Functional Interpretation Research Articles

Recommendations on interpretive strategies for routine lung function tests

During the annual conference of the German Respiratory Society (DGP = Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin) in 2024, updated recommendations for lung function testing have been published. The original full-length version can be downloaded free of charge as pfd-paper from the journal entitled "Atemwegs- und Lungenkrankheiten, Jahrgang 50 (2024) März (111-184)". In the current recommendations new approaches have been embedded that focus on modern interpretations of lung function results, as has been proposed by the ERS (European Respiratory Society) in collaboration with the ATS (American Thoracic Society). This targets the spirometry, the whole bodyplethysmography, diffusion capacity testing, testing for bronchodilation, unspecific bronchoprovocation in addition to the reference values. Oscillometry and respiratory muscle function testing are also included in the recommendations. The current publication considers itself as a short version of the most important topics of the full-length lung function recommendations. However, reading also the full-length paper is strongly emphasised based on the understanding that lung function testing is highly important in daily clinical practice when dealing with patients suffering from respiratory diseases.

Accuracy of Point-Of-Care Cardiac Ultrasound Performed on Patients Admitted to a Pediatric Intensive Care Unit in Shock.

To assess agreement between a novice pediatric critical care fellow's interpretation of left and right ventricular (LV, RV) function using point-of-care ultrasound (POCUS) compared with assessments by pediatric cardiologists and echocardiography. Echocardiographic clips (parasternal long axis, parasternal short axis, and apical four-chamber) and measurements for LV and RV functions (E-point septal separation, ejection fraction, and tricuspid annular plane systolic excursion) were obtained by PICU fellow in patients 0-18 years old with shock. A pediatric cardiologist reviewed the POCUS images. Agreement between the interpretations by the intensivist, cardiologist, and comprehensive echocardiograms were analyzed using Cohen's kappa. Thirty-one patients were included: 22 had comprehensive echocardiograms. The PICU fellow detected LV dysfunction with 100% sensitivity and > 85% specificity compared with the cardiologist's interpretation and formal echocardiography. Substantial agreement (κ = 0.62) was noted between the intensivist and cardiologist for interpretation of LV function and RV size and pressure (κ = 0.72). The intensivist's assessments showed perfect agreement (κ = 1.0) with echocardiography for LV and RV function. POCUS images ranged from 100% adequate in the parasternal long axis, 90% in the parasternal short axis, and 43% in apical four-chambered views. A novice PICU fellow could reliably use POCUS to assess the cardiac function in pediatric patients with shock.

Upregulation of ENAH by a PI3K/AKT/β-catenin cascade promotes oral cancer cell migration and growth via an ITGB5/Src axis

BackgroundOral cancer accounts for 2% of cancer-related deaths globally, with over 90% of cases being oral cavity squamous cell carcinomas (OSCCs). Approximately 50% of patients with OSCC succumb to the disease within 5 years, primarily due to the advanced stage at which it is typically diagnosed. This underscores an urgent need to identify proteins related to OSCC progression to develop effective diagnostic and therapeutic strategies.MethodsTo identify OSCC progression-related proteins, we conducted integrated proteome and transcriptome analyses on cancer tissues from patients and patient-derived xenograft (PDX) model mice. We investigated the role of protein-enabled homolog (ENAH), identified as an OSCC progression-associated protein, through proliferation, transwell migration, and invasion assays in OSCC cells. The mechanisms underlying ENAH-mediated functions were elucidated using gene knockdown and ectopic expression techniques in OSCC cells.ResultsENAH was identified as a candidate associated with OSCC progression based on integrated analyses, which showed increased ENAH levels in primary OSCC tissues compared with adjacent noncancerous counterparts, and sustained overexpression in the cancer tissues of PDX models. We confirmed that level of ENAH is increased in OSCC tissues and that its elevated expression correlates with poorer survival rates in patients with OSCC. Furthermore, the upregulation of ENAH in OSCC cells results from the activation of the GSK3β/β-catenin axis by the EGFR/PI3K/AKT cascade. ENAH expression enhances cell proliferation and mobility by upregulating integrin β5 in oral cancer cells.ConclusionsThe upregulation of ENAH through a PI3K/AKT/β-catenin signaling cascade enhances oral cancer cell migration and growth via the ITGB5/Src axis. These findings offer a new interpretation of the ENAH function in the OSCC progression and provide crucial information for developing new OSCC treatment strategies.

