Search

Background: Advanced-stage non-small cell lung cancer (NSCLC) poses treatment challenges, with immune checkpoint inhibitors (ICIs) as the main therapy. Emerging evidence suggests the gut microbiome significantly influences ICI efficacy. This study explores the link between the gut microbiome and ICI outcomes in NSCLC patients, using metatranscriptomic (MTR) signatures., Methods: We utilized a de novo assembly-based MTR analysis on fecal samples from 29 NSCLC patients undergoing ICI therapy, segmented according to progression-free survival (PFS) into long (> 6 months) and short (≤ 6 months) PFS groups. Through RNA sequencing, we employed the Trinity pipeline for assembly, MMSeqs2 for taxonomic classification, DESeq2 for differential expression (DE) analysis. We constructed Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost) machine learning (ML) algorithms and comprehensive microbial profiles., Results: We detected no significant differences concerning alpha-diversity, but we revealed a biologically relevant separation between the two patient groups in beta-diversity. Actinomycetota was significantly overrepresented in patients with short PFS (vs long PFS, 36.7% vs. 5.4%, p < 0.001), as was Euryarchaeota (1.3% vs. 0.002%, p = 0.009), while Bacillota showed higher prevalence in the long PFS group (66.2% vs. 42.3%, p = 0.007), when comparing the abundance of corresponding RNA reads. Among the 120 significant DEGs identified, cluster analysis clearly separated a large set of genes more active in patients with short PFS and a smaller set of genes more active in long PFS patients. Protein Domain Families (PFAMs) were analyzed to identify pathways enriched in patient groups. Pathways related to DNA synthesis and Translesion were more enriched in short PFS patients, while metabolism-related pathways were more enriched in long PFS patients. E. coli-derived PFAMs dominated in patients with long PFS. RF, SVM and XGBoost ML models all confirmed the predictive power of our selected RNA-based microbial signature, with ROC AUCs all greater than 0.84. Multivariate Cox regression tested with clinical confounders PD-L1 expression and chemotherapy history underscored the influence of n = 6 key RNA biomarkers on PFS., Conclusion: According to ML models specific gut microbiome MTR signatures' associate with ICI treated NSCLC outcomes. Specific gene clusters and taxa MTR gene expression might differentiate long vs short PFS., Competing Interests: Declarations Ethics approval and consent to participate In the current study, we adhered to the Helsinki Declaration’s study criteria established by the World Medical Association. The study was formally approved by the national ethics committee, specifically the Hungarian Scientific and Research Ethics Committee of the Medical Research Council (ETTTUKEB- 50302-2/2017/EKU). Participation in the study was contingent upon the provision of permission by all patients involved. To maintain confidentiality, patient IDs were removed after the collection of clinicopathological data, thereby preventing direct or indirect identification of patients. Consent for publication All authors agree to submit the article for publication. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024. The Author(s).)

Background: The organism-wide effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection are well studied, but little is known about the dynamics of how the infection spreads in time among or within cells due to the scarcity of suitable high-resolution experimental systems. It has been reported that SARS-CoV-2 infection pathways converge at calcium influx and subcellular calcium distribution changes. Imaging combined with a proper staining technique is an effective tool for studying subcellular calcium-related infection and replication mechanisms at such resolutions., Methods: Using two-photon (2P) fluorescence imaging with our novel Ca-selective dye, automated image analysis and clustering analysis were applied to reveal titer and variant effects on SARS-CoV-2-infected Vero E6 cells., Results: The application of a new calcium sensor molecule is shown, combined with a high-end 2P technique for imaging and identifying the patterns associated with cellular infection damage within cells. Vero E6 cells infected with SARS-CoV-2 variants, D614G or B.1.1.7, exhibit elevated cytosolic calcium levels, allowing infection monitoring by tracking the cellular changes in calcium level by the internalized calcium sensor. The imaging provides valuable information on how the level and intracellular distribution of calcium are perturbed during the infection. Moreover, two-photon calcium sensing allowed the distinction of infections by two studied viral variants via cluster analysis of the image parameters. This approach will facilitate the study of cellular correlates of infection and their quantification depending on viral variants and viral load., Conclusions: We propose a new two-photon microscopy-based method combined with a cell-internalized sensor to quantify the level of SARS-CoV-2 infection. We optimized the applied dye concentrations to not interfere with viral fusion and viral replication events. The presented method ensured the proper monitoring of viral infection, replication, and cell fate. It also enabled distinguishing intracellular details of cell damage, such as vacuole and apoptotic body formation. Using clustering analysis, 2P microscopy calcium fluorescence images were suitable to distinguish two different viral variants in cell cultures. Cellular harm levels read out by calcium imaging were quantitatively related to the initial viral multiplicity of infection numbers. Thus, 2P quantitative calcium imaging might be used as a correlate of infection or a correlate of activity in cellular antiviral studies., (© 2024. The Author(s).)

