Structure-function Relationships Research Articles

Topographic correlation of microperimetry with foveal microstructure characteristics in idiopathic epiretinal membrane patients with an ectopic inner foveal layer

PurposeTo identify foveal structure-function topographic association and relationship in patients with idiopathic epiretinal membrane (ERM) related to ectopic inner foveal layer (EIFL).MethodsThis was a cross-sectional, observational study that involved 40 individuals with idiopathic ERM: 22 without EIFL (Group 1) and 18 with EIFL (Group 2). Quantitative foveal light sensitivity was measured using microperimetry, and foveal microstructure was assessed using spectral-domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA). Multiple indices of microvascular parameters of OCTA images were further processed using the AngioTool software. LASSO regression and quantile regression analyses were performed to identify the spatial distribution correlation between foveal light sensitivity and foveal microstructure parameters.ResultsGroup 2 exhibited reduced light sensitivity across all parameters of microperimetry compared to Group 1 (P < 0.001). Additionally, the central foveal thickness, the percentage of ellipsoid zone disruption, and the foveal avascular zone area were significantly lower in Group 1 than in Group 2 (all P < 0.005). Compared to Group 1, the vessel density (VD) and perfusion density of the foveal region was significantly increased in Group 2 (P < 0.001). In contrast, Group 2 showed significantly decreased VD in the parafoveal region compared with Group 1 (P < 0.05). Significant differences in OCTA parameters including ‘total number of junctions’, ‘junction density’, ‘total vessel length’, ‘average vessel length’, ‘total number of end points’ were observed between Group 1 and Group 2 (all P < 0.01). The foveal light sensitivity was significantly positively correlated with VD in the parafoveal region and negatively correlated with EIFL alteration, best-corrected visual acuity and ellipsoid zone disruption [Log(λ) = − 0.18303, λ = 0.6561].ConclusionsThe presence of EIFL and decreased VD in the parafoveal region, factors that collectively elevate the risk of disease progression, are significantly and independently correlated with reduced microperimetric retinal sensitivity in patients with idiopathic ERM.

In vitro Antileishmanial Activity and In Silico Molecular Modeling Studies of Novel Analogs of Dermaseptins S4 and B2.

Leishmaniasis is responsible for approximately 65,000 annual deaths. Various Leishmania species are the predominant cause of visceral, cutaneous, or mucocutaneous leishmaniasis, affecting millions worldwide. The lack of a vaccine, emergence of resistance, and undesirable side effects caused by antileishmanial medications have prompted researchers to look for novel therapeutic approaches to treat this disease. Antimicrobial peptides (AMPs) offer an alternative for promoting the discovery of new drugs. In this study, we detail the synthesis process and investigate the antileishmanial activity against Leishmania (Viannia) braziliensis for peptides belonging to the dermaseptin (DS) family and their synthetic analogs. The MTT assay was performed to investigate the cytotoxicity of these peptides on the murine macrophage cell line RAW 264.7. Subsequently, we performed molecular modeling analysis to explore the structure-function correlation of the derivatives interacting with the parasitic membrane. All examined derivatives displayed concentration-dependent antileishmanial effect at low concentrations. Their effectiveness varied according to the peptide's proprieties. Notably, peptides with higher levels of charge demonstrated the most pronounced activities. Cytotoxicity assays showed that all the tested peptides were not cytotoxic compared to the tested conventional drug. The structure-function relationships demonstrated that the charged N-terminus could be responsible for the antileishmanial effect observed on promastigotes. Collectively, these results propose that dermaseptins (DS) might offer potential as promising candidates for the development of effective antileishmanial therapies.