The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance.

Functional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics. In this study, we evaluated the efficacy of genetic screening technologies in accurately predicting pathogenic variants and their corresponding disease prevalence in a cohort of over 6000 healthy individuals involved in assisted reproduction programs. Using data from 305 genes associated with recessive disorders, we determined the frequency of carriers of pathogenic variants and VOUS in our dataset and compared the predicted prevalence based on this information with reported population prevalence data. The higher predicted prevalence in some disorders when considering VOUS suggests a mostly benign effect.

Projectile points, dangers and Amerindian ontologies at eastern Catamarca (Argentina) during the first millennium CE

ABSTRACT Evaluating the links between South American Amerindian ontologies and the contextual study of knapped lithic technology is the main goal of this paper. To this end, we focus on a study case from eastern Catamarca province, Argentina, during the 1st millennium A.D. We identified projectile points in only one context, a rock art rock shelter (Oyola 7), while in other archaeological sites in the area, we have not recorded this type of stone tool. Drawing on ethnohistoric and ethnographic data regarding the connection between arrows and shamanic practices of illness and healing, we propose considering the agencies of these objects, as well as their intrinsic danger and their multiple possibilities of affecting beyond their traditional functional interpretation.

The solution of the task of dynamic interpretation of seismic data using machine learning methods

This article examines the problem of dynamically interpreting seismic data using machine learning models, which include Extremely Randomized Trees (Extra Trees), Gradient Boosting (GB), and Adaptive Boosting (AdaBoost) for the given problem. The study analyzes some existing solutions of the problem and describes the advantages of these machine learning models. Accuracy is estimated using the root mean square error metric. The authors found that dynamic interpretation and prediction of seismic data using these machine learning methods had not been extensively explored in research on related topics, which became the main focus of the study. The article formalizes the use of the mentioned models and highlights features and advantages for the given problem. Several common machine learning methods were investigated to find functional relationships between input parameters. Computational experiments were conducted to evaluate their applicability and compare the algorithms. The results show that the Extra Trees method is the most suitable for practical use for the given problem, as it demonstrates the highest accuracy in determining functional relationships and dynamic interpretation.

A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.

Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo.

Translation of genome-wide association study: from genomic signals to biological insights.

Since the turn of the 21st century, genome-wide association study (GWAS) have successfully identified genetic signals associated with a myriad of common complex traits and diseases. As we transition from establishing robust genetic associations with diverse phenotypes, the central challenge is now focused on characterizing the underlying functional mechanisms driving these signals. Previous GWAS efforts have revealed multiple variants, each conferring relatively subtle susceptibility, collectively contributing to the pathogenesis of various common diseases. Such variants can further exhibit associations with multiple other traits and differ across ancestries, plus disentangling causal variants from non-causal due to linkage disequilibrium complexities can lead to challenges in drawing direct biological conclusions. Combined with cellular context considerations, such challenges can reduce the capacity to definitively elucidate the biological significance of GWAS signals, limiting the potential to define mechanistic insights. This review will detail current and anticipated approaches for functional interpretation of GWAS signals, both in terms of characterizing the underlying causal variants and the corresponding effector genes.

Cortical development in the structural model and free energy minimization.

