Muscle activity during crouched walking.

OBJECTIVES: Muscle activity during crouched walking has been previously studied in the context of the evolution of hominin bipedalism and human movement disorders. However, crouched walking could also be used in approach hunting where postural height (actual height of the body from the ground to the top of the head during locomotion) is the limiting factor. Here, we aim to analyze the relationship between relative postural height (%stature), kinematics, and muscle activity during crouched walking. MATERIALS AND METHODS: Adult males (n = 19) walked with extended limbs and at three degrees of crouch while their 3D motion capture kinematics and lower limb muscle electromyography were recorded. We measured activation of tibialis anterior, soleus, gastrocnemius medialis, gastrocnemius lateralis, vastus lateralis, rectus femoris, biceps femoris, and gluteus maximus. We analyzed the effects of postural height on kinematics and muscle activation using linear mixed effects model. RESULTS: Flexion angles, individual muscle activation (except for medial gastrocnemius), and total muscle activation were negatively related to relative postural height, that is, were greater at more crouched postures. Relative postural height had a stronger effect on the activation of the thigh and gluteal muscles compared to shank muscles. DISCUSSION: General increase in lower limb muscle activation at lower postural heights suggests a negative relationship between relative postural height and fatigue, and may indicate a possible mechanism by which short stature could benefit the hunter in approach hunting. Greater activation of thigh and gluteal muscles relative to shank muscles may help to identify crouched walking in past human populations.

How E-, L-, and P-Selectins Bind to sLex and PSGL-1: A Quantification of Critical Residue Interactions.

Selectins and their ability to interact with specific ligands are a cornerstone in cell communication. Over the last three decades, a considerable wealth of experimental and molecular modeling insights into their structure and modus operandi were gathered. Nonetheless, explaining the role of individual selectin residues on a quantitative level remained elusive, despite its importance in understanding the structure-function relationship in these molecules and designing their inhibitors. This work explores essential interactions of selectin-ligand binding, employing a multiscale approach that combines molecular dynamics, quantum-chemical calculations, and residue interaction network models. Such an approach successfully reproduces most of the experimental findings. It proves to be helpful, with the potential for becoming an established tool for quantitative predictions of residue contribution to the binding of biomolecular complexes. The results empower us to quantify the importance of particular residues and functional groups in the protein-ligand interface and to pinpoint differences in molecular recognition by the three selectins. We show that mutations in the E-, L-, and P-selectins, e.g., different residues in positions 46, 85, 97, and 107, present a crucial difference in how the ligand is engaged. We assess the role of sulfation of tyrosine residues in PSGL-1 and suggest that TyrSO3- in position 51 interacting with Arg85 in P-selectin is a significant factor in the increased affinity of P-selectin to PSGL-1 compared to E- and L-selectins. We propose an original pharmacophore targeting five essential PSGL-binding sites based on the analysis of the selectin···PSGL-1 interactions.

The Importance of Charge Transfer and Solvent Screening in the Interactions of Backbones and Functional Groups in Amino Acid Residues and Nucleotides.

Quantum mechanical (QM) calculations at the level of density-functional tight-binding are applied to a protein-DNA complex (PDB: 2o8b) consisting of 3763 atoms, averaging 100 snapshots from molecular dynamics simulations. A detailed comparison of QM and force field (Amber) results is presented. It is shown that, when solvent screening is taken into account, the contributions of the backbones are small, and the binding of nucleotides in the double helix is governed by the base-base interactions. On the other hand, the backbones can make a substantial contribution to the binding of amino acid residues to nucleotides and other residues. The effect of charge transfer on the interactions is also analyzed, revealing that the actual charge of nucleotides and amino acid residues can differ by as much as 6 and 8% from the formal integer charge, respectively. The effect of interactions on topological models (protein -residue networks) is elucidated.

Comparing walking and running in persistence hunting.

