Widespread macromolecular interaction perturbations in human genetic disorders.

How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.

A reference map of the human binary protein interactome.

Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype-phenotype relationships1,2. Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration of HuRI with genome3, transcriptome4 and proteome5 data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein-protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes.

Neuroscience Needs Network Science.

The brain is a complex system comprising a myriad of interacting neurons, posing significant challenges in understanding its structure, function, and dynamics. Network science has emerged as a powerful tool for studying such interconnected systems, offering a framework for integrating multiscale data and complexity. To date, network methods have significantly advanced functional imaging studies of the human brain and have facilitated the development of control theory-based applications for directing brain activity. Here, we discuss emerging frontiers for network neuroscience in the brain atlas era, addressing the challenges and opportunities in integrating multiple data streams for understanding the neural transitions from development to healthy function to disease. We underscore the importance of fostering interdisciplinary opportunities through workshops, conferences, and funding initiatives, such as supporting students and postdoctoral fellows with interests in both disciplines. By bringing together the network science and neuroscience communities, we can develop novel network-based methods tailored to neural circuits, paving the way toward a deeper understanding of the brain and its functions, as well as offering new challenges for network science.

Host space, not energy or symbiont size, constrains feather mite abundance across passerine bird species.

Comprehending symbiont abundance among host species is a major ecological endeavour, and the metabolic theory of ecology has been proposed to understand what constrains symbiont populations. We parameterized metabolic theory equations to investigate how bird species' body size and the body size of their feather mites relate to mite abundance according to four potential energy (uropygial gland size) and space constraints (wing area, total length of barbs and number of feather barbs). Predictions were compared with the empirical scaling of feather mite abundance across 106 passerine bird species (26,604 individual birds sampled), using phylogenetic modelling and quantile regression. Feather mite abundance was strongly constrained by host space (number of feather barbs) but not by energy. Moreover, feather mite species' body size was unrelated to the body size of their host species. We discuss the implications of our results for our understanding of the bird-feather mite system and for symbiont abundance in general.

Proteomic Analysis Uncovers Measles Virus Protein C Interaction With p65-iASPP Protein Complex.

Viruses manipulate the central machineries of host cells to their advantage. They prevent host cell antiviral responses to create a favorable environment for their survival and propagation. Measles virus (MV) encodes two nonstructural proteins MV-V and MV-C known to counteract the host interferon response and to regulate cell death pathways. Several molecular mechanisms underlining MV-V regulation of innate immunity and cell death pathways have been proposed, whereas MV-C host-interacting proteins are less studied. We suggest that some cellular factors that are controlled by MV-C protein during viral replication could be components of innate immunity and the cell death pathways. To determine which host factors are targeted by MV-C, we captured both direct and indirect host-interacting proteins of MV-C protein. For this, we used a strategy based on recombinant viruses expressing tagged viral proteins followed by affinity purification and a bottom-up mass spectrometry analysis. From the list of host proteins specifically interacting with MV-C protein in different cell lines, we selected the host targets that belong to immunity and cell death pathways for further validation. Direct protein interaction partners of MV-C were determined by applying protein complementation assay and the bioluminescence resonance energy transfer approach. As a result, we found that MV-C protein specifically interacts with p65-iASPP protein complex that controls both cell death and innate immunity pathways and evaluated the significance of these host factors on virus replication.

Uncovering the genetic blueprint of the C. elegans nervous system.

Despite rapid advances in connectome mapping and neuronal genetics, we lack theoretical and computational tools to unveil, in an experimentally testable fashion, the genetic mechanisms that govern neuronal wiring. Here we introduce a computational framework to link the adjacency matrix of a connectome to the expression patterns of its neurons, helping us uncover a set of genetic rules that govern the interactions between neurons in contact. The method incorporates the biological realities of the system, accounting for noise from data collection limitations, as well as spatial restrictions. The resulting methodology allows us to infer a network of 19 innexin interactions that govern the formation of gap junctions in Caenorhabditis elegans, five of which are already supported by experimental data. As advances in single-cell gene expression profiling increase the accuracy and the coverage of the data, the developed framework will allow researchers to systematically infer experimentally testable connection rules, offering mechanistic predictions for synapse and gap junction formation.

Elevated FAI Index of Pericoronary Inflammation on Coronary CT Identifies Increased Risk of Coronary Plaque Vulnerability after COVID-19 Infection.

