Bioinstructive Liquefied Pockets in Hierarchical Hydrogels and Bioinks.

This study proposes a novel, versatile, and modular platform for constructing porous and heterogeneous microenvironments based on the embedding of liquefied-based compartments in hydrogel systems. Using a bottom-up approach, microgels carrying the necessary cargo components, including cells and microparticles, are combined with a hydrogel precursor to fabricate a hierarchical structured (HS) system. The HS system possesses three key features that can be fully independently controlled: I) liquefied pockets enabling free cellular mobility; II) surface modified microparticles facilitating 3D microtissue organization inside the liquefied pockets; III) at a larger scale, the pockets are jammed in the hydrogel, forming a macro-sized construct. After crosslinking, the embedded microgels undergo a liquefaction process, forming a porous structure that ensures high diffusion of small biomolecules and enables cells to move freely within their miniaturized compartmentalized volume. More importantly, this platform allows the creation of multimodular cellular microenvironments within a hydrogel with controlled macrostructures, while decoupling micro- and macroenvironments. As a proof of concept, the enhancement of cellular functions using the HS system by encapsulating human adipose-derived mesenchymal stem cells (hASCs) is successfully demonstrated. Finally, the potential application of this system as a hybrid bioink for bioprinting complex 3D structures is showcased.

Subcortical origin of nonlinear sound encoding in auditory cortex.

A major challenge in neuroscience is to understand how neural representations of sensory information are transformed by the network of ascending and descending connections in each sensory system. By recording from neurons at several levels of the auditory pathway, we show that much of the nonlinear encoding of complex sounds in auditory cortex can be explained by transformations in the midbrain and thalamus. Modeling cortical neurons in terms of their inputs across these subcortical populations enables their responses to be predicted with unprecedented accuracy. By contrast, subcortical responses cannot be predicted from descending cortical inputs, indicating that ascending transformations are irreversible, resulting in increasingly lossy, higher-order representations across the auditory pathway. Rather, auditory cortex selectively modulates the nonlinear aspects of thalamic auditory responses and the functional coupling between subcortical neurons without affecting the linear encoding of sound. These findings reveal the fundamental role of subcortical transformations in shaping cortical responses.

Harnessing Disparities in Magnetic Microswarms: From Construction to Collaborative Tasks.

Individual differences in size, experience, and task specialization in natural swarms often result in heterogeneity and hierarchy, facilitating efficient and coordinated task accomplishment. Drawing inspiration from this phenomenon, a general strategy is proposed for organizing magnetic micro/nanorobots (MNRs) with apparent differences in size, shape, and properties into cohesive microswarms with tunable heterogeneity, controlled spatial hierarchy, and collaborative tasking capability. In this strategy, disparate magnetic MNRs can be manipulated to show reversible transitions between synchronization and desynchronization by elaborately regulating parameter sets of the rotating magnetic field. Utilizing these transitions, alongside local robust hydrodynamic interactions, diverse heterospecific pairings of disparate magnetic MNRs can be organized into heterogeneous microswarms, and their spatial organization can be dynamically adjusted from egalitarian to leader-follower-like hierarchies on the fly, both in open space and complex microchannels. Furthermore, when specializing the disparate MNRs with distinct functions ("division of labor") such as sensing and drug carrying, they can execute precise drug delivery targeting unknown sites in a collaborative sensing-navigating-cargo dropping sequence, demonstrating significant potential for precise tumor treatment. These findings highlight the critical roles of attribute differences and hierarchical organization in designing efficient swarming micro/nanorobots for biomedical applications.

Urea as hydrogelator of surfactants.

HYPOTHESIS: The formation of adducts via urea interaction with distinct classes of surfactants (cationic, anionic, nonionic, and zwitterionic), leading to their assembly into lamellar structures and subsequent formation of hydrogels. The characteristics of these hydrogels are associated with both, the length of the alkyl chain, and the specific head group of the surfactant molecules. EXPERIMENTS: Characterization of adduct formation was conducted using Wide-Angle X-ray Scattering (WAXS), while Small-Angle X-ray Scattering (SAXS) was employed to probe the subsequent assembly into lamellar structures. The kinetics of hydrogel formation were assessed through rheological measurements and observed thermal transitions utilizing Differential Scanning Calorimetry (DSC). FINDINGS: The investigation revealed a universal propensity for hydrogel formation across all surfactant classes. The formation arises from the interactions between urea molecules via hydrogen bonding, forming adducts around the surfactant chains. In sequence, the adducts self-assemble in lamellae. This process constructs the intricate three-dimensional network characteristic of the hydrogel. Furthermore, the kinetics of hydrogel formation, and their rheological properties under equilibrated conditions, were found to be significantly influenced by the nature of the polar head group of the surfactant molecules. This is the first evidence on the formation of adducts of urea with classes of surfactants. As they are common components in cosmetic, supramolecular hydrogels have high potential to be used in formulations.

