Functional Interpretation Research Articles

Slack-based tunable damping leads to a trade-off between robustness and efficiency in legged locomotion

Animals run robustly in diverse terrain. This locomotion robustness is puzzling because axon conduction velocity is limited to a few tens of meters per second. If reflex loops deliver sensory information with significant delays, one would expect a destabilizing effect on sensorimotor control. Hence, an alternative explanation describes a hierarchical structure of low-level adaptive mechanics and high-level sensorimotor control to help mitigate the effects of transmission delays. Motivated by the concept of an adaptive mechanism triggering an immediate response, we developed a tunable physical damper system. Our mechanism combines a tendon with adjustable slackness connected to a physical damper. The slack damper allows adjustment of damping force, onset timing, effective stroke, and energy dissipation. We characterize the slack damper mechanism mounted to a legged robot controlled in open-loop mode. The robot hops vertically and planarly over varying terrains and perturbations. During forward hopping, slack-based damping improves faster perturbation recovery (up to 170%) at higher energetic cost (27%). The tunable slack mechanism auto-engages the damper during perturbations, leading to a perturbation-trigger damping, improving robustness at a minimum energetic cost. With the results from the slack damper mechanism, we propose a new functional interpretation of animals’ redundant muscle tendons as tunable dampers.

Homotopy of Linearly Ordered Split–Join Chains in Covering Spaces of Foliated n-Manifold Charts

Topological spaces can be induced by various algebraic ordering relations such as, linear, partial and the inclusion-ordering of open sets forming chains and chain complexes. In general, the classifications of covering spaces are made by using fundamental groups and lifting. However, the Riesz ordered n-spaces and Urysohn interpretations of real-valued continuous functions as ordered chains provide new perspectives. This paper proposes the formulation of covering spaces of n-space charts of a foliated n-manifold containing linearly ordered chains, where the chains do not form topologically separated components within a covering section. The chained subspaces within covering spaces are subjected to algebraic split–join operations under a bijective function within chain-subspaces to form simply directed chains and twisted chains. The resulting sets of chains form simply directed chain-paths and oriented chain-paths under the homotopy path-products involving the bijective function. It is shown that the resulting embedding of any chain in a leaf of foliated n-manifold is homogeneous and unique. The finite measures of topological subspaces containing homotopies of chain-paths in covering spaces generate multiplicative and cyclic group varieties of different orders depending upon the types of measures. As a distinction, the proposed homotopies of chain-paths in covering spaces and the homogeneous chain embedding in a foliated n-manifold do not consider the formation of circular nerves and the Nachbin topological preordering, thereby avoiding symmetry/asymmetry conditions.

DNA-Methylation Signatures of Tobacco Smoking in a High Cardiovascular Risk Population: Modulation by the Mediterranean Diet.

Biomarkers based on DNA methylation are relevant in the field of environmental health for precision health. Although tobacco smoking is one of the factors with a strong and consistent impact on DNA methylation, there are very few studies analyzing its methylation signature in southern European populations and none examining its modulation by the Mediterranean diet at the epigenome-wide level. We examined blood methylation smoking signatures on the EPIC 850 K array in this population (n = 414 high cardiovascular risk subjects). Epigenome-wide methylation studies (EWASs) were performed analyzing differential methylation CpG sites by smoking status (never, former, and current smokers) and the modulation by adherence to a Mediterranean diet score was explored. Gene-set enrichment analysis was performed for biological and functional interpretation. The predictive value of the top differentially methylated CpGs was analyzed using receiver operative curves. We characterized the DNA methylation signature of smoking in this Mediterranean population by identifying 46 differentially methylated CpGs at the EWAS level in the whole population. The strongest association was observed at the cg21566642 (p = 2.2 × 10-32) in the 2q37.1 region. We also detected other CpGs that have been consistently reported in prior research and discovered some novel differentially methylated CpG sites in subgroup analyses. In addition, we found distinct methylation profiles based on the adherence to the Mediterranean diet. Particularly, we obtained a significant interaction between smoking and diet modulating the cg5575921 methylation in the AHRR gene. In conclusion, we have characterized biomarkers of the methylation signature of tobacco smoking in this population, and suggest that the Mediterranean diet can increase methylation of certain hypomethylated sites.