Thermoresponsive and cytocompatible infernan-based hydrogels exhibiting poroelastic properties

Thermoresponsive polymers sensitive to temperature changes are particularly well adapted for applications in tissue engineering due to their in situ sol-gel transition at physiological temperature, enabling a rapid gel formation after injection. Infernan, a bacterial exopolysaccharide (EPS) of marine origin endowed with glycosaminoglycan-mimetic properties was grafted with a thermoresponsive polymer, poly(N-isopropylacrylamide) (pNIPAM) using carbodiimide chemistry. The resulting infernan-pNIPAM polymers were shown to form thermoresponsive hydrogels at physiological temperature. Their mechanical properties determined in fully hydrated state at 37°C by Atomic Force Microscopy (AFM) through force-indentation and force-relaxation experiments revealed their poroelastic behavior. Based on AFM measurements, a set of mechanical parameters was extracted, including the elastic modulus, the solvent diffusion coefficient and the pore size. Cytocompatibility of hydrogels evaluated in 3D culture using HEK293 cells was impacted by polysaccharide amount within the hydrogel and the cross-linking density of the network. Elucidation of the structure-function relationship of infernan-pNIPAM hydrogels was essential for their further optimal use in cartilage engineering.

Mutational study of a lytic polysaccharide monooxygenase from Myceliophthora thermophila (MtLPMO9F): Structural insights into substrate specificity and regioselectivity.

Lytic polysaccharide monooxygenases (LPMOs) are key enzymes for the biotechnological exploitation of lignocellulosic biomass, yet their efficient application depends on the in-depth understanding of their mechanism of action. Here, we describe the structural and mutational characterization of a C4-active LPMO from Myceliophthora thermophila, MtLPMO9F, that belongs to auxiliary activity family 9 (AA9). MtLPMO9F is active on cellulose, cello-oligosaccharides and xyloglucan. The crystal structure of MtLPMO9F catalytic domain, determined at 2.3Å resolution, revealed a double conformation for loop L3 with a potential implication in the formation of aglycon subsites. Product analysis of reactions with cello-oligosaccharides showed a prevalent -4 to +2 binding mode. Subsequent biochemical characterization of 4 MtLPMO9F point mutants further provided insights in LPMO structure-function relationships regarding both substrate binding and the role of second-coordination sphere residues.

Structure-function relation of cytokinins determines their differential efficiency in mediating tobacco resistance against Pseudomonas syringae.

The classic plant growth-promoting phytohormone cytokinin has been identified and established as a mediator of pathogen resistance in different plant species. However, the resistance effect of structurally different cytokinins appears to vary and may regulate diverse mechanisms to establish resistance. Hence, we comparatively analysed the impact of six different adenine- and phenylurea-type cytokinins on the well-established pathosystem Nicotiana tabacum-Pseudomonas syringae. The efficiency of resistance effects was evaluated based on impacts on the host plant defence response by scoring infection symptoms and the direct impact on the pathogen by assessment of proliferation in planta. To identify common and cytokinin-specific components involved in resistance effects, transcriptome profiling and targeted metabolomics were conducted in leaves treated with the different cytokinins. We observed clearly different potentials of the tested cytokinins in either suppressing infection symptoms or pathogen proliferation. Gene regulation and metabolite analyses revealed cytokinin-type specific impacts on defence components, such as salicylic acid and related signalling, expression of PR proteins, and regulation of specialised metabolism. Cytokinins also strongly affected plant cell physiological parameters, such as a remarkable decrease in amino acid pools. Hence, this study provides comparative information on the efficiency of diverse cytokinins in mediating resistance in one well-studied pathosystem and insights into the specific regulation of resistance effects mediated by different cytokinin molecules. This is particularly relevant for studies on the function of cytokinins or other phytohormones and compounds interacting with cytokinin activities in the context of pathogen infections and other stress scenarios, considering the diverse cytokinins present in plants.

Structural Basis of Differential Gene Expression at eQTLs Loci from High-Resolution Ensemble Models of 3D Single-Cell Chromatin Conformations.