Background: The postsynaptic density is an elaborate protein network beneath the postsynaptic membrane involved in the molecular processes underlying learning and memory. The postsynaptic density is built up from the same major proteins but its exact composition and organization differs between synapses. Mutations perturbing protein: protein interactions generally occurring in this network might lead to effects specific for cell types or processes, the understanding of which can be especially challenging., Results: In this work we use systems biology-based modeling of protein complex distributions in a simplified set of major postsynaptic proteins to investigate the effect of a hypomorphic Shank mutation perturbing a single well-defined interaction. We use data sets with widely variable abundances of the constituent proteins. Our results suggest that the effect of the mutation is heavily dependent on the overall availability of all the protein components of the whole network and no trivial correspondence between the expression level of the directly affected proteins and overall complex distribution can be observed., Conclusions: Our results stress the importance of context-dependent interpretation of mutations. Even the weakening of a generally occurring protein: protein interaction might have well-defined effects, and these can not easily be predicted based only on the abundance of the proteins directly affected. Our results provide insight on how cell-specific effects can be exerted by a mutation perturbing a generally occurring interaction even when the wider interaction network is largely similar., (© 2024. The Author(s).)

Extracellular vesicles (EVs) constitute a vital component of intercellular communication, exerting significant influence on metastasis formation and drug resistance mechanisms. Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of its high metastatic potential and often acquired resistance to oncotherapies. The prevalence of BRAF mutations in MM underscores the importance of BRAF-targeted therapies, such as vemurafenib and dabrafenib, alone or in combination with the MEK inhibitor, trametinib. This study aimed to elucidate the involvement of EVs in MM progression and ascertain whether EV-mediated metastasis promotion persists during single agent BRAF (vemurafenib, dabrafenib), or MEK (trametinib) and combined BRAF/MEK (dabrafenib/trametinib) inhibition.Using five pairs of syngeneic melanoma cell lines, we assessed the impact of EVs - isolated from their respective supernatants - on melanoma cell proliferation and migration. Cell viability and spheroid growth assays were employed to evaluate proliferation, while migration was analyzed through mean squared displacement (MSD) and total traveled distance (TTD) measurements derived from video microscopy and single-cell tracking.Our results indicate that while EV treatments had remarkable promoting effect on cell migration, they exerted only a modest effect on cell proliferation and spheroid growth. Notably, EVs demonstrated the ability to mitigate the inhibitory effects of BRAF inhibitors, albeit they were ineffective against a MEK inhibitor and the combination of BRAF/MEK inhibitors. In summary, our findings contribute to the understanding of the intricate role played by EVs in tumor progression, metastasis, and drug resistance in MM., (© 2024. The Author(s).)