Hardwiring truth in functional interpretations

We present four different approaches to prove the soundness theorem for variants with t-truth of functional interpretations. To showcase our different methods we focus on the intuitionistic nonstandard bounded functional interpretation of the nonstandard extensional Heyting arithmetic in all finite types because a version with t-truth for this interpretation has not been given before. Also, because it is a more involved interpretation than others since it includes both nonstandard principles and majorisability. This leads us to believe that if the approaches work for this more complicated functional interpretation, then they should also work for simpler functional interpretations (and realisabilities).

A matrix‐free variant of the distorted Born iterative method for seismic full‐waveform inversion

AbstractThe distorted Born iterative method reduces a nonlinear inverse scattering problem to a sequence of (ill‐posed) linear inverse scattering problems that can be solved using a regularized least‐squares formulation. This method was originally applied to two‐dimensional electromagnetic problems but has been implemented to solve acoustic and electromagnetic problems in three dimensions. It has also been applied to seismic problems but only for moderately large two‐dimensional models. Previous applications of the distorted Born iterative method to seismic inverse scattering were based on a matrix representation of the relevant integral operators. The matrix‐based implementation is simple and transparent but not very suitable for large‐scale computations since the memory requirement and computational cost scales like N2 and N3, where N is the number of grid blocks. In this paper, we introduce a matrix‐free variant of the distorted Born iterative method, which is much more suitable for large‐scale problems, since the memory requirements and computational cost have been reduced to N and Nlog(N), respectively. Our matrix‐free implementation utilizes a fast‐Fourier‐transform‐accelerated iterative method to solve the linear system that results after discretization. In the computation of Fréchet derivatives, we avoid the direct computation of Green's functions for heterogeneous media, by solving an equivalent direct scattering problem. The adjoint of the Fréchet derivative operator is also computed in an efficient matrix‐free manner, by exploiting the physical interpretation and reciprocity of the Green's function. We illustrate the potential of the matrix‐free variant of the distorted Born iterative method using synthetic waveform data for large two‐ and three‐dimensional models. The main conclusion is that the distorted Born iterative method has been transformed into a more practical tool for seismic as well as electromagnetic and acoustic nonlinear inverse scattering.

«Философия математики» Германа Когена, или Что не так с марбургским методом

Neo-Kantianism in general and the Marburg school are becoming an increas­ingly popular subject of research both in the Russian and global academic com­munity. Thanks to the meticulous archival work of H. Holzhey, K.Ch. Köhnke, U. Sieg and other scientists, rich historical and philosophical dimension of this phenomenon has been discovered. As a result, neo-Kantianism is no longer read strictly through the prism of an (unsuccessful) attempt to scientize philosophy in the image of natural scientific knowledge. At the same time, it seems interest­ing to analyze this attempt from the point of view of its internal content. The ob­ject of this study is mainly H. Cohen’s “Das Princip der Infinitesimal-Methode und seine Geschichte”, conjugated with the historical and theoretical context of psychological discussions. The term “Cohen’s method” in its early temporal localization of the beginning of the 1880’s, we expand to the “Marburg method”. It is based on a functional interpretation of the process of cognition using the ex­ample of infinitesimal calculus. Despite the declared opposition to the psycho­logical programs of philosophy, we believe that Cohen could not achieve this task at theoretical level. The intuitive definition of mathematical entities in gen­eral and the usage of a psychophysical mathematical model is an unsuccessful way of countering psychological programs of philosophy. At the same time, we believe that despite the outward exoticism of the philosopher’s conclusions, the desire to “dereify” and “denaturalize” the concept of reality finds full expression in his model, which is extremely important for the formation of the Marburg Neo-Kantianism. Reconstruction and comprehension of what we conditionally call "the philosophy of mathematics of Hermann Cohen" allows us to better un­derstand the essence of the theoretical superstructure that he created over the form of mathematical derivation.

