Functional Interpretation Research Articles

Isotropic reconstruction for electron tomography with deep learning

Cryogenic electron tomography (cryoET) allows visualization of cellular structures in situ. However, anisotropic resolution arising from the intrinsic “missing-wedge” problem has presented major challenges in visualization and interpretation of tomograms. Here, we have developed IsoNet, a deep learning-based software package that iteratively reconstructs the missing-wedge information and increases signal-to-noise ratio, using the knowledge learned from raw tomograms. Without the need for sub-tomogram averaging, IsoNet generates tomograms with significantly reduced resolution anisotropy. Applications of IsoNet to three representative types of cryoET data demonstrate greatly improved structural interpretability: resolving lattice defects in immature HIV particles, establishing architecture of the paraflagellar rod in Eukaryotic flagella, and identifying heptagon-containing clathrin cages inside a neuronal synapse of cultured cells. Therefore, by overcoming two fundamental limitations of cryoET, IsoNet enables functional interpretation of cellular tomograms without sub-tomogram averaging. Its application to high-resolution cellular tomograms should also help identify differently oriented complexes of the same kind for sub-tomogram averaging.

Exploration of Tools for the Interpretation of Human Non-Coding Variants.

The advent of Whole Genome Sequencing (WGS) broadened the genetic variation detection range, revealing the presence of variants even in non-coding regions of the genome, which would have been missed using targeted approaches. One of the most challenging issues in WGS analysis regards the interpretation of annotated variants. This review focuses on tools suitable for the functional annotation of variants falling into non-coding regions. It couples the description of non-coding genomic areas with the results and performance of existing tools for a functional interpretation of the effect of variants in these regions. Tools were tested in a controlled genomic scenario, representing the ground-truth and allowing us to determine software performance.

Unknown Gothic construction at the Latin Cathedral in Lviv

Little-known architectural and archaeological objects studied during the rescue archaeological research on the Cathedral Square in Lviv in 2006: remains of ancient wooden roads, a stone-brick building, and a brick fence of the temple area have been introduced into scientific circulation. Based on stratigraphic and historical-architectural analyses, the dating of the relics was justified, their functional interpretation was carried out, as well as the historical-cartographic identification of some of them. In the first cultural layers formed on a part of the area, complexes of finds from the Early Iron Age (VII–VI centuries BC) and Middle Ages (XI–XIII centuries) were discovered. Until the period of the locational city of the ХІV–ХVІ centuries two tiers of wooden roads were assigned, the discovered fragments of which have reached our days in a good condition of preservation. It was established that their construction consisted of transverse depressions, longitudinal timbers, and transverse boardwalks secured with wooden joints. It is noted that the found fragments of contours and directions of ancient roads indicate a freer planning structure of the Lviv city center in the Gothic period. An unknown stone-brick building located in the corner of the church area is recognized as one of the most mysterious. It was established that its deep pit cuts through a layer of stone paving on yellow sand, which covers a complex of wooden streets and can be dated back to the second quarter of the ХVІ century. Taking into account the Gothic style of brickwork preserved on the third tier of the interior, as well as the stratification of the internal filling, the construction is dated back to the third quarter of the ХVІ century and it was interpreted as the family tomb of one of the richest residents of the city. The unconventional spatial orientation of this type of building is associated with the possible contour of the fence of the area of the church cemetery, which in the plan had a corresponding break in the corner, and the later brick fence of the cathedral area appears in the ХVІІ – the first half of the ХVІІІ century when the burial construction was no longer functioning. It has been established that the cartographic analysis of the situation gives grounds to assume that in the 1760s the tomb was completely leveled, and in its place, there was a corner gate. It is noted that in 10 years, cartographers will record the appearance of a right angle of the fence at the corner of the plot, as well as the making of a new gate, limited by thickened pillars. It is indicated that the foundation of one of them was identified and recorded during archaeological research. As a result of rescue excavations, some architectural and archaeological relics were identified in the modern environment of the square to emphasize the importance of these objects of cultural heritage in the history of Lviv. Key words: Lviv, architectural archaeology, Gothic construction, stone fence, wooden streets, cultural heritage.

Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT

Rare copy number variants (CNVs) are among the most common genomic disorders underlying CAKUT. miRNAs located in rare CNVs represent well-founded functional variants for human CAKUT research. The study aimed to identify and functionally interpret miRNAs most frequently affected by rare CNVs in CAKUT and to estimate the overall burden of rare CNVs on miRNA genes in CAKUT. The additional aim of this study was to experimentally confirm the effect of a rare CNV in CAKUT on candidate miRNA’s expression and the subsequent change in mRNA levels of selected target genes. A database of CAKUT-associated rare CNV regions, created by literature mining, was used for mapping of the miRNA precursors. miRNAs and miRNA families, most frequently affected by rare CAKUT-associated CNVs, have been subjected to bioinformatic analysis. CNV burden analysis was performed to identify chromosomes with over/underrepresentation of miRNA genes in rare CNVs associated with CAKUT. A functional study was performed on HEK293 MIR484+/- KO and HEK293 WT cell lines, followed by the analysis of relative miRNA and mRNA target gene levels. 80% of CAKUT patients with underlying rare CNV had at least one miRNA gene overlapping the identified CNV. Network analysis of the most frequently affected miRNAs has revealed the dominant regulation of the two miRNAs, hsa-miR-484 and hsa-miR-185-5p. Additionally, miR-548 family members have shown substantial enrichment in rare CNVs in CAKUT. An over/underrepresentation of miRNA genes in rare CNVs associated with CAKUT was observed in multiple chromosomes, such as chr16, chr20, and chr21. A significant 0.37 fold downregulation of hsa-miR-484, followed by a notable upregulation of MDM2 and APAF1 and downregulation of NOTCH3 was detected in HEK293 MIR484+/- KO compared to HEK293 WT cell lines, supporting the study hypothesis. miRNA genes are frequently affected by rare CNVs in CAKUT patients. Understanding the potential of CNV-affected miRNAs to participate in CAKUT as genetic drivers represent a crucial implication for the development of novel therapeutic approaches.

DeepPerVar: a multi-modal deep learning framework for functional interpretation of genetic variants in personal genome.

Understanding the functional consequence of genetic variants, especially the non-coding ones, is important but particularly challenging. Genome-wide association studies (GWAS) or quantitative trait locus analyses may be subject to limited statistical power and linkage disequilibrium, and thus are less optimal to pinpoint the causal variants. Moreover, most existing machine-learning approaches, which exploit the functional annotations to interpret and prioritize putative causal variants, cannot accommodate the heterogeneity of personal genetic variations and traits in a population study, targeting a specific disease. By leveraging paired whole-genome sequencing data and epigenetic functional assays in a population study, we propose a multi-modal deep learning framework to predict genome-wide quantitative epigenetic signals by considering both personal genetic variations and traits. The proposed approach can further evaluate the functional consequence of non-coding variants on an individual level by quantifying the allelic difference of predicted epigenetic signals. By applying the approach to the ROSMAP cohort studying Alzheimer's disease (AD), we demonstrate that the proposed approach can accurately predict quantitative genome-wide epigenetic signals and in key genomic regions of AD causal genes, learn canonical motifs reported to regulate gene expression of AD causal genes, improve the partitioning heritability analysis and prioritize putative causal variants in a GWAS risk locus. Finally, we release the proposed deep learning model as a stand-alone Python toolkit and a web server. https://github.com/lichen-lab/DeepPerVar. Supplementary data are available at Bioinformatics online.