Background: A large body of evidence suggests that some people have a strong, obsessive attachment to a favorite celebrity. The absorption-addiction model attempts to account for this extreme attachment, sometimes labeled "celebrity worship." According to the model, a small portion of celebrity admirers ("celebrity worshipers") become absorbed in the personal lives of celebrities to compensate for perceived personal or social deficiencies. The purpose of this study is to examine how the absorption-addiction model relates to broader psychological theories that include non-celebrity contexts. Specifically, we examine how the absorption-addiction model relates to three theories: empty-self theory, extremism theory, and the dualistic model of passion., Methods: Participants (N = 399; 77.94% women, M age = 19.91 years, SD = 3.24) completed an online questionnaire measuring attraction to favorite celebrities. Constructs representing the three broader theories were compared to a measure of attraction to one's favorite celebrity., Results: Sense of emptiness, obsessive passion, and extremism were positively associated with celebrity attraction. The strongest association was found with extremism, though the effect was moderate., Conclusions: These findings suggest that extremism theory is the best fit of the three broader theories explaining celebrity worship, although its contribution to understanding celebrity worship is modest., (© 2024. The Author(s).)

Background: Finding and registering the maxillary-mandibular jaw relation is crucial in dental practice. Several comparative studies have been conducted to investigate the reproducibility and accuracy of techniques for determining the centric relation (CR) position of the mandible. The aim of our study was to determine which of seven different CR determination methods had the smallest deviation from the theoretical zero with the help of a digital mandibular motion analyser. The chosen theoretical zero position, the maximal intercuspal position (MIP), is the most reproducible and widely used position., Methods: Thirty-four volunteers (24 females and 10 males) with a mean (SD) age of 29.1 (± 7.3) years with a negative history of temporomandibular disorder (TMD) participated in the study. A digital mandibular motion analyser was used to register the condylar position after the use of each technique for the determination of CR. The calibration was performed to the maximal intercuspal position (MIP) for each volunteer. The investigated techniques were (A) the gothic arch tracer, (B) the adduction field method, (C) Dawson's bimanual manipulation, (D) the patient placing the tongue tip on the palatal rugae, (E) the patient placing the tongue tip to the border of the hard and soft palate, (F) the patient actively pulling the chin backwards, and (G) the examiner pushing the patient's chin back., Results: The position of the mandibular condyle was illustrated in a three-dimensional coordinate system, where the origin represented the MIP. Among the seven methods examined, five showed significant deviations compared to the MIP. Among these, two methods resulted in posterior deviation of the condyles. Methods C and E coincided with the MIP in all directions., Conclusions: Within the limitations of our study, we found that the smallest deviations from our theoretical zero (MIP) among the investigated centric relation determining methods were obtained with the bimanual mandibular manipulation technique derived from Dawson and the placement of the tongue tip on the border of the hard and soft palate (linguomandibular homotrophy theory)., (© 2024. The Author(s).)

Research has posited that social media use during the day may be reflected in nighttime dreams. Nevertheless, no prior studies have explored frightening, unpleasant dreams arising from social media use. This study introduces the construct of the social media-related nightmare by (a) developing and validating a scale capturing negative-valenced dreams with themes of helplessness, loss of control, inhibition, victimization, and making mistakes in social media, and (b) examining relationships between social media use, social media-related nightmares, sleep quality, and affective well-being. A convenience sample of 595 Iranian adult social media users (M age = 27.45, SD age = 11.42) reported on social media-related nightmare, social media use integration, anxiety, peace of mind, sleep quality, and nightmare distress. The Social Media-Related Nightmare Scale (SMNS) demonstrated a unidimensional structure with sound psychometric properties. The most common nightmares involved the inability to log in to social media and the disruption of relationships with other users. Social media use intensity predicted frequency of social media-related nightmares. These nightmares were correlated with increased anxiety, lower peace of mind, poor sleep quality, and nightmare distress. Importantly, social media-related nightmares mediated the relationship between social media use intensity and low affective well-being (i.e., anxiety and peace of mind), poor sleeping, and nightmare distress. The findings suggest that social media-related nightmares could be a potential pathway through which social media engagement may lead to affective distress and sleep difficulties., (© 2024. The Author(s).)