Migraine genetics: Status and road forward

Migraine is considered a multifactorial genetic disorder. Different platforms and methods are used to unravel the genetic basis of migraine. Initially, linkage analysis in multigenerational families followed by Sanger sequencing of protein-coding parts (exons) of genes in the genomic region shared by affected family members identified high-effect risk DNA mutations for rare Mendelian forms of migraine, foremost hemiplegic migraine. More recently, genome-wide association studies testing millions of DNA variants in large groups of patients and controls have proven successful in identifying many dozens of low-effect risk DNA variants for the more common forms of migraine with the number of associated DNA variants increasing steadily with larger sample sizes. Currently, next-generation sequencing, utilising whole exome and whole genome sequence data, and other omics data are being used to facilitate their functional interpretation and the discovery of additional risk factors. Various methods and analysis tools, such as genetic correlation and causality analysis, are used to further characterise genetic risk factors. We describe recent findings in genome-wide association studies and next-generation sequencing analysis in migraine. We show that the combined results of the two most recent and most powerful migraine genome-wide association studies have identified a total of 178 LD-independent (r2 < 0.1) genome-wide significant single nucleotide polymorphisms (SNPs), of which 99 were unique to Hautakangas etal., 11 were unique to Choquet etal., and 68 were identified by both studies. When considering that Choquet etal. also identified three SNPs in a female-specific genome-wide association studies then these two recent studies identified 181 independent SNPs robustly associated with migraine. Cross-trait and causal analyses are beginning to identify and characterise specific biological factors that contribute to migraine risk and its comorbid conditions. This review provides a timely update and overview of recent genetic findings in migraine.

Common neural correlates of vestibular stimulation and fear learning: an fMRI meta-analysis

BackgroundA bidirectional functional link between vestibular and fear-related disorders has been previously suggested.ObjectiveTo test a potential overlap of vestibular and fear systems with regard to their brain imaging representation maps.MethodsBy use of voxel-based mapping permutation of subject images, we conducted a meta-analysis of earlier functional magnetic resonance imaging (fMRI) studies applying vestibular stimulation and fear conditioning in healthy volunteers.ResultsCommon clusters of concordance of vestibular stimulation and fear conditioning were found in the bilateral anterior insula cortex, ventrolateral prefrontal cortex and the right temporal pole, bilaterally in the adjacent ventrolateral prefrontal cortex, cingulate gyrus, secondary somatosensory cortex, superior temporal and intraparietal lobe, supplementary motor area and premotor cortex, as well as subcortical areas, such as the bilateral thalamus, mesencephalic brainstem including the collicular complex, pons, cerebellar vermis and bilateral cerebellar hemispheres. Peak areas of high concordance for activations during vestibular stimulation but deactivations during fear conditioning were centered on the posterior insula and S2.ConclusionsThe structural overlap of both networks allows the following functional interpretations: first, the amygdala, superior colliculi, and antero-medial thalamus might represent a release of preprogramed sensorimotor patterns of approach or avoidance. Second, the activation (vestibular system) and deactivation (fear system) of the bilateral posterior insula is compatible with the view that downregulation of the fear network by acute vestibular disorders or unfamiliar vestibular stimulation makes unpleasant perceived body accelerations less distressing. This also fits the clinical observation that patients with bilateral vestibular loss suffer from less vertigo-related anxiety.

Comment on “Tidally Synchronized Solar Dynamo: A Rebuttal” by Nataf (Solar Phys. 297, 107, 2022)

Nataf (Solar Phys.297, 107, 2022) has recently asserted that the hypothesis that the solar dynamo may be synchronized by planetary tidal forces is unsupported by any evidence. He reached this conclusion by adopting a simplistic tidal model (which was discussed in his Appendix A) that relies solely on the effect of Mercury, Venus, Earth, and Jupiter whose orbits were assumed to be circular. His model was unable to produce tides with periods compatible with those of the Schwabe 11-year solar cycle. I demonstrate here that the modeling in Nataf (2022) is erroneous and that a correct modeling and interpretation of the planetary tidal function, which accounts for all planets and their true orbits, fits well with the spectral requirements of the Schwabe 11-year solar cycle. This result has been already shown and discussed in a substantial body of scholarly research on the subject, which Nataf apparently ignored. A recent and extended review of the empirical and theoretical evidences supporting the planetary synchronized solar dynamo theory was offered by Scafetta and Bianchini (Front. Astron. Space Sci.9, 937930, 2022).