It has been proposed that humans' exceptional locomotor endurance evolved partly with foraging in hot open habitats and subsequently about 2 million years ago with persistence hunting, for which endurance running was instrumental. However, persistence hunting by walking, if successful, could select for locomotor endurance even before the emergence of any running-related traits in human evolution. Using a heat exchange model validated here in 73 humans and 55 ungulates, we simulated persistence hunts for prey of three sizes (100, 250, and 400 kg) and three sweating capacities (nonsweating, low, high) at 6237 combinations of hunter's velocity (1-5 m s-1, intermittent), air temperature (25-45 °C), relative humidity (30-90%), and start time (8:00-16:00). Our simulations predicted that walking would be successful in persistence hunting of low- and nonsweating prey, especially under hot and humid conditions. However, simulated persistence hunts by walking yielded a 30-74% lower success rate than hunts by running or intermittent running. In addition, despite requiring 10-30% less energy, successful simulated persistence hunts by walking were twice as long and resulted in greater exhaustion of the hunter than hunts by running and intermittent running. These shortcomings of pursuit by walking compared to running identified in our simulations could explain why there is only a single direct description of persistence hunting by walking among modern hunter-gatherers. Nevertheless, walking down prey could be a viable option for hominins who did not possess the endurance-running phenotype of the proposed first persistence hunter, Homo erectus. Our simulation results suggest that persistence hunting could select for both long-distance walking and endurance running and contribute to the evolution of locomotor endurance seen in modern humans.

Semi-Infinite Structure Analysis with Bimodular Materials with Infinite Element.

The modulus of elasticity of some materials changes under tensile and compressive states is simulated by constructing a typical material nonlinearity in a numerical analysis in this paper. The meshless Finite Block Method (FBM) has been developed to deal with 3D semi-infinite structures in the bimodular materials in this paper. The Lagrange polynomial interpolation is utilized to construct the meshless shape function with the mapping technique to transform the irregular finite domain or semi-infinite physical solids into a normalized domain. A shear modulus strategy is developed to present the nonlinear characteristics of bimodular material. In order to verify the efficiency and accuracy of FBM, the numerical results are compared with both analytical and numerical solutions provided by Finite Element Method (FEM) in four examples.

Residue Folding Degree-Relationship to Secondary Structure Categories and Use as Collective Variable.

Recently, we have shown that the residue folding degree, a network-based measure of folded content in proteins, is able to capture backbone conformational transitions related to the formation of secondary structures in molecular dynamics (MD) simulations. In this work, we focus primarily on developing a collective variable (CV) for MD based on this residue-bound parameter to be able to trace the evolution of secondary structure in segments of the protein. We show that this CV can do just that and that the related energy profiles (potentials of mean force, PMF) and transition barriers are comparable to those found by others for particular events in the folding process of the model mini protein Trp-cage. Hence, we conclude that the relative segment folding degree (the newly proposed CV) is a computationally viable option to gain insight into the formation of secondary structures in protein dynamics. We also show that this CV can be directly used as a measure of the amount of α-helical content in a selected segment.

Geometrical Nonlinearity for a Timoshenko Beam with Flexoelectricity.

The Timoshenko beam model is applied to the analysis of the flexoelectric effect for a cantilever beam under large deformations. The geometric nonlinearity with von Kármán strains is considered. The nonlinear system of ordinary differential equations (ODE) for beam deflection and rotation are derived. Moreover, this nonlinear system is linearized for each load increment, where it is solved iteratively. For the vanishing flexoelectric coefficient, the governing equations lead to the classical Timoshenko beam model. Furthermore, the influence of the flexoelectricity coefficient and the microstructural length-scale parameter on the beam deflection and the induced electric intensity is investigated.

The Effect of Micro-Inertia and Flexoelectricity on Love Wave Propagation in Layered Piezoelectric Structures.

