Challenges in identifying and interpreting organizational modules in morphology

Form is a rich concept that agglutinates information about the proportions and topological arrangement of body parts. Modularity is readily measurable in both features, the variation of proportions (variational modules) and the organization of topology (organizational modules). The study of variational modularity and of organizational modularity faces similar challenges regarding the identification of meaningful modules and the validation of generative processes; however, most studies in morphology focus solely on variational modularity, while organizational modularity is much less understood. A possible cause for this bias is the successful development in the last twenty years of morphometrics, and specially geometric morphometrics, to study patters of variation. This contrasts with the lack of a similar mathematical framework to deal with patterns of organization. Recently, a new mathematical framework has been proposed to study the organization of gross anatomy using tools from Network Theory, so‐called Anatomical Network Analysis (AnNA). In this essay, I explore the potential use of this new framework—and the challenges it faces in identifying and validating biologically meaningful modules in morphological systems—by providing working examples of a complete analysis of modularity of the human skull and upper limb. Finally, I suggest further directions of research that may bridge the gap between variational and organizational modularity studies, and discuss how alternative modeling strategies of morphological systems using networks can benefit from each other

Comparison of musculoskeletal networks of the primate forelimb

Anatomical network analysis is a framework for quantitatively characterizing the topological organization of anatomical structures, thus providing a way to compare structural integration and modularity among species. Here we apply this approach to study the macroevolution of the forelimb in primates, a structure whose proportions and functions vary widely within this group. We analyzed musculoskeletal network models in 22 genera, including members of all major extant primate groups and three outgroup taxa, after an extensive literature survey and dissections. The modules of the proximal limb are largely similar among taxa, but those of the distal limb show substantial variation. Some network parameters are similar within phylogenetic groups (e.g., non-primates, strepsirrhines, New World monkeys, and hominoids). Reorganization of the modules in the hominoid hand compared to other primates may relate to functional changes such as coordination of individual digit movements, increased pronation/supination, and knuckle-walking. Surprisingly, humans are one of the few taxa we studied in which the thumb musculoskeletal structures do not form an independent anatomical module. This difference may be caused by the loss in humans of some intrinsic muscles associated with the digits or the acquisition of additional muscles that integrate the thumb more closely with surrounding structures

First anatomical network analysis of fore- and hindlimb musculoskeletal modularity in bonobos, common chimpanzees, and humans

Studies of morphological integration and modularity, and of anatomical complexity in human evolution typically focus on skeletal tissues. Here we provide the first network analysis of the musculoskeletal anatomy of both the fore- and hindlimbs of the two species of chimpanzee and humans. Contra long-accepted ideas, network analysis reveals that the hindlimb displays a pattern opposite to that of the forelimb: Pan big toe is typically seen as more independently mobile, but humans are actually the ones that have a separate module exclusively related to its movements. Different fore- vs hindlimb patterns are also seen for anatomical network complexity (i.e., complexity in the arrangement of bones and muscles). For instance, the human hindlimb is as complex as that of chimpanzees but the human forelimb is less complex than in Pan. Importantly, in contrast to the analysis of morphological integration using morphometric approaches, network analyses do not support the prediction that forelimb and hindlimb are more dissimilar in species with functionally divergent limbs such as bipedal humans

Primate modularity and evolution: first anatomical network analysis of primate head and neck musculoskeletal system

Network theory is increasingly being used to study morphological modularity and integration. Anatomical network analysis (AnNA) is a framework for quantitatively characterizing the topological organization of anatomical structures and providing an operational way to compare structural integration and modularity. Here we apply AnNA for the first time to study the macroevolution of the musculoskeletal system of the head and neck in primates and their closest living relatives, paying special attention to the evolution of structures associated with facial and vocal communication. We show that well-defined left and right facial modules are plesiomorphic for primates, while anthropoids consistently have asymmetrical facial modules that include structures of both sides, a change likely related to the ability to display more complex, asymmetrical facial expressions. However, no clear trends in network organization were found regarding the evolution of structures related to speech. Remarkably, the increase in the number of head and neck muscles – and thus of musculoskeletal structures – in human evolution led to a decrease in network density and complexity in humans

Anatomical network analysis of the musculoskeletal system reveals integration loss and parcellation boost during the fins-to-limbs transition

Tetrapods evolved from within the lobe-finned fishes around 370 Ma. The evolution of limbs from lobe-fins entailed a major re-organization of the skeletal and muscular anatomy of appendages in early tetrapods. Concurrently, a degree of similarity between pectoral and pelvic appendages also evolved. Here, we compared the anatomy of appendages in extant lobe-finned fishes (Latimeria and Neoceratodus) and anatomically plesiomorphic amphibians (Ambystoma, Salamandra) and amniotes (Sphenodon) to trace and reconstruct the musculoskeletal changes that took place during the fins-to-limbs transition. We quantified the anatomy of appendages using network analysis. First, we built network models—in which nodes represent bones and muscles, and links represent their anatomical connections—and then we measured network parameters related to their anatomical integration, heterogeneity, and modularity. Our results reveal an evolutionary transition toward less integrated, more modular appendages. We interpret this transition as a diversification of muscle functions in tetrapods compared to lobe-finned fishes. Limbs and lobe-fins show also a greater similarity between their pectoral and pelvic appendages than ray-fins do. These findings on extant species provide a basis for future quantitative and comprehensive reconstructions of the anatomy of limbs in early tetrapod fossils, and a way to better understand the fins-to-limbs transition

