologies have highlighted long non-coding RNAs (lncRNAs) as key regulators that perform essential biological functions without encoding proteins. Despite growing interest, the molecular mechanisms of most lncRNAs remain poorly understood, with only a few characterized in detail. A promising strategy to elucidate these mechanisms is to explore their structure–function relationships. Such studies require advanced biophysical and biochemical methods due to the large size and structural complexity of lncRNAs. Equally important is the analysis of lncRNA interactomes, which reveal how lncRNAs engage RNA-binding proteins and other biomolecules to drive conformational and functional changes underlying diverse biological pathways. Ultimately, integrative approaches combining structural and interactome analyses will yield deeper insight into lncRNA function and uncover new therapeutic opportunities. This review highlights recent advances in elucidating lncRNA structure–function relationships by integrating biophysical, biochemical, and sequencing-based approaches to overcome challenges of size and heterogeneity, identify functional binding partners, and inform therapeutic target development. Full article

Simplified and scalable models of physical systems are extremely valuable in a variety of different engineering fields to test and diagnose particular modes of failure and optimize build conditions. In this work, we develop a practical method to prepare and analyze giant unilamellar vesicles (GUVs) for detailed biophysical interrogations. The method is rapid, scalable, and versatile, where characterization of lipid membrane conformational changes can be performed on multiplexed samples using tissue culture plates and a convenient, high-throughput fluorescence microscopy setup. The simplicity of the setup is enabled by an AI image recognition model that, when trained on the appearance of GUVs in the images, outperforms other image segmentation methods such as the watershed algorithm or the Hough transform. The method allows for the rapid quantification of entire 96-well plates containing in total O (1,000,000) GUVs and provides a potential testbed for the development of drugs. We highlight the power of our system by including large-scale data on the screening of lipophilic analogs of the small molecule antimetabolite carmofur. Full article

P-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well-established that P-gp functions through conformational changes, yet its large-scale structural dynamics at work have been unexplored. Here, we directly visualized single P-gp molecules reconstituted in nanodiscs using high-speed atomic force microscopy (HS-AFM). The HS-AFM movies revealed that P-gp is intrinsically dynamic in its apo state, with its nucleotide-binding domains (NBDs) undergoing large, spontaneous opening and closing motions. However, addition of ATP stabilized a conformation characterized by NBD proximity with a strong tendency toward closure. We then leveraged this dynamic viewpoint to elucidate the relationship between Elacridar’s function and the resulting structural dynamics of P-gp. Elacridar is designed to overcome multidrug resistance (MDR) in cancer and acts as a potent dual inhibitor of both P-gp and the Breast Cancer Resistance Protein (BCRP), effectively blocking the drug efflux function of these transporters. This inhibitor has suggested concentration-dependent function: it is effluxed as a substrate at low concentrations and acts as an inhibitor at high concentrations. Our direct observations revealed that low concentrations induced active dynamics in P-gp, whereas high concentrations severely restricted its motion, leading to a rigid, non-productive state. Our study provides critical insights into how observing molecular motion itself can unravel complex biological mechanisms. Full article

Life is defined by self-governing networks of molecules that change conformation cyclically, converting thermodynamic motion into directional work and structure. A spectrum of scale, from nanoscopic to macroscopic, involves a shift from intracellular thermodynamically driven processes (thermal agitation ultimately rooted in quantum phenomena) to intercellular bulk flows described by classical physics; from short-distance transport involving diffusion and cytoskeletal transport to long-distance pressure fluxes in hydraulic networks. A review of internal transport systems in macroscopic eukaryotes suggests that a key evolutionary step favoring large size and multicellularity involved exploiting molecular-scale stochasticity to generate organized bulk flows (e.g., motor proteins collectively generating mechanical pressures in metazoan tissues such as cardiac muscle; within tracheophytes, active and passive phloem loading/unloading inducing pressure gradients, and active regulation enabling passive xylem function and hydraulic reliability; sieve-like conduction in heterokonts; and peristaltic shuttle streaming in myxogastrian plasmodia). Macroscopic physiologies are underpinned by Brownian molecular thermodynamics and thus quantum mechanics; the apparently disparate physiologies of large organisms share a fundamental operating principle at small scales. However, the specific translocation mechanisms that extend this functioning to larger scales are embroiled in bauplans, representing phylogenetic constraints to body size. Full article