Genome structural dynamics: insights from Gaussian network analysis of Hi-C data.

Characterization of the spatiotemporal properties of the chromatin is essential to gaining insights into the physical bases of gene co-expression, transcriptional regulation and epigenetic modifications. The Gaussian network model (GNM) has proven in recent work to serve as a useful tool for modeling chromatin structural dynamics, using as input high-throughput chromosome conformation capture data. We focus here on the exploration of the collective dynamics of chromosomal structures at hierarchical levels of resolution, from single gene loci to topologically associating domains or entire chromosomes. The GNM permits us to identify long-range interactions between gene loci, shedding light on the role of cross-correlations between distal regions of the chromosomes in regulating gene expression. Notably, GNM analysis performed across diverse cell lines highlights the conservation of the global/cooperative movements of the chromatin across different types of cells. Variations driven by localized couplings between genomic loci, on the other hand, underlie cell differentiation, underscoring the significance of the four-dimensional properties of the genome in defining cellular identity. Finally, we demonstrate the close relation between the cell type-dependent mobility profiles of gene loci and their gene expression patterns, providing a clear demonstration of the role of chromosomal 4D features in defining cell-specific differential expression of genes.

Role of middle managers in dealing with hierarchy and network logics: exploration in the context of Sino-Foreign Cooperative University.

While organizations tend to introduce network mechanism to activate the potential of members in the hierarchical dominated context, it is not clear how individual members deal with the complexity caused by two logics of hierarchy and network. To address this gap, this study focuses on the role of middle managers in collaborating with others in the multiple-logic complexity. We identify three types of collaboration scenarios, top-down, bottom-up, and horizontal, through 27 semi-structured interviews within a Sino-Foreign Cooperative University from 2021 to 2023. Guided by the grounded theory approach, we conceptualize the composite role of middle managers as the translucent hand of explicit and implicit connections, which help us to interpret middle managers' tangibly and intangibly impact under a hybrid organization context. The empirical results also reveal that the boundary perception of authority and responsibility as an important factor determines middle managers' awareness of power involvement in cooperation. The findings extend the understanding of middle managers in network organizations in the higher education context and provide suggestions for the dynamic role of middle managers and hybrid university management in the information age.

Compressed cerebellar functional connectome hierarchy in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an inherited movement disorder characterized by a progressive decline in motor coordination. Despite the extensive functional connectivity (FC) alterations reported in previous SCA3 studies in the cerebellum and cerebellar-cerebral pathways, the influence of these FC disturbances on the hierarchical organization of cerebellar functional regions remains unclear. Here, we compared 35 SCA3 patients with 48 age- and sex-matched healthy controls using a combination of voxel-based morphometry and resting-state functional magnetic resonance imaging to investigate whether cerebellar hierarchical organization is altered in SCA3. Utilizing connectome gradients, we identified the gradient axis of cerebellar hierarchical organization, spanning sensorimotor to transmodal (task-unfocused) regions. Compared to healthy controls, SCA3 patients showed a compressed hierarchical organization in the cerebellum at both voxel-level (p < .05, TFCE corrected) and network-level (p < .05, FDR corrected). This pattern was observed in both intra-cerebellar and cerebellar-cerebral gradients. We observed that decreased intra-cerebellar gradient scores in bilateral Crus I/II both negatively correlated with SARA scores (left/right Crus I/II: r = -.48/-.50, p = .04/.04, FDR corrected), while increased cerebellar-cerebral gradients scores in the vermis showed a positive correlation with disease duration (r = .48, p = .04, FDR corrected). Control analyses of cerebellar gray matter atrophy revealed that gradient alterations were associated with cerebellar volume loss. Further FC analysis showed increased functional connectivity in both unimodal and transmodal areas, potentially supporting the disrupted cerebellar functional hierarchy uncovered by the gradients. Our findings provide novel evidence regarding alterations in the cerebellar functional hierarchy in SCA3.