The non-classical linear governing equations of strain gradient piezoelectricity with micro-inertia effect are used to investigate Love wave propagation in a layered piezoelectric structure. The influence of flexoelectricity and micro-inertia effect on the phase wave velocity in a thin homogeneous flexoelectric layer deposited on a piezoelectric substrate is investigated. The dispersion relation for Love waves is obtained. The phase velocity is numerically calculated and graphically illustrated for the electric open-circuit and short-circuit conditions and for distinct material properties of the layer and substrate. The influence of direct flexoelectricity, micro-inertia effect, as well as the layer thickness on Love wave propagation is studied individually. It is found that flexoelectricity increases the Love-wave phase velocity, while the micro-inertia effect reduces its value. These effects become more significant for Love waves with shorter wavelengths and small guiding layer thicknesses.

Influence of upper limb training and analyzed muscles on estimate of physical activity during cereal grinding using saddle quern and rotary quern.

Experimental grinding has been used to study the relationship between human humeral robusticity and cereal grinding in the early Holocene. However, such replication studies raise two questions regarding the robusticity of the results: whether female nonathletes used in previous research are sufficiently comparable to early agricultural females, and whether previous analysis of muscle activation of only four upper limb muscles is sufficient to capture the stress of cereal grinding on upper limb bones. We test the influence of both of these factors. Electromyographic activity of eight upper limb muscles was recorded during cereal grinding in an athletic sample of 10 female rowers and in 25 female nonathletes and analyzed using both an eight- and four-muscle model. Athletes had lower activation than nonathletes in the majority of measured muscles, but except for posterior deltoid these differences were non-significant. Furthermore, both athletes and nonathletes had lower muscle activation during saddle quern grinding than rotary quern grinding suggesting that the nonathletes can be used to model early agricultural females during saddle and rotary quern grinding. Similarly, in both eight- and four-muscle models, upper limb loading was lower during saddle quern grinding than during rotary quern grinding, suggesting that the upper limb muscles may be reduced to the previously used four-muscle model for evaluation of the upper limb loading during cereal grinding. Another implication of our measurements is to question the assumption that skeletal indicators of high involvement of the biceps brachii muscle can be interpreted as specifically indicative of saddle quern grinding.

pyProGA-A PyMOL plugin for protein residue network analysis.

The field of protein residue network (PRN) research has brought several useful methods and techniques for structural analysis of proteins and protein complexes. Many of these are ripe and ready to be used by the proteomics community outside of the PRN specialists. In this paper we present software which collects an ensemble of (network) methods tailored towards the analysis of protein-protein interactions (PPI) and/or interactions of proteins with ligands of other type, e.g. nucleic acids, oligosaccharides etc. In parallel, we propose the use of the network differential analysis as a method to identify residues mediating key interactions between proteins. We use a model system, to show that in combination with other, already published methods, also included in pyProGA, it can be used to make such predictions. Such extended repertoire of methods allows to cross-check predictions with other methods as well, as we show here. In addition, the possibility to construct PRN models from various kinds of input is so far a unique asset of our code. One can use structural data as defined in PDB files and/or from data on residue pair interaction energies, either from force-field parameters or fragment molecular orbital (FMO) calculations. pyProGA is a free open-source software available from https://gitlab.com/Vlado_S/pyproga.

Challenging definitions and diagnostic approaches for ancient rare diseases: The case of poliomyelitis.

OBJECTIVE: This paper aims to contribute to the definition of ancient rare diseases in skeletons displaying pathologies associated with paralysis. It uses a new suite of methods, which can be applied to challenging cases of possible paralysis in archaeologically-derived human skeletal material, specifically applied to the identification of poliomyelitis. MATERIALS: An adult male skeleton from Roman Halbturn, Austria. METHODS: Morphological and entheseal change analyses, CT scans, X-rays, cross-section morphology, and histology, alongside modern clinical, as well as historic, literature were used to discuss paralyses. RESULTS: The results suggest a diagnosis of poliomyelitis; now considered a rare disease, but perhaps ubiquitous in antiquity, thus complicating the definition of 'rare disease'. CONCLUSIONS: The integrated methodological procedures employed for this case constitutes a replicable and thorough approach to diagnosis, and explores the nature of ancient rare diseases. Due to the socio-environmental aspects of poliomyelitis transmission, it is likely that polio was likely not rare in the past. Therefore, the definition of 'rare diseases in the past' must include rarely occurring rarely diagnosed diseases due to biases and challenges within the archaeological and environmental record. SIGNIFICANCE: The developed suite of methods has not been applied to establish a diagnosis of polio in the past. LIMITATIONS: The individual considered in this study is fairly well-preserved; thus, this set of analyses may not be applicable to all remains where preservation is poor or highly fragmentary, and the discussion of rare diseases requires relatively secure diagnoses and context. SUGGESTIONS FOR FURTHER RESEARCH: Large collections and series of skeletal human remains are recommended to develop definitive conclusions.