Constructing Wave Functions Using Mathematical Reasoning

Transfer of structural math knowledge to physics is difficult for students. While research suggests various improvement techniques, enhancing parallelism of algebraic structures used in physics to those studied in mathematics courses seems underrepresented. This paper proposes an alternative way of introducing wave functions as a set of parametric equations. Research shows that the mathematical underpinnings of the mechanical wave function are problematic for students. As seen from the math perspective, there can be several drawbacks that likely impede scientific analysis and interpretation of the wave function: y(x,t)=A cos(2πλx−2πTt).

A functional way of interpreting legal norms with evaluative concepts

The purpose of the article is to find out what is meant by the functional method of interpreting legal norms and what factors must be taken into account in the process of its application in practice. It was found that the functional interpretation of legal norms is the study of the practice of applying legal norms. It is shown that a functional way of interpreting legal norms is necessary for interpreting legal norms with evaluative concepts. The specified method of interpretation is carried out according to the rules and requirements that are used in the process of determining the content of evaluative concepts, taking into account specific historical conditions.&#x0D; It is justified that the interpreter must take into account the conditions and factors under which the norm is implemented. The practice of interpreting such an evaluative concept as "long-term crimes" was considered, and it was clarified that the provision of the norm, formalized by Article 146 of the Criminal code of Ukraine, combines two different actions that can be considered independent crimes. It has been established that formal technical-legal defects arise mainly during the formulation of a legal concept by the legislator in violation of the rules and requirements for normative definitions.&#x0D; The author came to the conclusion that at the doctrinal level, the existence and application of the functional method of interpreting legal norms is recognized in practical activity. After all, in certain cases, to clarify the meaning of a legal norm, it is not enough to pay attention only to its formal analysis and general conditions of implementation.&#x0D; However, functional interpretation is not the only way of interpreting legal norms with evaluative concepts. Such norms are subject to not only functional, but also linguistic, logical, systemic, etc. interpretation. When interpreting legal norms containing evaluative concepts, the result of interpretation may be different, however, the content of the norm must match its verbal expression.

Metabolic Pathway Analysis: Advantages and Pitfalls for the Functional Interpretation of Metabolomics and Lipidomics Data.

Over the past decades, pathway analysis has become one of the most commonly used approaches for the functional interpretation of metabolomics data. Although the approach is widely used, it is not well standardized and the impact of different methodologies on the functional outcome is not well understood. Using four publicly available datasets, we investigated two main aspects of topological pathway analysis, namely the consideration of non-human native enzymatic reactions (e.g., from microbiota) and the interconnectivity of individual pathways. The exclusion of non-human native reactions led to detached and poorly represented reaction networks and to loss of information. The consideration of connectivity between pathways led to better emphasis of certain central metabolites in the network; however, it occasionally overemphasized the hub compounds. We proposed and examined a penalization scheme to diminish the effect of such compounds in the pathway evaluation. In order to compare and assess the results between different methodologies, we also performed over-representation analysis of the same datasets. We believe that our findings will raise awareness on both the capabilities and shortcomings of the currently used pathway analysis practices in metabolomics. Additionally, it will provide insights on various methodologies and strategies that should be considered for the analysis and interpretation of metabolomics data.

What Drives Chorismate Mutase to Top Performance? Insights from a Combined In Silico and In Vitro Study.