Ordered hierarchical superlattice amplifies coated-CeO2 nanoparticles luminescence.

Achieving a controlled preparation of nanoparticle superstructures with spatially periodic arrangement, also called superlattices, is one of the most intriguing and open questions in soft matter science. The interest in such regular superlattices originates from the potentialities in tailoring the physicochemical properties of the individual constituent nanoparticles, eventually leading to emerging behaviors and/or functionalities that are not exhibited by the initial building blocks. Despite progress, it is currently difficult to obtain such ordered structures; the influence of parameters, such as size, softness, interaction potentials, and entropy, are neither fully understood yet and not sufficiently studied for 3D systems. In this work, we describe the synthesis and characterization of spatially ordered hierarchical structures of coated cerium oxide nanoparticles in water suspension prepared by a bottom-up approach. Covering the CeO2 surface with amphiphilic molecules having chains of appropriate length makes it possible to form ordered structures in which the particles occupy well-defined positions. In the present case superlattice arrangement is accompanied by an improvement in photoluminescence (PL) efficiency, as an increase in PL intensity of the superlattice structure of up to 400 % compared with that of randomly dispersed nanoparticles was observed. To the best of our knowledge, this is one of the first works in the literature in which the coexistence of 3D structures in solution, such as face-centered cubic (FCC) and Frank-Kasper (FK) phases, of semiconductor nanoparticles have been related to their optical properties.

Microplotter Printing of a Miniature Flexible Supercapacitor Electrode Based on Hierarchically Organized NiCo2O4 Nanostructures.

The hydrothermal synthesis of a nanosized NiCo2O4 oxide with several levels of hierarchical self-organization was studied. Using X-ray diffraction analysis (XRD) and Fourier-transform infrared (FTIR) spectroscopy, it was determined that under the selected synthesis conditions, a nickel-cobalt carbonate hydroxide hydrate of the composition M(CO3)0.5(OH)·0.11H2O (where M-Ni2+ and Co2+) is formed as a semi-product. The conditions of semi-product transformation into the target oxide were determined by simultaneous thermal analysis. It was found by means of scanning electron microscopy (SEM) that the main powder fraction consists of hierarchically organized microspheres of 3-10 µm in diameter, and individual nanorods are observed as the second fraction of the powder. Nanorod microstructure was further studied by transmission electron microscopy (TEM). A hierarchically organized NiCo2O4 film was printed on the surface of a flexible carbon paper (CP) using an optimized microplotter printing technique and functional inks based on the obtained oxide powder. It was shown by XRD, TEM, and atomic force microscopy (AFM) that the crystalline structure and microstructural features of the oxide particles are preserved when deposited on the surface of the flexible substrate. It was found that the obtained electrode sample is characterized by a specific capacitance value of 420 F/g at a current density of 1 A/g, and the capacitance loss during 2000 charge-discharge cycles at 10 A/g is 10%, which indicates a high material stability. It was established that the proposed synthesis and printing technology enables the efficient automated formation of corresponding miniature electrode nanostructures as promising components for flexible planar supercapacitors.

The hierarchical organization of the precuneus captured by functional gradients.

The precuneus shows considerable heterogeneity in multiple dimensions including anatomy, function, and involvement in brain disorders. Leveraging the state-of-the-art functional gradient approach, we aimed to investigate the hierarchical organization of the precuneus, which may hold promise for a unified understanding of precuneus heterogeneity. Resting-state functional MRI data from 793 healthy individuals were used to discover and validate functional gradients of the precuneus, which were calculated based on the voxel-wise precuneus-to-cerebrum functional connectivity patterns. Then, we further explored the potential relationships of the precuneus functional gradients with cortical morphology, intrinsic geometry, canonical functional networks, and behavioral domains. We found that the precuneus principal and secondary gradients showed dorsoanterior-ventral and ventroposterior-dorsal organizations, respectively. Concurrently, the principal gradient was associated with cortical morphology, and both the principal and secondary gradients showed geometric distance dependence. Importantly, precuneus functional subdivisions corresponding to canonical functional networks (behavioral domains) were distributed along both gradients in a hierarchical manner, i.e., from the sensorimotor network (somatic movement and sensation) at one extreme to the default mode network (abstract cognitive functions) at the other extreme for the principal gradient and from the visual network (vision) at one end to the dorsal attention network (top-down control of attention) at the other end for the secondary gradient. These findings suggest that the precuneus functional gradients may provide mechanistic insights into the multifaceted nature of precuneus heterogeneity.