Weak O2 binding and strong H2O2 binding at the non-heme diiron center of trypanosome alternative oxidase.

Alternative oxidase (AOX) catalyzes the four-electron reduction of dioxygen to water as an additional terminal oxidase, and the catalytic reaction is critical for the parasite to survive in its bloodstream form. Recently, the X-ray crystal structure of trypanosome alternative oxidase (TAO) complexed with ferulenol was reported and the molecular structure of the non-heme diiron center was determined. The binding of O2 was a unique side-on type compared to other iron proteins. In order to characterize the O2 binding state of TAO, the O2 binding states were searched at a quantum mechanics/molecular mechanics (QM/MM) theoretical level in the present study. We found that the most stable O2 binding state is the end-on type, and the binding states of the side-on type are higher in energy. Based on the binding energies and electronic structure analyses, O2 binds very weakly to the TAO iron center (ΔE =6.7 kcal mol-1) in the electronic state of Fe(II)…OO, not in the suggested charge transferred state such as the superoxide state (Fe(III)OO· -) as seen in hemerythrin. Coordination of other ligands such as water, Cl-, CN-, CO, N3- and H2O2 was also examined, and H2O2 was found to bind most strongly to the Fe(II) site by ΔE = 14.0 kcal mol-1. This was confirmed experimentally through the measurement of ubiquinol oxidase activity of TAO and Cryptosporidium parvum AOX which was found to be inhibited by H2O2 in a dose-dependent and reversible manner.

Non-destructive lock-picking of a historical treasure chest by means of X-ray computed tomography.

An innovative approach to a non-destructive lock mechanism examination by means of X-ray computed tomography (CT) was involved in a careful opening of a locked 19th century chest missing the key, as an interdisciplinary cooperation with the restorers. In regard of the exploration and conservation of such locked objects, their opening is important to the restorers. However, the opening may be complicated, if not impossible, without damaging the object when the key is missing. Moreover, the historical locks might be equipped with protective mechanisms. Despite the exceeding dimensions and the weight of the steel chest, a CT analysis was performed, which enabled a detailed exploration of the lock based on a system of levers and bolts handled by a single key, located in a case on the inside of the chest lid, including the dimensions essential for manufacturing of a new key copy. Moreover, two secret protective mechanisms were revealed, as well as all the damages of the object.

The Meshless Analysis of Scale-Dependent Problems for Coupled Fields.

The meshless local Petrov-Galerkin (MLPG) method was developed to analyze 2D problems for flexoelectricity and higher-grade thermoelectricity. Both problems were multiphysical and scale-dependent. The size effect was considered by the strain and electric field gradients in the flexoelectricity, and higher-grade heat flux in the thermoelectricity. The variational principle was applied to derive the governing equations within the higher-grade theory of considered continuous media. The order of derivatives in the governing equations was higher than in their counterparts in classical theory. In the numerical treatment, the coupled governing partial differential equations (PDE) were satisfied in a local weak-form on small fictitious subdomains with a simple test function. Physical fields were approximated by the moving least-squares (MLS) scheme. Applying the spatial approximations in local integral equations and to boundary conditions, a system of algebraic equations was obtained for the nodal unknowns.