Background: Sympathy-seeking negative online self-disclosure, or "sadfishing," has proliferated in social media. This study investigates sadfishing by developing and validating a brief self-report questionnaire of the construct and exploring potential psychological correlates., Methods: A total of 345 Iranian adolescent social media users (M age = 16.29, SD age = 1.52) participated in the study. Participants completed the newly constructed Social Media Sadfishing Questionnaire, in addition to measures of anxiety, depression, attention seeking, perceived social support, and social media use integration., Results: Factor analyses revealed a unidimensional structure of the 5-item Social Media Sadfishing Questionnaire. The questionnaire yielded sound construct validity and internal consistency. Anxiety, depression, and attention seeking were positively associated with sadfishing, while perceived social support from family and friends was negatively associated with sadfishing. Negative online reactions to sadfishing were rare. Boys reported higher sadfishing tendencies than girls at age 12; however, sadfishing in boys declined at a higher rate than in girls with age., Conclusions: The findings suggest that negative affect and attention seeking, combined with feelings of low social support, can be associated with adolescent sadfishing on social media. The quantitative results shed new light on the contribution of psychosocial factors to sadfishing., (© 2023. The Author(s).)

Background: According to the 2010 European Health Interview Survey, 51% of women in Hungary have a chronic disease, and is among the poorest quartile in the EU countries. Thyroid diseases affected more than 650,000 women in 2021 based on a recent report by the Hungarian Central Statistical Office. Despite the high prevalence rates, quality of life in these patients is scarcely researched in Hungary. To fill this gap, this study aims to explore the associations of the quality of life of thyroid patients in Hungary with social support and adherence., Methods: A cross-sectional study was conducted via an online questionnaire. Data from 885 female Hungarian thyroid patients with pharmacological treatment (M = 35.6 years, SD = 10.7, age range: 18-73 years) were analyzed. Participants were divided into two patient groups based on the type of thyroid disorder: hypothyroidism (n = 824; 93.1%) and hyperthyroidism (n = 61; 6.9%). Group comparisons, correlations, and a mediation model were performed to explore differences between thyroid patients., Results: No differences were found between patients with different types of thyroid disorders in quality of life, adherence, and social support. Consistent, weak associations were found between quality of life and social support in both patient groups. Higher perceived social support partially explained the relationship between adherence and life quality in thyroid patients.  CONCLUSIONS: No substantial differences were found between patients with different types of thyroid disease in mental well-being indicators. These patients are psychologically more vulnerable and need a socially supportive environment to recover, because higher adherence is associated with a better quality of life, and social support can facilitate this process., (© 2023. The Author(s).)

Background: The construct of meaningful work (MW) has become the subject of various studies. Workers who experience MW have higher career and organizational commitment, report fewer days absent, and are characterized by a higher level of well-being. The aim of this study is to test a measure of MW, the Work and Meaning Inventory by Steger et al. This measure was created on theoretical background, and it constructs MW from three dimensions: psychological meaning, meaning-making, and greater good motivation., Methods: The analysis was conducted in a Hungarian sample (N = 2,498), using confirmatory factor analysis (CFA), and multiple-group CFA., Results: The three-dimensional model of the WAMI was confirmed in the analysis. In our study, the measure proved to be reliable, even in the test-retest analysis. Moreover, the discriminant and convergent validity of the WAMI was tested, with various relevant constructs: the presence and the search for life meaning, life satisfaction, and job satisfaction. Also a multiple-group CFA was conducted with the three-factor model, confirming measurement invariance regarding sex and working position., Conclusions: In line with the original version of the WAMI, the three-dimensional model was confirmed, with good psychometric properties in the Hungarian working context., (© 2022. The Author(s).)