Organizing principles of astrocytic nanoarchitecture in the mouse cerebral cortex.

Astrocytes are increasingly understood to be important regulators of central nervous system (CNS) function in health and disease; yet, we have little quantitative understanding of their complex architecture. While broad categories of astrocytic structures are known, the discrete building blocks that compose them, along with their geometry and organizing principles, are poorly understood. Quantitative investigation of astrocytic complexity is impeded by the absence of high-resolution datasets and robust computational approaches to analyze these intricate cells. To address this, we produced four ultra-high-resolution datasets of mouse cerebral cortex using serial electron microscopy and developed astrocyte-tailored computer vision methods for accurate structural analysis. We unearthed specific anatomical building blocks, structural motifs, connectivity hubs, and hierarchical organizations of astrocytes. Furthermore, we found that astrocytes interact with discrete clusters of synapses and that astrocytic mitochondria are distributed to lie closer to larger clusters of synapses. Our findings provide a geometrically principled, quantitative understanding of astrocytic nanoarchitecture and point to an unexpected level of complexity in how astrocytes interact with CNS microanatomy.

Functional hierarchy of the angular gyrus and its underlying genetic architecture.

The angular gyrus (AG), given its rich connectivity and its location where multisensory information converges, is a functionally and anatomically heterogeneous structure. Using the state-of-the-art functional gradient approach and transcription-neuroimaging association analysis, we sought to determine whether there is an overarching hierarchical organization of the AG and if so, how it is modulated by the underlying genetic architecture. Resting-state functional MRI data of 793 healthy subjects were obtained from discovery and validation datasets. Functional gradients of the AG were calculated based on the voxel-wise AG-to-cerebrum functional connectivity patterns. Combined with the Allen Human Brain Atlas, we examined the spatial correlations between the AG functional gradient and gene expression. The dominant gradient topography showed a dorsoanterior-ventroposterior hierarchical organization of the AG, which was related to its intrinsic geometry. Concurrently, AG functional subdivisions corresponding to canonical functional networks (behavioral domains) were distributed along the dominant gradient in a hierarchical manner, that is, from the default mode network (abstract cognition) at one extreme to the visual and sensorimotor networks (perception and action) at the other extreme. Remarkably, we established a link between the AG dominant gradient and gene expression, with two gene sets strongly contributing to this link but diverging on their functional annotation and specific expression. Our findings represent a significant conceptual advance in AG functional organization, and may introduce novel approaches and testable questions to the investigation of AG function and anatomy in health and disease.

Functional connectivity gradients of the insula to different cerebral systems.

The diverse functional roles of the insula may emerge from its heavy connectivity to an extensive network of cortical and subcortical areas. Despite several previous attempts to investigate the hierarchical organization of the insula by applying the recently developed gradient approach to insula-to-whole brain connectivity data, little is known about whether and how there is variability across connectivity gradients of the insula to different cerebral systems. Resting-state functional MRI data from 793 healthy subjects were used to discover and validate functional connectivity gradients of the insula, which were computed based on its voxel-wise functional connectivity profiles to distinct cerebral systems. We identified three primary patterns of functional connectivity gradients of the insula to distinct cerebral systems. The connectivity gradients to the higher-order transmodal associative systems, including the prefrontal, posterior parietal, temporal cortices, and limbic lobule, showed a ventroanterior-dorsal axis across the insula; those to the lower-order unimodal primary systems, including the motor, somatosensory, and occipital cortices, displayed radiating transitions from dorsoanterior toward both ventroanterior and dorsoposterior parts of the insula; the connectivity gradient to the subcortical nuclei exhibited an organization along the anterior-posterior axis of the insula. Apart from complementing and extending previous literature on the heterogeneous connectivity patterns of insula subregions, the presented framework may offer ample opportunities to refine our understanding of the role of the insula in many brain disorders.

Spatial Distribution and Hierarchical Clustering of ß-Amyloid and Glucose Metabolism in Alzheimer's Disease.