Ab initio relativistic potential energy surfaces of benzene-Xe complex with application to intermolecular vibrations.

The benzene-Xe (BXe) complex in its electronic ground state is studied using ab initio methods. Since this complex contains the heavy Xe atom, the relativistic effects cannot be neglected. We test two different approaches that describe the scalar relativistic effects in the framework of the coupled-cluster level of theory with single, double, and perturbative triple excitations, used for the interaction energy calculations. The first one is based on the small core pseudopotential (PP), and the second one is based on the explicit treatment of scalar relativistic effects using the Douglas-Kroll-Hess (DKH) Hamiltonian. A few basis sets are tested with the PP and DKH, and for each one, the analytical potential energy surface (PES) is constructed. It is shown that the difference between PESs determined with PP and DKH methods is small, if the orbitals of the 4d subshell in Xe are correlated. We select the most appropriate approach for the calculation of the potential energy surface of BXe, with respect to accuracy and computational cost. The optimal level of theory includes a small Dunning's basis set for the benzene monomer and a larger PP basis set for Xe supplemented by midbond functions. The PES obtained using such an approach provides a reasonable accuracy when compared to the empirical one derived from the microwave spectra of BXe. The empirical and the theoretical values of intermolecular vibrational energies agree within 0.5 cm-1 up to second overtones. The vibrational energy level pattern of BXe is characterized by a distinct polyad structure.

Protein Dynamics and the Folding Degree.

The analysis of folding trajectories for proteins is an open challenge. One of the problems is how to describe the amount of folded secondary structure in a protein. We extend the use of Estradas' folding degree (Bioinformatics 2002, 18, 697) for the analysis of the evolution of the folding stage during molecular dynamics (MD) simulation. It is shown that residue contribution to the total folding degree is a predominantly local property, well-defined by the backbone dihedral angles at the given residue, without significant contribution from the backbone conformation of other residues. Moreover, the magnitude of this residue contribution can be quite easily associated with characteristic motifs of secondary protein structures such as the α-helix, ß-sheet (hairpin), and so on by means of a Ramachandran-like plot as a function of backbone dihedral angles φ,ψ. Additionally, the understanding of the free energy profile associated with the folding process becomes much simpler. Often a 1D profile is sufficient to locate global minima and the corresponding structure for short peptides.

Characterizing Protein-Protein Interactions with the Fragment Molecular Orbital Method.

Proteins are vital components of living systems, serving as building blocks, molecular machines, enzymes, receptors, ion channels, sensors, and transporters. Protein-protein interactions (PPIs) are a key part of their function. There are more than 645,000 reported disease-relevant PPIs in the human interactome, but drugs have been developed for only 2% of these targets. The advances in PPI-focused drug discovery are highly dependent on the availability of structural data and accurate computational tools for analysis of this data. Quantum mechanical approaches are often too expensive computationally, but the fragment molecular orbital (FMO) method offers an excellent solution that combines accuracy, speed and the ability to reveal key interactions that would otherwise be hard to detect. FMO provides essential information for PPI drug discovery, namely, identification of key interactions formed between residues of two proteins, including their strength (in kcal/mol) and their chemical nature (electrostatic or hydrophobic). In this chapter, we have demonstrated how three different FMO-based approaches (pair interaction energy analysis (PIE analysis), subsystem analysis (SA) and analysis of protein residue networks (PRNs)) have been applied to study PPI in three protein-protein complexes.

Dehydration and persistence hunting in Homo erectus.