Background: The investigation of possible interactions between two proteins in intracellular signaling is an expensive and laborious procedure in the wet-lab, therefore, several in silico approaches have been implemented to narrow down the candidates for future experimental validations. Reformulating the problem in the field of network theory, the set of proteins can be represented as the nodes of a network, while the interactions between them as the edges. The resulting protein-protein interaction (PPI) network enables the use of link prediction techniques in order to discover new probable connections. Therefore, here we aimed to offer a novel approach to the link prediction task in PPI networks, utilizing a generative machine learning model., Results: We created a tool that consists of two modules, the data processing framework and the machine learning model. As data processing, we used a modified breadth-first search algorithm to traverse the network and extract induced subgraphs, which served as image-like input data for our model. As machine learning, an image-to-image translation inspired conditional generative adversarial network (cGAN) model utilizing Wasserstein distance-based loss improved with gradient penalty was used, taking the combined representation from the data processing as input, and training the generator to predict the probable unknown edges in the provided induced subgraphs. Our link prediction tool was evaluated on the protein-protein interaction networks of five different species from the STRING database by calculating the area under the receiver operating characteristic, the precision-recall curves and the normalized discounted cumulative gain (AUROC, AUPRC, NDCG, respectively). Test runs yielded the averaged results of AUROC = 0.915, AUPRC = 0.176 and NDCG = 0.763 on all investigated species., Conclusion: We developed a software for the purpose of link prediction in PPI networks utilizing machine learning. The evaluation of our software serves as the first demonstration that a cGAN model, conditioned on raw topological features of the PPI network, is an applicable solution for the PPI prediction problem without requiring often unavailable molecular node attributes. The corresponding scripts are available at https://github.com/semmelweis-pharmacology/ppi&#95;pred ., (© 2022. The Author(s).)

Background: Almost two decades of research produced mixed findings on the relationship between celebrity worship and cognitive skills. Several studies demonstrated that cognitive performance slightly decreases with higher levels of celebrity worship, while other studies found no association between these constructs. This study has two aims: (1) to extend previous research on the association between celebrity worship and cognitive skills by applying the two-factor theory of intelligence by Cattell on a relatively large sample of Hungarian adults, and (2) to investigate the explanatory power of celebrity worship and other relevant variables in cognitive performance., Methods: A cross-sectional study design was used. Applying an online survey, a total of 1763 Hungarian adults (66.42% male, M age  = 37.22 years, SD = 11.38) completed two intelligence subtests designed to measure ability in vocabulary (Vocabulary Test) and digit symbol (Short Digit Symbol Test). Participants also completed the Celebrity Attitude Scale and the Rosenberg Self-esteem Scale. Subjective material wealth, current family income and general sociodemographics were also reported by participants., Results: Linear regression models indicated that celebrity worship was associated with lower performance on the cognitive tests even after controlling for demographic variables, material wealth and self-esteem, although the explanatory power was limited., Conclusions: These findings suggest that there is a direct association between celebrity worship and poorer performance on the cognitive tests that cannot be accounted for by demographic and socioeconomic factors., (© 2021. The Author(s).)

Background: For clinical practice it is important to evaluate and compare anxiety, depression and quality of life of glaucoma patients with painless one-eye blindness and a normal fellow eye to unaffected age-matched individuals from a similar environment., Methods: Twenty-eight stable glaucoma patients (age, mean ± SD: 69.0 ± 13.3 years) with one normal and one painless blind eye, and 26 controls (age: 67.0 ± 14.0 years) completed the standard Hungarian adaptations of the Beck Depression Inventory, Beck Anxiety Inventory, Spielberger-Trait Anxiety Inventory, Hopelessness Scale, and Quality of Life Questionnaire SF-36 with the assistance of trained psychologist interviewers within 3 months after a detailed ophthalmological examination., Results: The groups did not differ in age, gender distribution, number of children, grandchildren and people in their household (p ≥ 0.235). The best corrected visual acuity (BCVA) of the diseased eye was minimal (median: 0.00), while BCVA of their better eye (median: 1.0) did not differ from that of the control group (p ≥ 0.694). Compared to the control group, the patients' scores were significantly higher for depression (p ≤ 0.01), cognitive and psychophysiological symptoms of anxiety (p ≤ 0.05) and hopelessness (p ≤ 0.013), and lower (worse) for physical function, vitality, general health and bodily pain (p ≤ 0.045). No difference was found between the groups for mental health, physical role functioning, emotional role functioning and social role functioning (p ≥ 0.117)., Conclusion: Our results show that patients with glaucoma-related one-eye blindness may require regular psychological support even when the visual performance of the fellow eye is fully maintained on the long run, and the patients' everyday functioning is normal.