A model of neocortical development invoking Friston's Free Energy Principle is applied within the Structural Model of Barbas etal. and the associated functional interpretation advanced by Tucker and Luu. Evolution of a neural field with Hebbian and anti-Hebbian plasticity, maximizing synchrony and minimizing axonal length by apoptotic selection, leads to paired connection systems with mirror symmetry, interacting via Markov blankets along their line of reflection. Applied to development along the radial lines of development in the Structural Model, a primary Markov blanket emerges between the centrifugal synaptic flux in layers 2,3 and 5,6, versus the centripetal flow in layer 4, and axonal orientations in layer 4 give rise to the differing shape and movement sensitivities characteristic of neurons of dorsal and ventral neocortex. Prediction error minimization along the primary blanket integrates limbic and subcortical networks with the neocortex. Synaptic flux bypassing the blanket triggers the arousal response to surprising stimuli, enabling subsequent adaptation. As development progresses ubiquitous mirror systems separated by Markov blankets and enclosed blankets-within-blankets arise throughout neocortex, creating the typical order and response characteristics of columnar and noncolumnar cortex.

Evoked Component Analysis (ECA): Decomposing the Functional Ultrasound Signal With GLM-Regularization.

Analysis of functional neuroimaging data aims to unveil spatial and temporal patterns of interest. Existing analysis methods fall into two categories: fully data-driven approaches and those reliant on prior information, e.g. the stimulus time course. While using the stimulus signal directly can help identify the activated brain areas, it is known that the relationship between stimuli and the brain's response exhibits nonlinear and time-varying characteristics. As such, relying completely on the stimulus signal to describe the brain's temporal response leads to a restricted interpretation of the brain function. In this paper, we present a new technique called Evoked Component Analysis (ECA), which leverages prior information up to a defined extent. This is achieved by including the general linear model (GLM) design matrix as a regulatory term and estimating the factor matrices in both space and time through an alternating minimization approach. We apply ECA to 2D and swept-3D functional ultrasound (fUS) experiments conducted with mice. When decomposing 2D fUS data, we employ GLM regularization at various intensities to emphasize the role of prior information. Furthermore, we show that incorporating multiple hemodynamic response functions within the design matrix can provide valuable insights into region-specific characteristics of evoked activity. Finally, we use ECA to analyze swept-3D fUS data recorded from five mice engaged in two distinct visual tasks. Swept-3D fUS images the 3D brain sequentially using a moving probe, resulting in different slice acquisition time instants. We show that ECA can estimate factor matrices with a fine resolution at each slice acquisition time instant and yield higher t-statistics compared to GLM and correlation analysis for all subjects.

Metal-organic framework-derived hierarchical flower-like DyCo-layered double hydroxide amalgamated nitrogen-doped graphene for diphenylamine detection in fruit samples: Theoretical density functional theory interpretation

Diphenylamine (DPA) is an environmental pollutant that can be potentially toxic. As a result, it is crucial to use basic and affordable analytical techniques to detect DPA. Electrochemical detection of DPA is a cost-effective and simple method. Modifying the electrodes with nanomaterials can enhance the electrochemical characteristics and sensitivity of the sensor. Herein, metal-organic framework (MOF) derived dysprosium cobalt-layered double hydroxide integrated nitrogen-doped graphene (DyCo-LDH/NG) is reported for the fabrication of the DPA sensing platform. The electrochemical oxidation of DPA is enhanced by the exceptional electrocatalytic activity and electron transfer properties of the DyCo-LDH/NG nanocomposite. Interestingly, the glassy carbon electrode (GCE) modified with DyCo-LDH/NG nanocomposite demonstrates a large linear detection range (0.05-470μM) and a low limit of detection (0.012µM). The density functional theory (DFT) study is employed to examine the energy levels and electron transfer sites of DPA during the electro-oxidation process. Furthermore, the practical efficiency test of the developed DPA sensor demonstrates a substantial recovery in fruit samples.

DAVID Ortholog: an integrative tool to enhance functional analysis through orthologs.