Increased amyloid burden and decreased glucose metabolism are important characteristics of Alzheimer's disease (AD), but their spatial distribution and hierarchical clustering organization are still poorly understood. In this study, we explored the distribution and clustering organization of amyloid and glucose metabolism based on 18F-florbetapir and 18F-fluorodeoxyglucose PET data from 68 AD patients and 20 cognitively normal individuals. We found that: (i) cortical regions with highest florbetapir binding were the regions with high glucose metabolism; (ii) the percentage changes of amyloid deposition were greatest in the frontal and temporal areas, and the hypometabolism was greatest in the parietal and temporal areas; (iii) brain areas can be divided into three hierarchical clusters by amyloid and into five clusters by metabolism using a hierarchical clustering approach, indicating that adjacent regions are more likely to be grouped into one sub-network; and (iv) there was a significant positive correlation in any pair of amyloid-amyloid and metabolism-metabolism sub-networks, and a significant negative correlation in amyloid-metabolism sub-networks. This may suggest that the influence forms and brain regions of AD on different pathological markers may not be synchronous, but they are closely related.

The nervous system as a solution for implementing closed negative feedback control loops.

Behavior can be regarded as the output of a system (action), as a function linking stimulus to response (reaction), or as an abstraction of the bidirectional relationship between the environment and the organism (interaction). When considering the latter possibility, a relevant question arises concerning how an organism can materially and continuously implement such a relationship during its lifetime in order to perpetuate itself. The feedback control approach has taken up the task of answering just that question. During the last several decades, said approach has been progressing and has started to be recognized as a paradigm shift, superseding certain canonical notions in mainstream behavior analysis, cognitive psychology, and even neuroscience. In this paper, we describe the main features of feedback control theory and its associated techniques, concentrating on its critiques of behavior analysis, as well as the commonalities they share. While some of feedback control theory's major critiques of behavior analysis arise from the fact that they focus on different levels of organization, we believe that some are legitimate and meaningful. Moreover, feedback control theory seems to blend with neurobiology more smoothly as compared to canonical behavior analysis, which only subsists in a scattered handful of fields. If this paradigm shift truly takes place, behavior analysts-whether they accept or reject this new currency-should be mindful of the basics of the feedback control approach.

Evaporation-Driven Coassembly of Hierarchical, Multicomponent Networks.

Self-assembly is an increasingly popular approach to systematically control the formation of complex, multicomponent materials with structural features orders of magnitude larger than the constituent colloidal nanocrystals. Common approaches often involve templating via prefabricated patterns to control particle organization- or programming-specific interactions between individual building blocks. While effective, such fabrication methods suffer from major bottlenecks due to the complexity required in mask creation for patterning or surface modification techniques needed to program directed interactions between particles. Here, we propose an alternative strategy that aims to bypass such limitations. First, we design a ligand structure that can bridge two distinct nanocrystal types. Then, by leveraging the solvent's evaporative dynamics to drive particle organization, we direct a cross-linked, multicomponent system of nanocrystals to organize hierarchically into ordered, open-network structures with domain sizes orders of magnitude larger than the constituent building blocks. We employ simulation and theory to rationalize the driving forces governing this evaporation-driven process, showing excellent agreement across theory, simulations, and experiments. These results suggest that evaporation-driven organization can be a powerful approach to designing and fabricating hierarchical, multifunctional materials.

Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy.

Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at birth, with pathological remodeling developing over years to decades, leading to a phenotype characterized by asymmetric ventricular hypertrophy, scattered fibrosis and myofibrillar/cellular disarray with ultimate mechanical heart failure and/or severe arrhythmias. The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. However, other ideas that mutation-induced hypocontractility or non-uniformities with contractile instabilities, instead, constitute primary triggers cannot yet be discarded. Here, we review evidence for and criticism against the mentioned hypotheses. In this process, we find support for previous ideas that inefficient energy usage and a blunted Frank-Starling mechanism have central roles in pathogenesis, although presumably representing effects secondary to the primary mutation-induced changes. While first trying to reconcile apparently diverging evidence for the different hypotheses in one unified model, we also identify key remaining questions and suggest how experimental systems that are built around isolated primarily expressed proteins could be useful.

Hierarchical organization of bone in three dimensions: A twist of twists.