Unlike typical chorismate mutases, the enzyme from Mycobacterium tuberculosis (MtCM) has only low activity on its own. Remarkably, its catalytic efficiency kcat/Km can be boosted more than 100-fold by complex formation with a partner enzyme. Recently, an autonomously fully active MtCM variant was generated using directed evolution, and its structure was solved by X-ray crystallography. However, key residues were involved in crystal contacts, challenging the functional interpretation of the structural changes. Here, we address these challenges by microsecond molecular dynamics simulations, followed up by additional kinetic and structural analyses of selected sets of specifically engineered enzyme variants. A comparison of wild-type MtCM with naturally and artificially activated MtCMs revealed the overall dynamic profiles of these enzymes as well as key interactions between the C-terminus and the active site loop. In the artificially evolved variant of this model enzyme, this loop is preorganized and stabilized by Pro52 and Asp55, two highly conserved residues in typical, highly active chorismate mutases. Asp55 stretches across the active site and helps to appropriately position active site residues Arg18 and Arg46 for catalysis. The role of Asp55 can be taken over by another acidic residue, if introduced at position 88 close to the C-terminus of MtCM, as suggested by molecular dynamics simulations and confirmed by kinetic investigations of engineered variants.

Функциональный подход к праву в российской социологической юриспруденции конца XIX — начала XX вв.

At the turn of the XIX–XX centuries, the problem of the functions of law becomes the subject of stable scientific interest of representatives of Russian sociological jurisprudence. By the function of law, the authors understand both the social purpose of law and the direction of legal influence on the relevant sphere of public relations. Distinguishing between the functions of common law, sectoral rules of law and norms of law, scientists lay the foundations for their future classification. A fundamental role in determining the proper legal functions of law is played by the legal understanding of the authors, according to which priority is given to the function of either protective or regulatory. During the interpretation of social functions (economic, political and educational), theoretical disagreements lose their significance, giving way to liberal ideology.

Determination of in-plane residual stress and eigenstrain in laser peened thin sheet using unit pulse function and equilibrium constraint

The residual stress field is a critical physical quantity for the predicting fatigue life and adjusting forming shape in the peening industry. It is an important engineering requirement to accurately obtain the reliable residual stress of treated coupons and components. To improve the spatial resolution and accuracy of stress measurements in laser peened targets, the slitting method via unit pulse function was carried out in the present study. A 4 mm thick rectangular sheet subjected to uniform laser peening was studied thoroughly via theoretical analysis and experimental tests. First, the physical interpretation and basic implementation of the unit pulse function were described. The relevant regularization, error reduction, and analysis methods were expounded. Then, a safe distance of multiple slitting measurements was proposed and further investigated through numerical simulation. The effect of stress relaxation and the positions of the strain gauges employed were also verified. Experimentally, a biaxial through-thickness distribution of residual stress was calculated using the unit pulse approach. Then, a cross-method validation procedure was performed through an incremental X-ray diffraction (XRD). Finally, the distribution patterns of the bending and elongating stress components were analyzed. The unbalanced laser peening-induced stress was obtained through a backward calculation using the equilibrium constraint. The results indicated that general stress field was in a biaxial state, which possessed a roughly equivalent amplitude and uniform distribution. Along the depth direction, both the peened and unpeened faces were under compression, while the sheet center was in tension for global compensation. Further research revealed that the residual stress introduced by laser peening was fundamental to the process, which can provide a test-oriented solution for eigenstrain and reliable data support for deformation prediction.

Innovation in identifying metabolites from complex metabolome-Highlights of recent analytical platforms and protocols.

Metabolites are closely intertwined genotypes that can provide clear information about the final phenotype. The high-throughput analysis platform used to identify candidate metabolites and describe their contributions can help to quickly detect metabolic characteristics from large spectral data, which may lead to peak data preprocessing, statistical analysis and functional interpretation. Developing a comprehensive strategy for discovering and verifying bioactive metabolites can provide a large number of new functional biomarkers, and then more closely reveal their functional changes, which has relevant biological significance for disease diagnosis and prognosis treatment.

Chromosome conformation capture approaches to investigate 3D genome architecture in Ankylosing Spondylitis.