Persistence hunting has been suggested to be a key strategy for meat acquisition in Homo erectus. However, prolonged locomotion in hot conditions is associated with considerable water losses due to sweating. Consequently, dehydration has been proposed to be a critical limiting factor, effectively curtailing the usefulness of persistence hunting prior to the invention of water containers. In this study, we aimed to determine the extent to which dehydration limited persistence hunting in H. erectus. We simulated ambient conditions and spatiotemporal characteristics of nine previously reported persistence hunts in the Kalahari. We used a newly developed and validated heat exchange model to estimate the water loss in H. erectus and a recent Kalahari hunter. Water loss equivalent to 10% of the hunter's body mass was considered the physiological limit of a hunt with no drinking. Our criterion for ruling dehydration out of being a limit for persistence hunting was the ability to hunt without drinking for at least 5 h, as this was the longest duration reported for a successful persistence hunt of large prey. Our results showed that H. erectus would reach the dehydration limit in 5.5-5.7 h of persistence hunting at the reported Kalahari conditions, which we argue represent a conservative model also for Early Pleistocene East Africa. Maximum hunt duration without drinking was negatively related to the relative body surface area of the hunter. Moreover, H. erectus would be able to persistence hunt over 5 h without drinking despite possible deviations from modern-like heat dissipation capacity, aerobic capacity, and locomotor economy. We conclude that H. erectus could persistence hunt large prey without the need to carry water.

Nontargeted Parallel Cascade Selection Molecular Dynamics Based on a Nonredundant Selection Rule for Initial Structures Enhances Conformational Sampling of Proteins.

Nontargeted parallel cascade selection molecular dynamics (nt-PaCS-MD) is a method for enhanced conformational sampling of proteins. To search a broad conformational subspace, nt-PaCS-MD repeats cycles of conformational resampling from relevant initial structures. Generally, the conformational sampling efficiency of nt-PaCS-MD depends on a selection rule for the initial structures. In the original nt-PaCS-MD, the initial structures were selected by referring to structural distributions of protein configurations generated by conformational resampling (multiple short-time MD simulations). However, their structural redundancy among the initial structures was neglected for the cycles of conformational resampling, indicating that similar protein configurations might be frequently specified and resampled in every cycle in the original nt-PaCS-MD. To reduce the possibility of resampling from redundant initial structures, we propose an alternative selection rule that accounts for structural similarity among the initial structures. Specifically, a pairwise root-mean-square deviation (RMSD) is defined for all of the initial structures selected for all of the past cycles. Then a set of protein configurations with a larger pairwise RMSD is sequentially specified and resampled in the next cycle, which is regarded to as a history-dependent selection of initial structures by considering a profile of the past specified initial structures. The present scheme, termed extended nt-PaCS-MD, prevents us from resampling a set of redundant protein configurations. To check the conformational sampling efficiency of the extended nt-PaCS-MD, we used a middle-sized protein, T4 lysozyme, in explicit water. Through the assessment, this extended nt-PaCS-MD identified the open-closed transitions of T4 lysozyme more efficiently than the original nt-PaCS-MD.

Nontargeted Parallel Cascade Selection Molecular Dynamics Using Time-Localized Prediction of Conformational Transitions in Protein Dynamics.

Nontargeted parallel cascade selection molecular dynamics (nt-PaCS-MD) is an enhanced conformational sampling method of proteins, which does not rely on knowledge of the target structure. It makes use of cyclic resampling from some relevant initial structures to expand the searched conformational subspace. The efficiency of nt-PaCS-MD depends on the selections of these initial structures. They are usually stochastically occurring perturbed structures at which larger conformation transitions are about to happen. Reliable identification of these is the key to using nt-PaCS-MD. Two new parameters, the moving root-mean-square deviation (mRMSD) and the inner products of the backbone dihedral angles Φ and Ψ, are introduced as indicators of conformational outliers in MD trajectories. Both are based on the analysis of a time-localized set of coordinates, overcoming the need for a target structure while still capturing the complexity of the conformational transition. The reference to which the mRMSD relates is the close surrounding of the i-th conformation, often the (i-1)st one. Hence the name "time-localized" analysis. In this work, we focus on its interplay with nt-PaCS-MD and show that it increases its effectiveness compared to older versions. The target system is the midsized protein T4 lysozyme (in explicit water) on which we demonstrate the open-closed transition without referring to any target configuration. Additionally, we show that the short MD trajectories can be used for the construction of a free energy landscape of the conformational transition based on the Markov state model.