Structural hierarchy of bone - observed across multiple scales and in three dimensions (3D) - is essential to its mechanical performance. While the mineralized extracellular matrix of bone consists predominantly of carbonate-substituted hydroxyapatite, type I collagen fibrils, water, and noncollagenous organic constituents (mainly proteins and small proteoglycans), it is largely the 3D arrangement of these inorganic and organic constituents at each length scale that endow bone with its exceptional mechanical properties. Focusing on recent volumetric imaging studies of bone at each of these scales - from the level of individual mineralized collagen fibrils to that of whole bones - this graphical review builds upon and re-emphasizes the original work of James Bell Pettigrew and D'Arcy Thompson who first described the ubiquity of spiral structure in Nature. Here we illustrate and discuss the omnipresence of twisted, curved, sinusoidal, coiled, spiraling, and braided motifs in bone in at least nine of its twelve hierarchical levels - a visualization undertaking that has not been possible until recently with advances in 3D imaging technologies (previous 2D imaging does not provide this information). From this perspective, we hypothesize that the twisting motif occurring across each hierarchical level of bone is directly linked to enhancement of function, rather than being simply an energetically favorable way to assemble mineralized matrix components. We propose that attentive consideration of twists in bone and the skeleton at different scales will likely develop, and will enhance our understanding of structure-function relationships in bone.

Efficient coding in the economics of human brain connectomics.

In systems neuroscience, most models posit that brain regions communicate information under constraints of efficiency. Yet, evidence for efficient communication in structural brain networks characterized by hierarchical organization and highly connected hubs remains sparse. The principle of efficient coding proposes that the brain transmits maximal information in a metabolically economical or compressed form to improve future behavior. To determine how structural connectivity supports efficient coding, we develop a theory specifying minimum rates of message transmission between brain regions to achieve an expected fidelity, and we test five predictions from the theory based on random walk communication dynamics. In doing so, we introduce the metric of compression efficiency, which quantifies the trade-off between lossy compression and transmission fidelity in structural networks. In a large sample of youth (n = 1,042; age 8-23 years), we analyze structural networks derived from diffusion-weighted imaging and metabolic expenditure operationalized using cerebral blood flow. We show that structural networks strike compression efficiency trade-offs consistent with theoretical predictions. We find that compression efficiency prioritizes fidelity with development, heightens when metabolic resources and myelination guide communication, explains advantages of hierarchical organization, links higher input fidelity to disproportionate areal expansion, and shows that hubs integrate information by lossy compression. Lastly, compression efficiency is predictive of behavior-beyond the conventional network efficiency metric-for cognitive domains including executive function, memory, complex reasoning, and social cognition. Our findings elucidate how macroscale connectivity supports efficient coding and serve to foreground communication processes that utilize random walk dynamics constrained by network connectivity.

A study of a hierarchical structure of proteins and ligand binding sites of receptors using the triangular spatial relationship-based structure comparison method and development of a size-filtering feature designed for comparing different sizes of protein structures.

The presence of receptors and the specific binding of the ligands determine nearly all cellular responses. Binding of a ligand to its receptor causes conformational changes of the receptor that triggers the subsequent signaling cascade. Therefore, systematically studying structures of receptors will provide insight into their functions. We have developed the triangular spatial relationship (TSR)-based method where all possible triangles are constructed with Cα atoms of a protein as vertices. Every triangle is represented by an integer denoted as a "key" computed through the TSR algorithm. A structure is thereby represented by a vector of integers. In this study, we have first defined substructures using different types of keys. Second, using different types of keys represents a new way to interpret structure hierarchical relations and differences between structures and sequences. Third, we demonstrate the effects of sequence similarity as well as sample size on the structure-based classifications. Fourth, we show identification of structure motifs, and the motifs containing multiple triangles connected by either an edge or a vertex are mapped to the ligand binding sites of the receptors. The structure motifs are valuable resources for the researchers in the field of signal transduction. Next, we propose amino-acid scoring matrices that capture "evolutionary closeness" information based on BLOSUM62 matrix, and present the development of a new visualization method where keys are organized according to evolutionary closeness and shown in a 2D image. This new visualization opens a window for developing tools with the aim of identification of specific and common substructures by scanning pixels and neighboring pixels. Finally, we report a new algorithm called as size filtering that is designed to improve structure comparison of large proteins with small proteins. Collectively, we provide an in-depth interpretation of structure relations through the detailed analyses of different types of keys and their associated key occurrence frequencies, geometries, and labels. In summary, we consider this study as a new computational platform where keys are served as a bridge to connect sequence and structure as well as structure and function for a deep understanding of sequence, structure, and function relationships of the protein family.