Maria Hämeen-Anttila and Jan von Plato, eds,Kurt Gödel: The Princeton Lectures on Intuitionism

This book publishes for the first time notes from two notebooks of Gödel which formed the basis of a course on intuitionism Gödel delivered at Princeton in the spring of 1941. These notes contain by far the most detailed treatment by Gödel (and anyone prior to Luckhardt [1973] and Troelstra [1973]) of his now famous functional (‘Dialectica’) interpretation which was published by Gödel himself only much later in the very brief paper [Gödel, 1958]. The essence of the Princeton notes is close to that of Gödel’s lecture at Yale from April 15, 1941, which was posthumously published in [Gödel, 1995], pp. 189–200. (See [Troelstra, 1995] for insightful comments on these notes.) However, the notes for the course given at Princeton are much more detailed covering in total nine lectures and contain interesting additional material and insights into what Gödel aimed to achieve by his interpretation. After Gödel’s functional interpretation was made public first by Kreisel in [1959] and then by Gödel himself in the aforementioned paper [1958], it received some constant interest until the early 70s, but then this interest declined for a while as Gentzen-style methods were considered to be superior being ‘ordinal informative’ and in 1978 the so-called |$A$|-translation [Friedman, 1978; Dragalin, 1980] provided a simple proof of the closure of intuitionistic systems such as Heyting arithmetic (HA) under Markov’s rule which by that time was considered to be a main application of the Dialectica interpretation. Beginning in the 90s (starting with [Kohlenbach, 1992]), Gödel’s functional interpretation saw a revival as a major tool in the emerging proof mining paradigm which aims at extracting new effective data from prima facie noneffective proofs in many areas of mathematics, most prominently in (nonlinear) analysis (see, e.g., [Kohlenbach, 2008]). This led to the development of many variants and extensions of Gödel’s original interpretation and numerous applications to core mathematics. By now, Gödel’s Dialectica paper [1958] is his second most cited (both according to Zentralblatt and MathSciNet) work on mathematical logic next to his celebrated incompleteness paper. Given this massive renewed interest in the Dialectica interpretation in the past thirty years, the publication of Gödel’s extensive course notes on the subject is of course highly relevant although some of its content had been already commented on in [Troelstra, 1995] (while certain parts of the notes were only discovered in 2017 according to the preface1). As these notes were written at the time when Gödel conceived his interpretation and contain many comments for himself on how to present things best in the lectures, they provide an insight into the way Gödel worked allowing the reader to, in a sense, look over his shoulder while he is working. That Gödel is still struggling himself with the material is illustrated by the fact that in one lecture he gives a wrong definition for the interpretation of ‘|$\vee$|’ (as in the notes to his Yale lecture) which he then acknowledges as false in the next lecture presenting a second attempt which is the final solution as known today.

Unveiling the complete genome sequence of Alicyclobacillus acidoterrestris DSM 3922T, a taint-producing strain.

Several species from the Alicyclobacillus genus have received much attention from the food and beverages industries. Their presence has been co-related with spoilage events of acidic food matrices, namely fruit juices and other fruit-based products, the majority attributed to Alicyclobacillus acidoterrestris. In this work, a combination of short and long reads enabled the assembly of the complete genome of A. acidoterrestris DSM 3922T, perfecting the draft genome already available (AURB00000000), and revealing the presence of one chromosome (4,222,202 bp; GC content 52.3%) as well as one plasmid (124,737 bp; GC content 46.6%). From the 4,288 genes identified, 4,004 sequences were attributed to coding sequences with proteins, with more than 80% being functionally annotated. This allowed the identification of metabolic pathways and networks and the interpretation of high-level functions with significant reliability. Furthermore, the additional genes of interest related to spore germination, off-flavor production, namely the vdc cluster, and CRISPR arrays, were identified. More importantly, this is the first complete and closed genome sequence for a taint-producing Alicyclobacillus species and thus represents a valuable reference for further comparative and functional genomic studies.