Techniques such as high-throughput chromosome conformation capture (Hi-C) have provided a wealth of information on nucleus organization and genome important for understanding gene expression regulation. Genome-Wide Association Studies (GWASs) have identified numerous loci associated with complex traits. Expression quantitative trait loci (eQTL) studies have further linked the genetic variants to alteration in expression levels of associated target genes across individuals. However, the functional roles of many eQTLs in non-coding regions remain unclear. Current joint analyses of Hi-C and eQTLs data lack advanced computational tools, limiting what can be learned from these data. We developed a computational method for simultaneous analysis of Hi-C and eQTL data, capable of identifying a small set of non-random interactions from all Hi-C interactions. Using these non-random interactions, we reconstructed large ensembles (×105) of high-resolution single-cell 3D chromatin conformations with thorough sampling, accurately replicating Hi-C measurements. Our results revealed many-body interactions in chromatin conformation at the single-cell level within eQTL loci, providing a detailed view of how 3D chromatin structures form the physical foundation for gene regulation, including how genetic variants of eQTLs affect the expression of associated eGenes. Furthermore, our method can deconvolve chromatin heterogeneity and investigate the spatial associations of eQTLs and eGenes at subpopulation level, revealing their regulatory impacts on gene expression. Together, ensemble modeling of thoroughly sampled single-cell chromatin conformations combined with eQTL data, helps decipher how 3D chromatin structures provide the physical basis for gene regulation, expression control, and aid in understanding the overall structure-function relationships of genome organization. It is available at https://github.com/uic-liang-lab/3DChromFolding-eQTL-Loci. Supplementary data are available at Bioinformatics online.

Overcoming Challenges in Plant Biomechanics: Methodological Innovations and Technological Integration.

Plant biomechanics, an emerging interdisciplinary field, plays an irreplaceable role in revealing the structure-function relationships in plant life processes. This field integrates classical mechanical theories with modern biological methods, providing novel perspectives for plant phenotype research and offering significant theoretical guidance for crop breeding, cultivation management, and ecological protection. This review comprehensively examines existing research from three dimensions: research perspectives, methodologies, and content. Using maize lodging as a case study, key scientific questions, research methods, and modeling strategies are analyzed across scales from molecular to population levels. Furthermore, this paper identifies the main challenges in plant biomechanics research, particularly in methodology development, theoretical framework refinement, model simulation, and 3D modeling. Finally, innovative directions and application prospects are explored for integrating plant biomechanics with artificial intelligence technology, multi-scale modeling, genetic improvement, and biomimetics. These research advances will pave new paths for theoretical innovation and practical applications in plant biomechanics.

The enigmatic SLC26A6 multifunctional anion transporter: recent advances in structure-function relationship, pathophysiological significance and novel pharmacological inhibitors

The enigmatic SLC26A6 multifunctional anion transporter: recent advances in structure-function relationship, pathophysiological significance and novel pharmacological inhibitors

Mechanistic studies of chondroitin sulfate/dermatan sulfate isolated from freshwater fish discards on osteogenesis in MC3T3-E1 cells.

Glycosaminoglycans (GAGs) are essential bone extracellular matrix molecules that regulate osteoblast differentiation. Numerous studies have explored endogenous and exogenous GAG osteoanabolic activities using appropriate in vitro and in vivo models. However, GAGs' underlying the mechanism of action and structure-function relationships need to be elucidated in detail. Earlier, we showed that exogenous GAG can bring about osteogenesis in pre-osteoblast cells. In the present study, we have elucidated the mechanism of action of exogenous GAGs, especially of the chondroitin sulfate/dermatan sulfate (CS/DS) class on osteogenesis. GAGs were immobilized, and osteoblast differentiation was evaluated in MC3T3-E1 cells. Results indicated that GAGs supported osteoblast differentiation by promoting collagen production, extracellular matrix formation, and subsequent mineralization. We elucidated the mechanisms underlying these effects by assessing the key signaling molecules involved in osteogenesis in response to exogenous CS/DS with/without BMP2. CS/DS alone significantly increased pERK1/2 and ATF4 expression levels differentially in a time-dependent manner without significant effects on BMP2, RUNX2, and pSMAD5 protein expression. On the other hand, CS/DS, in the presence of BMP2, differentially increased BMP2, pSMAD5, pERK1/2, RUNX2, and ATF4 expression levels at various time points. Collectively, these results strongly suggest that CS/DS can promote osteogenesis, and in the presence of BMP2, it could promote SMAD-mediated ERK-dependent osteogenesis.