Background: For the understanding of human nature, the evolutionary roots of human moral behaviour are a key precondition. Our question is as follows: Can the altruistic moral rule "Risk your life to save your family members, if you want them to save your life" be evolutionary stable? There are three research approaches to investigate this problem: kin selection, group selection and population genetics modelling. The present study is strictly based on the last approach., Results: We consider monogamous and exogamous families, where at an autosomal locus, dominant-recessive alleles determine the phenotypes in a sexual population. Since all individuals' survival rate is determined by their altruistic family members, we introduce a new population genetics model based on the mating table approach and adapt the verbal definition of evolutionary stability to genotypes. In general, when the resident is recessive, a homozygote is an evolutionarily stable genotype (ESG), if the number of survivors of the resident genotype of the resident homozygote family is greater than that of non-resident heterozygote survivors of the family of the resident homozygote and mutant heterozygote genotypes. Using the introduced genotype dynamics we proved that in the recessive case ESG implies local stability of the altruistic genotype. We apply our general ESG conditions for self-sacrificing life history strategy when the number of new-born offspring does not depend on interactions within the family and the interactions are additive. We find that in this case our ESG conditions give back Hamilton's rule for evolutionary stability of the self-sacrificing life history strategy., Conclusions: In spite of the fact that the kidney transplantations was not a selection factor during the earlier human evolution, nowadays "self-sacrificing" can be observed in the live donor kidney transplantations, when the donor is one of the family members. It seems that selection for self-sacrificing in family produced an innate moral tendency in modulating social cognition in human brain.

Background: Switch-like and oscillatory dynamical systems are widely observed in biology. We investigate the simplest biological switch that is composed of a single molecule that can be autocatalytically converted between two opposing activity forms. We test how this simple network can keep its switching behaviour under perturbations in the system., Results: We show that this molecule can work as a robust bistable system, even for alterations in the reactions that drive the switching between various conformations. We propose that this single molecule system could work as a primitive biological sensor and show by steady state analysis of a mathematical model of the system that it could switch between possible states for changes in environmental signals. Particularly, we show that a single molecule phosphorylation-dephosphorylation switch could work as a nucleotide or energy sensor. We also notice that a given set of reductions in the reaction network can lead to the emergence of oscillatory behaviour., Conclusions: We propose that evolution could have converted this switch into a single molecule oscillator, which could have been used as a primitive timekeeper. We discuss how the structure of the simplest known circadian clock regulatory system, found in cyanobacteria, resembles the proposed single molecule oscillator. Besides, we speculate if such minimal systems could have existed in an RNA world.

Background: Bacterial species present in multispecies microbial communities often react to the same chemical signal but at vastly different concentrations. The existence of different response thresholds with respect to the same signal molecule has been well documented in quorum sensing which is one of the best studied inter-cellular signalling mechanisms in bacteria. The biological significance of this phenomenon is still poorly understood, and cannot be easily studied in nature or in laboratory models. The aim of this study is to establish the role of differential signal response thresholds in stabilizing microbial communities., Results: We tested binary competition scenarios using an agent-based model in which competing bacteria had different response levels with respect to signals, cooperation factors or both, respectively. While in previous scenarios fitter species outcompete slower growing competitors, we found that stable equilibria could form if the fitter species responded to a higher chemical concentration level than the slower growing competitor. We also found that species secreting antibiotic could form a stable community with other competing species if antibiotic production started at higher response thresholds., Conclusions: Microbial communities in nature rely on the stable coexistence of species that necessarily differ in their fitness. We found that differential response thresholds provide a simple and elegant way for keeping slower growing species within the community. High response thresholds can be considered as self-restraint of the fitter species that allows metabolically useful but slower growing species to remain within a community, and thereby the metabolic repertoire of the community will be maintained., Reviewers: This article was reviewed by Michael Gromiha, Sebastian Maurer-Stroh, István Simon and L. Aravind.