Technical note: investigating activity-induced 3d hand entheseal variation in a documented South African sample

For reconstructing physical activity in the past, the surfaces of bones where muscles and ligaments attach, “entheses,” are routinely studied. Previous research has introduced an experimentally validated virtual approach for reconstructing habitual activity based on entheses. The present study relies on this virtual method to further investigate the effects of various biological factors on entheses, including variation by ancestry. Our skeletal sample includes 39 individuals from the well-preserved Pretoria Bone Collection in South Africa. Although the size of the sample is limited, all selected individuals present excellently preserved left- and right-hand bones. Moreover, all individuals are reliably documented for sex, biological age, and ancestry (i.e., African or European origin). Multivariate analyses were run on both raw and size-adjusted hand entheseal three-dimensional measurements. Our findings showed that, after size adjustment, entheseal multivariate patterns did not significantly vary by sex, biological age, or estimated body mass. However, a significant (p-value = 0.01) variation was found between individuals of different ancestries in only the right-hand side of our South African skeletal sample. The observed entheseal patterns were consistent with the habitual performance of power grasping in individuals of African origin, while our small sample’s European individuals showed distinctive indications of precision grasping behaviors. This pilot research provided important new insights into potentially activity-induced differences between population samples from South Africa, supporting the value of the applied protocol in reconstructing aspects of past human lifestyles. In the future, the functional interpretations of this study on interpopulation variation may be validated using increased sample sizes and individuals with long-term occupational documentation.

Porosity, Porosity Heterogeneity and Morphology Characterization of Microporous Layers of Commercial Gdls

Porosity and morphology of MPLs have a remarkable influence on the performance of PEFCs. However, until now, MPL porosity is largely undetermined for all commercial gas diffusion layers and the MPLs are commonly thought of as a homogeneous layer in thickness and porosity. Many model studies are based on this picture. However, these assumptions are not evidence-based, and can lead to erroneous interpretations of MPL functions. The challenge of having realistic models of MPLs lies in the lack of descriptions of MPL properties on the representative millimeter scale, while its pore structure is on the nanometer scale.Here, we use laboratory-based, X-ray tomographic microscopy (XTM) to determine the porosity, thickness and their spatial heterogeneity of microporous layers from 15 commercial GDL materials on the operation-relevant, millimeter scale. These properties are relevant to the diffusive transport through diffusion media (cf. Fick’s law).The porosity distribution is measured by quantifying the volume fraction of a saturating liquid, n-decane, in the fully saturated MPL with a large field of view (FoV) of >10 mm2 and a voxel edge length (determining the image resolution) of 3.6 μm. With optimized X-ray quantum noise control, regional average porosity differences >4.7% can be determined with a 95% confidence level (for every 50 μm 50 μm regions). This resolution in porosity determination allows to define and quantify the degree of spatial porosity heterogeneity for every MPL—a property of MPL that was previously unclear.Together with the MPL thickness heterogeneity (related to intrusion depth), the MPLs of the 15 commercially available gas diffusion layers from the three international manufactures Freudenberg, Sigracet® and CeTech, are characterized and classified into 5 groups. Contrary to the common homogeneous assumption, the majority of characterized MPLs (especially from Sigracet® and CeTech) actually come with various degrees of porosity and thickness heterogeneity. These differences among MPLs could result in very different water management properties of the respective GDL materials. The representative descriptions of MPL porosity, porosity heterogeneity and thickness heterogeneity also provides realistic input to modeling. Figure 1

Imago Dei, Ontological and Relational Interpretations. Introducing Edith Stein to the Debate

The complex theological treatment of the person as imago Dei has focused on ontological, functional, relational or eschatological interpretations, which either belong or possibly belong to all human beings. It is however unusual to encounter a reflection on the person’s intrinsic uniqueness as imago Dei. For Edith Stein intrinsic or a priori individuality refers to a unique quality of the person’s soul which unfolds more or less fully in the unity of the person’s body-soul-spirit unity: «the soul is destined for eternal being, and this destination explains why the soul is called upon to be an image of God in a “wholly personal manner.”» (FEB 504 [422]) This ontological approach contributes to a consideration of interpersonal enrichment through love, as a way to personal fulfilment and to complementarity through communion. An ontological approach to personal individuality thus paradoxically leads to the discovery of the existential primacy of relationality.