Analytical method development and validation for monosaccharide profiling in Lignosus rhinocerotis using rP-HPLC

Lignosus rhinocerotis is rich in polysaccharide with diverse ­bioactivities. This study developed a pre-column derivatization reversed-phase high-performance liquid chromatography (RP-HPLC) method for analyzing monosaccharides in Lignosus rhinocerotis polysaccharides (LRP). LRP underwent hydrolysis, derivatization, and separation on a Cosmosil 5C18-MS-II column at 254 nm. Baseline separation of eight standard monosaccharides was achieved within 45 min. Calibration curves, precision, and accuracy were validated. Quantitative analysis revealed LRP as a heteropolysaccharide containing mannose, ribose, rhamnose, glucose, galactose, xylose, and arabinose, with 100.28-111.02% recovery. This optimized RP-HPLC offers a simple, reproducible, and accurate tool for LRP monosaccharides analysis, facilitating in understanding its structure-function relationship.

In-Cell Mass Spectrometry and Ultraviolet Photodissociation Navigates the Intracellular Protein Heterogeneity.

Directly probing the heterogeneous conformations of intracellular proteins within their native cellular environment remains a significant challenge in mass spectrometry (MS). Here, we establish an in-cell MS and ultraviolet photodissociation (UVPD) strategy that directly ejects proteins from living cells into a mass spectrometer, followed by 193 nm UVPD for structural analysis. Applying this approach to calmodulin (CaM), we reveal that it adopts more extended conformations within living cells compared with purified samples in vitro, highlighting the unique influence of intracellular environments on protein folding. Furthermore, UVPD analysis of calcium ion (Ca2+)-binding variants of CaM unveils not only the conformational heterogeneity induced by multiple Ca2+ modulations but also reveals distinct preferences of Ca2+ binding sites across different conformations. This strategy provides a powerful tool for interrogating the structure-function relationships of intracellular protein variants with sophisticated metal ion binding, paving the way for a deeper understanding of protein conformations within their native cellular context.

Scaled and Weighted Laplacian Matrices as Functional Descriptors for GPCR Ligands.

The G protein-coupled receptor (GPCR) pharmacology accounts for a significant field in research, clinical studies, and therapeutics. Computer-aided drug discovery is an evolving suite of techniques and methodologies that facilitate accelerated progress in drug discovery and repositioning. However, the structure-activity relationships of molecules targeting GPCRs are highly challenging in many cases since slight structural modifications can lead to drastic changes in biological functionality. Numerous molecular descriptors have been described, many of which successfully characterize the structural and physicochemical features of drug sets. Nonetheless, elucidating the structure-functionality relationships over extensive sets of drugs with multiple structural variations and known biological activity remains challenging in various biological systems. This work presents novel topological descriptors using Laplacian matrices, weighted, and scaled by atomic mass and partial charges. We tested these descriptors on three sets of GPCR ligands: muscarinic, β-adrenergic, and δ-opioid receptor ligands, evaluating their potential as functional descriptors of these receptors.

Enhancing catalytic efficiency of two microbial uricases making by directed evolution.

Uricase is a key enzyme in purine metabolism that catalyzes the oxidation of uric acid to allantoin, widely used in the treatment of hyperuricemia and gout. In this study, error-prone PCR and one high-throughput screening method were employed to generate uricase mutants with enhanced enzymatic activity from Aspergillus flavus and Candida utilis. After several rounds of mutation and selection, an A. flavus uricase mutant, af-UAM, with activity of 46.21 U/mg, and a C. utilis uricase mutant, cu-UAM, with activity of 31.43 U/mg, were obtained-representing the highest uricase activities reported up to date. Site-directed mutagenesis revealed that the Thr231Ala substitution in A. flavus uricase and the Val234Met substitution in C. utilis uricase were key factors driving their enhanced activities. Furthermore, in vivo experiments demonstrated significant clinical potential of these mutants. These findings offer new insights into the structure-function relationship of uricase and present promising candidates for therapeutic applications in hyperuricemia treatment.