Structural analysis of network models in tetrapod skulls : evolutionary trends and structural constraints in morphological complexity, integration and modularity

Background Ever since classic anatomists like George Cuvier, Geoffroy St. Hilaire, or Richard Owen laid down the fundamental principles of comparative anatomy in the 19th century, connections among anatomical parts have been essential for the recognition of biological homologies. However, few studies have addressed the possibility of implementing an adequate methodological tool to use connections among parts to unveil problems in morphology; although Woodger, Rashevsky, Riedl, and, more recently, Rasskin-Gutman pointed in this direction. In the last decades Network Theory has been developed as a novel conceptual and methodological framework to deal with the relational properties that emerge due to connections between parts in any organized system (e.g., robustness, self-organization, and modularity). Network analysis was readily applied to a wide range of complex biological systems, such as gene regulatory pathways, brain neuronal systems, or ecological communities. However, a seemingly natural arena to use this mathematical tool such as comparative anatomy has never been systematically studied using current network analysis tools. Aims The aim of my thesis is to carry out a comparative analysis of connectivity patterns in tetrapod skulls to assess problems on the evolution and ontogeny of morphological complexity, integration, and modularity. This kind of analysis can reveal key morphological properties of the skull that most common studies, based solely on shape and size, would keep unravel. Empirical and theoretical outcomes of this comparative analysis of skull networks have been used to assess how connectivity patterns affect the formation and evolution of the skull morphology in tetrapods. Methods I formalize the structure of connections in the skull (i.e., connectivity pattern) using network models, in which nodes and links represent bones and suture contacts, respectively. Thereby, skull networks were built for extant and extinct species, including some human newborn skulls with different craniosynostosis conditions. These skull networks were analyzed using current network analysis methods and null models to reveal the properties of their morphological organization related to complexity, integration, and modularity. To this end, I also developed a complete framework of anatomical interpretations for the most common parameters used in networks analysis (e.g., density, clustering coefficient, and path length), which, in general, have been never applied in a morphological context. Finally, the results of skull networks analysis have been discussed in an evolutionary and developmental context. Conclusions 1. Morphological complexity increases during evolution in tetrapod skulls, due to the random loss of poorly connected bones and the selective fusion of highly connected ones. 2. The organization of connectivity modules decreases in disparity during skull evolution, due to an increase in morphological integration of connectivity patterns. 3. Bones within the same connectivity module share the same allometric growth pattern in humans; as a consequence, connectivity modules resemble units of allometric growth. 4. The analysis of network models in human skulls with craniosynostosis indicates that modifications of connectivity patterns due to premature fusion of bones have similar effects than those observed during the evolution of the tetrapod skull (e.g., changes in complexity, variations in modular organization). This further suggests a strong relation between bone fusion during development and skull evolution. 5. Tetrapod skulls have occupied the space of possible forms following a directional pattern during their evolution; from forms with more bones and higher variability available, to forms with fewer bones and lower variability. 6. The null model that better explains this directional pattern is based on structural constraints imposed by the bilateral symmetry of the skull and a growth rule to establish connections between bones based on geometric proximity (Gabriel rule)

Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures

Pseudopeptidic Macrocycles as Cooperative Minimalistic Synzyme Systems for the Remarkable Activation and Conversion of CO2 in the Presence of Chloride Anion

A series of pseudopeptidic compounds have been assayed as organocatalyts for the conversion of CO2 into organic car-bonates through a cooperative multifunctional mechanism. Conformationally constrained pseudopeptidic macrocycles 3a and 3b have revealed to be excellent synzymes for this purpose, being able to provide a suitable preorganization of the different functional elements and reaction components to activate the CO2 molecule and stabilize the different anionic intermediates involved, through a series of cooperative supramolecular interactions. As a result, remarkable catalytic efficiencies are found at low CO2 pressures and moderate temperatures, with TON and TOF values surpassing those reported for other organocatalytic supramolecular systems under similar conditions. The process works well for monosubstituted epoxides. The involvement of the different structural elements has been analyzed in detail and preliminary studies show the potential for recovering and reuse of these catalytic systems

Highly Selective Anion Template Effect in the Synthesis of Constrained Pseudopeptidic Macrocyclic Cyclophanes

Herein, we report the synthesis of a novel family of constrained pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo[3,4-f]isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Although the increase in the number of steps involved in the macrocyclization could lead to a larger number of possible side products, the optimization of the methodology and the study of the driving forces have made it possible to obtain the desired macrocycles in excellent yields. A thorough computational study has been carried out to understand the macrocyclization process, and the results obtained nicely agree with experimental data. Moreover, the bromide anion had a clear catalytic template effect in the macrocyclization reaction, and surprisingly, the chloride anion had a negative template effect in opposition to the results obtained for analogous macrocycles. The parameters responsible for the specific kinetic template effect observed have been studied in detail