Background: Model based analysis of human upper limb movements has key importance in understanding the motor control processes of our nervous system. Various simulation software packages have been developed over the years to perform model based analysis. These packages provide computationally intensive-and therefore off-line-solutions to calculate the anatomical joint angles from motion captured raw measurement data (also referred as inverse kinematics). In addition, recent developments in inertial motion sensing technology show that it may replace large, immobile and expensive optical systems with small, mobile and cheaper solutions in cases when a laboratory-free measurement setup is needed. The objective of the presented work is to extend the workflow of measurement and analysis of human arm movements with an algorithm that allows accurate and real-time estimation of anatomical joint angles for a widely used OpenSim upper limb kinematic model when inertial sensors are used for movement recording., Methods: The internal structure of the selected upper limb model is analyzed and used as the underlying platform for the development of the proposed algorithm. Based on this structure, a prototype marker set is constructed that facilitates the reconstruction of model-based joint angles using orientation data directly available from inertial measurement systems. The mathematical formulation of the reconstruction algorithm is presented along with the validation of the algorithm on various platforms, including embedded environments., Results: Execution performance tables of the proposed algorithm show significant improvement on all tested platforms. Compared to OpenSim's Inverse Kinematics tool 50-15,000x speedup is achieved while maintaining numerical accuracy., Conclusions: The proposed algorithm is capable of real-time reconstruction of standardized anatomical joint angles even in embedded environments, establishing a new way for complex applications to take advantage of accurate and fast model-based inverse kinematics calculations.

Background: ChIP-seq provides a wealth of information on the approximate location of DNA-binding proteins genome-wide. It is known that the targeted motifs in most cases can be found at the peak centers. A high resolution mapping of ChIP-seq peaks could in principle allow the fine mapping of the protein constituents within protein complexes, but the current ChIP-seq analysis pipelines do not target the basepair resolution strand specific mapping of peak summits., Results: The approach proposed here is based on i) locating regions that are bound by a sufficient number of proteins constituting a complex; ii) determining the position of the underlying motif using either a direct or a de novo motif search approach; and iii) determining the exact location of the peak summits with respect to the binding motif in a strand specific manner. We applied this method for analyzing the CTCF/cohesin complex, which holds together DNA loops. The relative positions of the constituents of the complex were determined with one-basepair estimated accuracy. Mapping the positions on a 3D model of DNA made it possible to deduce the approximate local topology of the complex that allowed us to predict how the CTCF/cohesin complex locks the DNA loops. As the positioning of the proteins was not compatible with previous models of loop closure, we proposed a plausible "double embrace" model in which the DNA loop is held together by two adjacent cohesin rings in such a way that the ring anchored by CTCF to one DNA duplex encircles the other DNA double helix and vice versa., Conclusions: A motif-centered, strand specific analysis of ChIP-seq data improves the accuracy of determining peak positions. If a genome contains a large number of binding sites for a given protein complex, such as transcription factor heterodimers or transcription factor/cofactor complexes, the relative position of the constituent proteins on the DNA can be established with an accuracy that allow one to deduce the local topology of the protein complex. The proposed high resolution mapping approach of ChIP-seq data is applicable for detecting the contact topology of DNA-binding protein complexes.

Unlabelled: Histone lysine methyltransferases (HKMTs), catalyze mono-, di- and trimethylation of lysine residues, resulting in a regulatory pattern that controls gene expression. Their involvement in many different cellular processes and diseases makes HKMTs an intensively studied protein group, but scientific interest so far has been concentrated mostly on their catalytic domains. In this work we set out to analyze the structural heterogeneity of human HKMTs and found that many contain long intrinsically disordered regions (IDRs) that are conserved through vertebrate species. Our predictions show that these IDRs contain several linear motifs and conserved putative binding sites that harbor cancer-related SNPs. Although there are only limited data available in the literature, some of the predicted binding regions overlap with interacting segments identified experimentally. The importance of a disordered binding site is illustrated through the example of the ternary complex between MLL1, menin and LEDGF/p75. Our suggestion is that intrinsic protein disorder plays an as yet unrecognized role in epigenetic regulation, which needs to be further elucidated through structural and functional studies aimed specifically at the disordered regions of HKMTs., Reviewers: This article was reviewed by Arne Elofsson and Piotr Zielenkiewicz.