Imago Dei, Ontological and Relational Interpretations. Introducing Edith Stein to the Debate

The complex theological treatment of the person as imago Dei has focused on ontological, functional, relational or eschatological interpretations, which either belong or possibly belong to all human beings. It is however unusual to encounter a reflection on the person’s intrinsic uniqueness as imago Dei. For Edith Stein intrinsic or a priori individuality refers to a unique quality of the person’s soul which unfolds more or less fully in the unity of the person’s body-soul-spirit unity: «the soul is destined for eternal being, and this destination explains why the soul is called upon to be an image of God in a “wholly personal manner.”» (FEB 504 [422]) This ontological approach contributes to a consideration of interpersonal enrichment through love, as a way to personal fulfilment and to complementarity through communion. An ontological approach to personal individuality thus paradoxically leads to the discovery of the existential primacy of relationality.

Neuromaps: structural and functional interpretation of brain maps

Imaging technologies are increasingly used to generate high-resolution reference maps of brain structure and function. Comparing experimentally generated maps to these reference maps facilitates cross-disciplinary scientific discovery. Although recent data sharing initiatives increase the accessibility of brain maps, data are often shared in disparate coordinate systems, precluding systematic and accurate comparisons. Here we introduce neuromaps, a toolbox for accessing, transforming and analyzing structural and functional brain annotations. We implement functionalities for generating high-quality transformations between four standard coordinate systems. The toolbox includes curated reference maps and biological ontologies of the human brain, such as molecular, microstructural, electrophysiological, developmental and functional ontologies. Robust quantitative assessment of map-to-map similarity is enabled via a suite of spatial autocorrelation-preserving null models. neuromaps combines open-access data with transparent functionality for standardizing and comparing brain maps, providing a systematic workflow for comprehensive structural and functional annotation enrichment analysis of the human brain.

Walking speed influences spatiotemporal but not symmetry measures of gait in children and adolescents with hemiplegia

BackgroundThe measurement of gait is likely influenced by walking speed in children with hemiplegia, but this relationship is not well characterized. Research questionWhat is the influence of walking speed on spatiotemporal and symmetry measures of gait in children with hemiplegia, with consideration of side and footwear condition? MethodsChildren with hemiparetic gait due to stroke were recruited for a small pilot intervention study. Participants walked at self-selected and fast speeds while barefoot and while wearing shoes. Data from baseline sessions were included in this analysis. The influence of walking speed on five spatiotemporal gait measures was determined using a generalized estimating equation to calculate the proportion of variability in the gait measures that was explained by walking speed. Differences between sides and footwear conditions, and the relationships between walking speed and two symmetry measures, are also reported. ResultsA total of 820 steps were analyzed from ten children (11.2 ± 4.1 years). Walking velocity significantly influenced all spatiotemporal measures of gait. As speed increased, step length increased and all temporal measures decreased, on both paretic and nonparetic sides. Wearing shoes increased step length and stance time for both paretic and nonparetic sides, and slowed step time on the nonparetic side. Regardless of footwear, the paretic side demonstrated slower step and swing times, and faster stance and single support times. We did not observe significant relationships between walking speed and gait symmetry. SignificanceOur observations suggest that walking speed alone influences the spatiotemporal measurement of gait in children with hemiplegia and should be considered in the interpretation of walking function. Yet, controlling for walking speed is often not feasible or not preferred in this population. We offer suggestions for clinicians and researchers who seek to measure gait during overground walking at freely-selected speeds.

Characterization of circular RNAs with advanced sequencing technologies in human complex diseases.