The Database for Annotation, Visualization, and Integrated Discovery (DAVID) is a web-based bioinformatics system for the functional interpretation of large lists of genes/proteins generated from high-throughput assays. It has been cited in 72 287 papers since its debut in 2003 as of 23 July 2024. The analysis is usually limited to the species of study. However, the knowledge of genes may be incomplete or unavailable for some species. Model organisms have been studied more extensively and analyzing gene lists in the context of these species can offer valuable insights, helping users better understand the genes and biological themes in their species of interest. We developed DAVID Ortholog for the conversion of gene lists between species. We utilized the ortholog data downloaded from Orthologous MAtrix (OMA) and Ensembl Compara as the base for the conversion. The OMA ortholog IDs and Ensembl gene IDs were converted to DAVID gene IDs and the pairing information of these IDs from these two sources was integrated into the DAVID Knowledgebase. DAVID Ortholog can convert the user's source gene list to an ortholog list of a desired species and the downstream DAVID analysis, in the context of that species, can be continued seamlessly, allowing users to further understand the biological meaning of their gene list based on the functional annotation found for the orthologs. https://davidbioinformatics.nih.gov/ortholog.jsp.

Prediction and functional interpretation of inter-chromosomal genome architecture from DNA sequence with TwinC.

Three-dimensional nuclear DNA architecture comprises well-studied intra-chromosomal (cis) folding and less characterized inter-chromosomal (trans) interfaces. Current predictive models of 3D genome folding can effectively infer pairwise cis-chromatin interactions from the primary DNA sequence but generally ignore trans contacts. There is an unmet need for robust models of trans-genome organization that provide insights into their underlying principles and functional relevance. We present TwinC, an interpretable convolutional neural network model that reliably predicts trans contacts measurable through genome-wide chromatin conformation capture (Hi-C). TwinC uses a paired sequence design from replicate Hi-C experiments to learn single base pair relevance in trans interactions across two stretches of DNA. The method achieves high predictive accuracy (AUROC=0.80) on a cross-chromosomal test set from Hi-C experiments in heart tissue. Mechanistically, the neural network learns the importance of compartments, chromatin accessibility, clustered transcription factor binding and G-quadruplexes in forming trans contacts. In summary, TwinC models and interprets trans genome architecture, shedding light on this poorly understood aspect of gene regulation.

Confidence and second-order errors in cortical circuits.

Minimization of cortical prediction errors has been considered a key computational goal of the cerebral cortex underlying perception, action, and learning. However, it is still unclear how the cortex should form and use information about uncertainty in this process. Here, we formally derive neural dynamics that minimize prediction errors under the assumption that cortical areas must not only predict the activity in other areas and sensory streams but also jointly project their confidence (inverse expected uncertainty) in their predictions. In the resulting neuronal dynamics, the integration of bottom-up and top-down cortical streams is dynamically modulated based on confidence in accordance with the Bayesian principle. Moreover, the theory predicts the existence of cortical second-order errors, comparing confidence and actual performance. These errors are propagated through the cortical hierarchy alongside classical prediction errors and are used to learn the weights of synapses responsible for formulating confidence. We propose a detailed mapping of the theory to cortical circuitry, discuss entailed functional interpretations, and provide potential directions for experimental work.

Electrophysiological (EEG) microstates during dream-like bizarre experiences in a naturalistic scenario using immersive virtual reality.

Monitoring the reality status of conscious experience is essential for a human being to interact successfully with the external world. Despite its importance for everyday functioning, reality monitoring can systematically become erroneous, for example, while dreaming or during hallucinatory experiences. To investigate brain processes associated with reality monitoring occurring online during an experience, i.e., perceptual reality monitoring, we assessed EEG microstates in healthy, young participants. In a within-subjects design, we compared the experience of reality when being confronted with dream-like bizarre elements versus realistic elements in an otherwise highly naturalistic real-world scenario in immersive virtual reality. Dream-like bizarreness induced changes in the subjective experience of reality and bizarreness, and led to an increase in the contribution of a specific microstate labelled C'. Microstate C' was related to the suspension of disbelief, i.e. the suppression of bizarre mismatches. Together with the functional interpretation of microstate C' as reported by previous studies, the findings of this study point to the importance of prefrontal meta-conscious control processes in perceptual reality monitoring.