Ankylosing Spondylitis (AS) is a chronic inflammatory arthritis of the spine exhibiting a strong genetic background. The mechanistic and functional understanding of the AS-associated genomic loci, identified with Genome Wide Association Studies (GWAS), remains challenging. Chromosome conformation capture (3C) and derivatives are recent techniques which are of great help in elucidating the spatial genome organization and of enormous support in uncover a mechanistic explanation for disease-associated genetic variants. The perturbation of three-dimensional (3D) genome hierarchy may lead to a plethora of human diseases, including rheumatological disorders. Here we illustrate the latest approaches and related findings on the field of genome organization, highlighting how the instability of 3D genome conformation may be among the causes of rheumatological disease phenotypes. We suggest a new perspective on the inclusive potential of a 3C approach to inform GWAS results in rheumatic diseases. 3D genome organization may ultimately lead to a more precise and comprehensive functional interpretation of AS association, which is the starting point for emerging and more specific therapies.

Prediction of protein solubility based on sequence physicochemical patterns and distributed representation information with DeepSoluE

BackgroundProtein solubility is a precondition for efficient heterologous protein expression at the basis of most industrial applications and for functional interpretation in basic research. However, recurrent formation of inclusion bodies is still an inevitable roadblock in protein science and industry, where only nearly a quarter of proteins can be successfully expressed in soluble form. Despite numerous solubility prediction models having been developed over time, their performance remains unsatisfactory in the context of the current strong increase in available protein sequences. Hence, it is imperative to develop novel and highly accurate predictors that enable the prioritization of highly soluble proteins to reduce the cost of actual experimental work.ResultsIn this study, we developed a novel tool, DeepSoluE, which predicts protein solubility using a long-short-term memory (LSTM) network with hybrid features composed of physicochemical patterns and distributed representation of amino acids. Comparison results showed that the proposed model achieved more accurate and balanced performance than existing tools. Furthermore, we explored specific features that have a dominant impact on the model performance as well as their interaction effects.ConclusionsDeepSoluE is suitable for the prediction of protein solubility in E. coli; it serves as a bioinformatics tool for prescreening of potentially soluble targets to reduce the cost of wet-experimental studies. The publicly available webserver is freely accessible at http://lab.malab.cn/~wangchao/softs/DeepSoluE/.

Functional interpretation, cataloging, and analysis of 1,341 glucose-6-phosphate dehydrogenase variants

Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects over 500 million individuals who can experience anemia in response to oxidative stressors such as certain foods and drugs. Recently, the World Health Organization (WHO) called for revisiting G6PD variant classification as a priority to implement genetic medicine in low- and middle-income countries. Toward this goal, we sought to collect reports of G6PD variants and provide interpretations. We identified 1,341 G6PD variants in population and clinical databases. Using the ACMG standards and guidelines for the interpretation of sequence variants, we provided interpretations for 268 variants, including 186 variants that were not reported or of uncertain significance in ClinVar, bringing the total number of variants with non-conflicting interpretations to 400. For 414 variants with functional or clinical data, we analyzed associations between activity, stability, and current classification systems, including the new 2022 WHO classification. We corroborated known challenges with classification systems, including phenotypic variation, emphasizing the importance of comparing variant effects across individuals and studies. Biobank data made available by All of Us illustrate the benefit of large-scale sequencing and phenotyping by adding additional support connecting variants to G6PD-deficient anemia. By leveraging available data and interpretation guidelines, we created a repository for information on G6PD variants and nearly doubled the number of variants with clinical interpretations. These tools enable better interpretation of G6PD variants for the implementation of genetic medicine.

Trilobite tridents demonstrate sexual combat at 400 Mya

The Devonian trilobite Walliserops carries a remarkable anterior cephalic trident posing a challenge to functional interpretation. A unique teratological specimen of Walliseropstrifurcatus showing four, rather than three tines, is inconsistent with possible hypotheses connecting the trident to feeding techniques and suggests a sexually selected function. Malformations in a variety of living organisms support this conclusion. Morphometric comparisons to similar structures used for intraspecific combat in dynastine beetles show that the trident occupies a comparable shape space consistent with the hypothesis that it was a sexual combat weapon, the oldest reported example of its kind. This lends further credibility to the idea that some trilobites may have been strongly sexually dimorphic.