Circular RNAs (circRNAs) are one category of non-coding RNAs that do not possess 5' caps and 3' free ends. Instead, they are derived in closed circle forms from pre-mRNAs by a non-canonical splicing mechanism named "back-splicing." CircRNAs were discovered four decades ago, initially called "scrambled exons." Compared to linear RNAs, the expression levels of circRNAs are considerably lower, and it is challenging to identify circRNAs specifically. Thus, the biological relevance of circRNAs has been underappreciated until the advancement of next generation sequencing (NGS) technology. The biological insights of circRNAs, such as their tissue-specific expression patterns, biogenesis factors, and functional effects in complex diseases, namely human cancers, have been extensively explored in the last decade. With the invention of the third generation sequencing (TGS) with longer sequencing reads and newly designed strategies to characterize full-length circRNAs, the panorama of circRNAs in human complex diseases could be further unveiled. In this review, we first introduce the history of circular RNA detection. Next, we describe widely adopted NGS-based methods and the recently established TGS-based approaches capable of characterizing circRNAs in full-length. We then summarize data resources and representative circRNA functional studies related to human complex diseases. In the last section, we reviewed computational tools and discuss the potential advantages of utilizing advanced sequencing approaches to a functional interpretation of full-length circRNAs in complex diseases. This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA in Disease and Development > RNA in Disease.

Population-level variation in enhancer expression identifies disease mechanisms in the human brain.

Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding population-level variation in enhancer function in the human brain. Besides regulating tissue-specific and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. By jointly analyzing large-scale cell-type-specific transcriptome and regulome data, we cataloged 30,795 neuronal and 23,265 non-neuronal candidate transcribed enhancers. Examination of the transcriptome in 1,382 brain samples identified robust expression of transcribed enhancers. We explored gene-enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified expression quantitative trait loci (eQTLs) for both genes and enhancers and found that enhancer eQTLs mediate a substantial fraction of neuropsychiatric trait heritability. Inclusion of enhancer eQTLs in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the gene-enhancer regulome and genetic mechanisms in the human cortex in both healthy and diseased states.

Molecular Mechanisms Underlying Qi-Invigorating Effects in Traditional Medicine: Network Pharmacology-Based Study on the Unique Functions of Qi-Invigorating Herb Group.

Qi-invigorating herbs (QIHs) are a group of herbs that invigorate Qi, the most vital force for maintaining the physiological functions of the human body in traditional medicine. However, the mechanism underlying the Qi-invigorating effects remains unclear. This study aimed to elucidate the unique mechanisms of QIHs based on unique compounds, using a network pharmacology approach. QIHs and their compounds were identified using existing literature and the TCMSP database, respectively. Subsequently, a method was proposed to screen for unique compounds that are common in QIHs but rare in other traditional herbs. Unique compounds’ targets were predicted using the TCMSP, BATMAN-TCM, and SwissTargetPrediction databases. Finally, enriched GO and KEGG pathways were obtained using DAVID to uncover the biomolecular functions and mechanisms. Thirteen unique compounds, mainly including amino acids and vitamins that participate in energy metabolism and improve Qi deficiency syndrome, were identified among the eight QIHs. GO and KEGG pathway analyses revealed that these compounds commonly participate in neuroactive ligand–receptor interaction and the metabolism of amino acids, and are related to the components of mitochondria and neuronal cells. Our results appropriately reflect the characteristics of traditional Qi-invigorating effects; therefore, this study facilitates the scientific interpretation of Qi functions and provides evidence regarding the treatment effectiveness of QIHs.