A zero precision loss framework for EEG channel selection: enhancing efficiency and maintaining interpretability

The brain-computer interface (BCI) systems based on motor imagery typically rely on a large number of electrode channels to acquire information. The rational selection of electroencephalography (EEG) channel combinations is crucial for optimizing computational efficiency and enhancing practical applicability. However, evaluating all potential channel combinations individually is impractical. This study aims to explore a strategy for quickly achieving a balance between maximizing channel reduction and minimizing precision loss. To this end, we developed a spatio-temporal attention perception network named STAPNet. Based on the channel contributions adaptively generated by its subnetwork, we propose an extended step bi-directional search strategy that includes variable ratio channel selection (VRCS) and strided greedy channel selection (SGCS), designed to enhance global search capabilities and accelerate the optimization process. Experimental results show that on the High Gamma and BCI Competition IV 2a public datasets, the framework respectively achieved average maximum accuracies of 91.47% and 84.17%. Under conditions of zero precision loss, the average number of channels was reduced by a maximum of 87.5%. Additionally, to investigate the impact of neural information loss due to channel reduction on the interpretation of complex brain functions, we employed a heatmap visualization algorithm to verify the universal importance and complete symmetry of the selected optimal channel combination across multiple datasets. This is consistent with the brain’s cooperative mechanism when processing tasks involving both the left and right hands.

Multi-Omics Analysis Revealed the rSNPs Potentially Involved in T2DM Pathogenic Mechanism and Metformin Response.

The goal of our study was to identify and assess the functionally significant SNPs with potentially important roles in the development of type 2 diabetes mellitus (T2DM) and/or their effect on individual response to antihyperglycemic medication with metformin. We applied a bioinformatics approach to identify the regulatory SNPs (rSNPs) associated with allele-asymmetric binding and expression events in our paired ChIP-seq and RNA-seq data for peripheral blood mononuclear cells (PBMCs) of nine healthy individuals. The rSNP outcomes were analyzed using public data from the GWAS (Genome-Wide Association Studies) and Genotype-Tissue Expression (GTEx). The differentially expressed genes (DEGs) between healthy and T2DM individuals (GSE221521), including metformin responders and non-responders (GSE153315), were searched for in GEO RNA-seq data. The DEGs harboring rSNPs were analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We identified 14,796 rSNPs in the promoters of 5132 genes of human PBMCs. We found 4280 rSNPs to associate with both phenotypic traits (GWAS) and expression quantitative trait loci (eQTLs) from GTEx. Between T2DM patients and controls, 3810 rSNPs were detected in the promoters of 1284 DEGs. Based on the protein-protein interaction (PPI) network, we identified 31 upregulated hub genes, including the genes involved in inflammation, obesity, and insulin resistance. The top-ranked 10 enriched KEGG pathways for these hubs included insulin, AMPK, and FoxO signaling pathways. Between metformin responders and non-responders, 367 rSNPs were found in the promoters of 131 DEGs. Genes encoding transcription factors and transcription regulators were the most widely represented group and many were shown to be involved in the T2DM pathogenesis. We have formed a list of human rSNPs that add functional interpretation to the T2DM-association signals identified in GWAS. The results suggest candidate causal regulatory variants for T2DM, with strong enrichment in the pathways related to glucose metabolism, inflammation, and the effects of metformin.