Evolution beats random chance: Performance-dependent network evolution for enhanced computational capacity

The quest to understand relationships in networks across scientific disciplines has intensified. However, the optimal network architecture remains elusive, particularly for complex information processing. Therefore, we investigate how optimal and specific network structures form to efficiently solve distinct tasks using a framework of performance-dependent network evolution, leveraging reservoir computing principles. Our study demonstrates that task-specific minimal network structures obtained through this framework consistently outperform networks generated by alternative growth strategies and Erdős-Rényi random networks. Evolved networks exhibit unexpected sparsity and adhere to scaling laws in node-density space while showcasing a distinctive asymmetry in input and information readout node distribution. Consequently, we propose a heuristic for quantifying task complexity from performance-dependently evolved networks, offering valuable insights into the evolutionary dynamics of the network structure-function relationship. Our findings advance the fundamental understanding of process-specific network evolution and shed light on the design and optimization of complex information processing mechanisms, notably in machine learning. Published by the American Physical Society 2025

Cysteine S-conjugate sulfoxide β-lyase activity for human ACCS.

1-Aminocyclopropane-1-carboxylate synthase (ACCS) catalyzes the conversion of S-adenosyl-methionine to 1-aminocyclopropane-1-carboxylate (ACC), a rate-limiting step in ethylene biosynthesis. A gene encoding a putative ACCS protein was identified in the human genome two decades ago. It has been shown to not exhibit any canonical ACC synthase activity and its true function remains obscure. In this study, through a biochemical profiling approach, we demonstrate that human ACCS possesses cysteine conjugate sulfoxide β-lyase activity. This function is unexpected but reasonable, as it somewhat parallels the activity of ACCS proteins found in non-seed plants. Structure-function relationship study of human ACCS, guided by an AlphaFold2 model, allowed us to identify key active site residues that are important for its β-lyase activity. Our biochemical study of human ACCS also provided insights into the function of other mammalian ACCS homologs.

Impact of frequent ARID1A mutations on protein stability provides insights into cancer pathogenesis

The ARID1A gene, frequently mutated in cancer, encodes the AT-rich interactive domain-containing protein 1 A, a key component of the chromatin remodeling SWI/SNF complex. The ARID1A protein features a conserved DNA-binding domain (ARID domain) of approximately 100 residues crucial for its function. Despite the frequency of mutations, the impact on ARID1A’s stability and contribution to cancer progression remains unclear. We analyzed five frequent missense mutations R1020S, M1022K, K1047Q, G1063V, and A1089T identified in The Cancer Genome Atlas (TCGA) to assess their effects on the stability of the ARID domain using a hybrid experimental and computational approach. By combining computational stability from web server tools, the structural dynamics from replica exchange discrete molecular simulation (rexDMD), and thermal and chemical denaturation experiments, we found that the R1020S mutation severely decreases structural stability, making it the most impactful, while M1022K has minimal effect, and others lie in between. These findings enhance our understanding of the structural-functional relationship of ARID1A missense mutations at the molecular levels and their role in cancer pathogenesis. This research paves the way for identifying and categorizing which ARID1A mutations are most pathogenic, potentially guiding the development of targeted therapies tailored to specific mutation profiles in cancer treatment.

Polysaccharides with antioxidant activity: Extraction, beneficial roles, biological mechanisms, structure-function relationships, and future perspectives: A review.

Polysaccharides are valuable macromolecules due to their multiple bioactivities, safety, and a wide range of sources. Recently, a series of polysaccharides with antioxidant activity have been intensively reported. In this review, the latest advances in polysaccharides with antioxidant activity have been reviewed, primarily based on the investigations of polysaccharides regarding advanced extraction methods, roles in oxidative stress-related diseases, intracellular signaling pathways associated with antioxidant responses, activating pathways in the gut, structure-function relationships, and methods to improve antioxidant activity. The summarized information highlighted that much work needs to be conducted, from laboratory to industry, to understand and fully utilize the antioxidant potential of polysaccharides. Finally, future perspectives, including scaling-up of advanced extraction methods, standardizing the protocols for assessing and screening polysaccharides, bridging gaps on the biological mechanisms underlying antioxidant activity, performing clinical trials, and elucidating structure-antioxidant relationships, have been addressed. The information present in this review will be helpful to the scientific community when studying on polysaccharides with antioxidant potential and provides research directions for a better understanding of the polysaccharides and promotes their successful applications in functional foods and nutraceuticals.