Effects of weight loss through lifestyle changes on heart rate variability in overweight and obese patients: A systematic review

The effects of calorie restriction and physical activity on autonomic regulation and cardiac vagal control in overweight and obese individuals remain inconsistent. Thus, this systematic review aimed to evaluate the weight loss effects through lifestyle changes on heart rate variability (HRV) markers in overweight and obese subjects. A systematic search for studies published up to November 2021 was conducted in MEDLINE, Embase, EBSCO host and VHL REGIONAL/LILACS. The main outcomes were changes in HRV indices from pre- and post-nutritional intervention and exercise in overweight and obese individuals. This review was registered in PROSPERO: CRD42021274467. The literature search retrieved 959 articles, of which 12 were included in this review. The intervention in nine studies was diet only, in two studies was diet and exercise, and in one study diet was compared to diet and exercise. The weight loss was greater than 10% in four studies and between 5 and 10% in three studies. Most of the studies revealed that weight loss through lifestyle changes seems to promote beneficial effects on HRV, restoring sympathovagal balance by increasing parasympathetic activity and reducing sympathetic activation. This systematic review exhibited the beneficial effects of weight loss through lifestyle changes on cardiac autonomic control in overweight and obese individuals. Future investigations need standardization of HRV indices for better interpretation of autonomic function in different clinical situations.

D-StructMAn: Containerized structural annotation on the scale from genetic variants to whole proteomes.

BackgroundStructural annotation of genetic variants in the context of intermolecular interactions and protein stability can shed light onto mechanisms of disease-related phenotypes. Three-dimensional structures of related proteins in complexes with other proteins, nucleic acids, or ligands enrich such functional interpretation, since intermolecular interactions are well conserved in evolution.ResultsWe present d-StructMAn, a novel computational method that enables structural annotation of local genetic variants, such as single-nucleotide variants and in-frame indels, and implements it in a highly efficient and user-friendly tool provided as a Docker container. Using d-StructMAn, we annotated several very large sets of human genetic variants, including all variants from ClinVar and all amino acid positions in the human proteome. We were able to provide annotation for more than 46% of positions in the human proteome representing over 60% proteins.Conclusionsd-StructMAn is the first of its kind and a highly efficient tool for structural annotation of protein-coding genetic variation in the context of observed and potential intermolecular interactions. d-StructMAn is readily applicable to proteome-scale datasets and can be an instrumental building machine-learning tool for predicting genotype-to-phenotype relationships.

Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion.

Thyroid hormones (THs), including T4 and T3, are produced and released by the thyroid gland under the stimulation of thyroid-stimulating hormone (TSH). The homeostasis of THs is regulated via the coordination of the hypothalamic-pituitary-thyroid axis, plasma binding proteins, and local metabolism in tissues. TH synthesis and secretion in the thyrocytes-containing thyroid follicles are exquisitely regulated by an elaborate molecular network comprising enzymes, transporters, signal transduction machineries, and transcription factors. In this article, we synthesized the relevant literature, organized and dissected the complex intrathyroidal regulatory network into structures amenable to functional interpretation and systems-level modeling. Multiple intertwined feedforward and feedback motifs were identified and described, centering around the transcriptional and posttranslational regulations involved in TH synthesis and secretion, including those underpinning the Wolff-Chaikoff and Plummer effects and thyroglobulin-mediated feedback regulation. A more thorough characterization of the intrathyroidal network from a systems biology perspective, including its topology, constituent network motifs, and nonlinear quantitative properties, can help us to better understand and predict the thyroidal dynamics in response to physiological signals, therapeutic interventions, and environmental disruptions.

Forest formulas of discrete Green's functions

AbstractThe discrete Green's functions are the pseudoinverse (or the inverse) of the Laplacian (or its variations) of a graph. In this article, we will give combinatorial interpretations of Green's functions in terms of enumerating trees and forests in a graph that will be used to derive further formulas for several graph invariants. For example, we show that the trace of the Green's function associated with the combinatorial Laplacian of a connected simple graph on vertices satisfies where denotes the eigenvalues of the combinatorial Laplacian, denotes the number of spanning trees, and denotes the set of rooted spanning 2‐forests in . We will prove forest formulas for discrete Green's functions for directed and weighted graphs and apply them to study random walks on graphs and digraphs. We derive a forest expression of the hitting time for digraphs, which gives combinatorial proofs to old and new results about hitting times, traces of discrete Green's functions, and other related quantities.