Protecting victims of international crimes: A reflection on the functional interpretation of the Statute of the International Criminal Court

This study identified essential factors concerning the safeguarding of victims of international crimes within the context of the functional interpretation of the Rome Statute. The study examined the principal worldwide legal frameworks governing the protection of victims of these crimes. The study employed hermeneutic, system-structural analysis, comparative legal, and other methods. The analysis results indicated that the legislation of Kazakhstan lacks clearly defined norms that relate to the responsibility of the state to victims, as well as their right to adequate reparation, including compensation and rehabilitation, as mandated by the UN Convention against Torture. Kazakhstan and China have not ratified the Rome Statute, largely due to political considerations. Kazakhstanʼs accession to the Rome Statute could lead to the harmonisation of national standards with international demands concerning the rule of law and the protection of human rights, as well as strengthen global efforts to counteract the evils that threaten peace and security. It was also found that the lack of clarity in the normative terminology and methods of interpretation of the Rome Statute, as well as conflicts between different objectives, led to the use of a functionalist approach by the court in interpreting the Statute. This weakens its basic function of protecting peopleʼs rights, violates the competences of the participating states and interferes with the principle of national sovereignty. The study addressed the need for victimological prevention of victims of international crimes, which should include improving the practice of treating victims, revising legislation, and developing new structures and services. It is also essential to provide information about the methods of abuse and the diversity of victims through various media formats

Noncanonical formation of SNX5 gene-derived circular RNA regulates cancer growth

Oral squamous cell carcinoma (OSCC) is a prevalent cancer worldwide, exhibiting unique regional prevalence. Despite advancements in diagnostics and therapy, the 5-year survival rate for patients has seen limited improvement. A deeper understanding of OSCC pathogenesis, especially its molecular underpinnings, is essential for improving detection, prevention, and treatment. In this context, noncoding RNAs, such as circular RNAs (circRNAs), have gained recognition as crucial regulators and potential biomarkers in OSCC progression. Our study highlights the discovery of previously uncharacterized circRNAs, including a SNX5 gene-derived circRNA, circSNX5, through deep sequencing of OSCC patient tissue transcriptomes. We established circSNX5’s tumor-specific expression and its strong correlation with patient survival using structure-specific and quantitative PCR analyses. In vitro and in vivo experiments underscored circSNX5 RNA’s regulatory role in cancer growth and metastasis. Further, our omics profiling and functional assays revealed that ADAM10 is a critical effector in circSNX5-mediated cancer progression, with circSNX5 maintaining ADAM10 expression by sponging miR-323. This novel circRNA-miRNA-mRNA regulatory axis significantly contributes to oral cancer progression and malignancy. Moreover, we discovered that circSNX5 RNA is produced via noncanonical sequential back-splicing of pre-mRNA, a process negatively regulated by the RNA-binding protein STAU1. This finding adds a new dimension to our understanding of exonic circRNA biogenesis in the eukaryotic transcriptome. Collectively, our findings offer a detailed mechanistic dissection and functional interpretation of a novel circRNA, shedding light on the role of the noncoding transcriptome in cancer biology and potentially paving the way for innovative therapeutic strategies.

Cancer Stemness Online: A Resource for Investigating Cancer Stemness and Associations with Immune Response.

Cancer progression involves the gradual loss of a differentiated phenotype and the acquisition of progenitor and stem-cell-like features, which are potential culprits of immunotherapy resistance. Although the state-of-art predictive computational methods have facilitated the prediction of cancer stemness, currently there is no efficient resource that can meet various usage requirements. Here, we present the Cancer Stemness Online, an integrated resource for efficiently scoring cancer stemness potential at the bulk and single-cell levels. The resource integrates 8 robust predictive algorithms as well as 27 signature gene sets associated with cancer stemness for predicting stemness scores. Downstream analyses were performed from five different aspects, including identifying the signature genes of cancer stemness, exploring the associations with cancer hallmarks, cellular states, the immune response, and communication with immune cells; investigating the contributions to patient survival; and performing a robustness analysis of cancer stemness among different methods. Moreover, the pre-calculated cancer stemness atlas for more than 40 cancer types can be accessed by users. Both the tables and diverse visualizations of the analytical results are available for download. Together, Cancer Stemness Online is a powerful resource for scoring cancer stemness and expanding the downstream functional interpretation, including immune response as well as cancer hallmarks. Cancer Stemness Online is freely accessible at http://bio-bigdata.hrbmu.edu.cn/CancerStemnessOnline.