Network mechanisms underlying the regional diversity of variance and time scales of the brain's spontaneous activity fluctuations.

The brain's activity fluctuations have different temporal scales across the brain regions, with associative regions displaying slower timescales than sensory areas. This so-called hierarchy of timescales has been shown to correlate with both structural brain connectivity and intrinsic regional properties. Here, using publicly available human resting-state fMRI and dMRI data it was found that, while more structurally connected brain regions presented activity fluctuations with longer timescales, their activity fluctuations presented lower variance. The opposite relationships between the structural connectivity and the variance and temporal scales of resting-state fluctuations, respectively, were not trivially explained by simple network propagation principles. To understand these structure-function relationships, two commonly used whole-brain models were studied, namely the Hopf and Wilson-Cowan models. These models use the brain's connectome to coupled local nodes (representing brain regions) displaying noise-driven oscillations. The models show that the variance and temporal scales of activity fluctuations can oppositely relate to connectivity within specific model's parameter regions, even when all nodes have the same intrinsic dynamics -but also when intrinsic dynamics are constrained by the myelinization-related macroscopic gradient. These results show that, setting aside intrinsic regional differences, connectivity and network state are sufficient to explain the regional differences in fluctuations' scales. State-dependence supports the vision that structure-function relationships can serve as biomarkers of altered brain states. Finally, the results indicate that the hierarchies of timescales and variances reflect a balance between stability and responsivity, with greater and faster responsiveness at the network periphery, while the network core ensures overall system robustness.Significance Statement Brain regions exhibit activity fluctuations at different temporal scales, with associative areas displaying slower timescales than sensory areas. This hierarchical organization is shaped by both large-scale connectivity and local properties. The present study demonstrates that the variance of fluctuations is also hierarchically organized but, in contrast to timescales, it decreases as a function of structural connectivity. Whole-brain models show that the hierarchies of timescales and variances jointly emerge within specific parameter regions, indicating a state-dependence that could serve as a biomarker for brain states and disorders. Furthermore, these hierarchies link to the responsivity of different network parts, with greater and faster responsiveness at the network periphery and more stable dynamics at the core, achieving a balance between stability and responsiveness.

Unfolding of von Willebrand Factor Type D Like Domains Promotes Mucin Adhesion.

Mucins are the macromolecular key components of mucus. On wet epithelia of mammals, mucin solutions and gels act as powerful biolubricants and reduce friction and wear by generating a sacrificial layer and establishing hydration lubrication. Yet the structure-function relationship of mucin adhesion and lubrication remains elusive. We study the adhesion behavior of mucin using atomic force microscopy-based single molecule force spectroscopy with covalently attached, lab-purified salivary MUC5B and gastric MUC5AC. We can resolve the structural motifs mediating adhesion on chemically distinct substrates, such as highly oriented pyrolytic graphite and steel. We report on force-induced partial unfolding of the von Willebrand factor type D like domains and deliver their unfolding rates and free energy barriers. These domains serve to dissipate energy during the desorption process of mucins. Partial mucin unfolding might significantly contribute to the stability of a sacrificial mucin layer during shearing processes, enhancing the lubrication potential of mucin solutions.

The Dynamics, Degradation, and Afterlives of Pectins: Influences on Cell Wall Assembly and Structure, Plant Development and Physiology, Agronomy, and Biotechnology.

Pectins underpin the assembly, molecular architecture, and physical properties of plant cell walls and through their effects on cell growth and adhesion influence many aspects of plant development. They are some of the most dynamic components of plant cell walls, and pectin remodeling and degradation by pectin-modifying enzymes can drive developmental programming via physical effects on the cell wall and the generation of oligosaccharides that can act as signaling ligands. Here, we introduce pectin structure and synthesis and discuss pectin functions in plants. We highlight recent advances in understanding the structure-function relationships of pectin-modifying enzymes and their products and how these advances point toward new approaches to bridging key knowledge gaps and manipulating pectin dynamics to control plant development. Finally, we discuss how a deeper understanding of pectin dynamics might enable innovations in agronomy and biotechnology, unlocking new benefits from these ubiquitous but complex polysaccharides.