Inflammation is a key factor in the development of atherosclerosis, a disease characterized by the buildup of plaque in the arteries. COVID-19 infection is known to cause systemic inflammation, but its impact on local plaque vulnerability is unclear. Our study aimed to investigate the impact of COVID-19 infection on coronary artery disease (CAD) in patients who underwent computed tomography angiography (CCTA) for chest pain in the early stages after infection, using an AI-powered solution called CaRi-Heart®. The study included 158 patients (mean age was 61.63 ± 10.14 years) with angina and low to intermediate clinical likelihood of CAD, with 75 having a previous COVID-19 infection and 83 without infection. The results showed that patients who had a previous COVID-19 infection had higher levels of pericoronary inflammation than those who did not have a COVID-19 infection, suggesting that COVID-19 may increase the risk of coronary plaque destabilization. This study highlights the potential long-term impact of COVID-19 on cardiovascular health, and the importance of monitoring and managing cardiovascular risk factors in patients recovering from COVID-19 infection. The AI-powered CaRi-Heart® technology may offer a non-invasive way to detect coronary artery inflammation and plaque instability in patients with COVID-19.

The EntOptLayout Cytoscape plug-in for the efficient visualization of major protein complexes in protein-protein interaction and signalling networks.

MOTIVATION: Network visualizations of complex biological datasets usually result in 'hairball' images, which do not discriminate network modules. RESULTS: We present the EntOptLayout Cytoscape plug-in based on a recently developed network representation theory. The plug-in provides an efficient visualization of network modules, which represent major protein complexes in protein-protein interaction and signalling networks. Importantly, the tool gives a quality score of the network visualization by calculating the information loss between the input data and the visual representation showing a 3- to 25-fold improvement over conventional methods. AVAILABILITY AND IMPLEMENTATION: The plug-in (running on Windows, Linux, or Mac OS) and its tutorial (both in written and video forms) can be downloaded freely under the terms of the MIT license from: http://apps.cytoscape.org/apps/entoptlayout. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

TiO2/Ag-TiO2 Nanohybrid Films are Cytocompatible with Primary Epithelial Cells of Human Origin: An In Vitro Study.

Failure of dental implants is caused mainly by peri-implant infections resulting in loss of supporting bone. Since there is no ideal therapy of peri-implantitis, the focus of research has been shifted toward better prevention and the development of antibacterial surfaces. In our study we examined the attachment and proliferation of primary epithelial and MG-63 osteosarcoma cells on Ti dental implants coated with photocatalytic nanohybrid films. Two polyacrylate resin based layers were investigated on commercially pure (CP4) Ti discs: 60 wt% TiO2/40 wt% copolymer and 60 wt% Ag-TiO2/40 wt% copolymer ([Ag] = 0,001 wt%). Surface properties were examined by scanning electron microscopy (SEM) and profilometry. Cell responses were investigated via dimethylthiazol-diphenyl tetrazolium bromide (MTT) and visualized with fluorescence microscopy. Profilometry revealed significant changes in surface roughness of TiO2 (Ra = 1.79 µm) and Ag-TiO2 layers (Ra = 5.76 µm) compared to the polished (Ra(P) = 0.13 µm) and sandblasted, acid-etched control surfaces (Ra(SA) = 1.26 µm). MTT results demonstrated that the attachment (24 h) of epithelial cells was significantly higher on the Ag-TiO2 coated samples (OD540 = 0.079) than on the polished control surfaces (OD540 = 0.046), whereas MG-63 cells did not show any difference in attachment between the groups. After one week, epithelial cells showed slightly increased survival as compared to MG-63 cells. The results suggest that the tested coatings are cytocompatible with epithelial cells, which means that they are not only antibacterial, but they also appear to be promising candidates for implantological use.

Disappearance of Idiopathic Outflow Tract Premature Ventricular Contractions After Catheter Ablation of Overt Accessory Pathways.

BACKGROUND: Multiple mechanisms have been proposed for idiopathic premature ventricular contractions (PVCs) originating from the outflow tracts (OTs). Recent observations such as the coexistence of these arrhythmias with atrioventricular nodal reentrant tachycardias and the association between discrete prepotentials and successful ablation sites of ventricular arrhythmias (VAs) from the OTs suggest a common link. OBJECTIVE: In this case series we draw attention to a unique association between accessory pathways (APs) and idiopathic PVCs from the OTs, disappearing after AP ablation. METHODS: We identified 6 cases in collaboration with several international electrophysiology centers, which presented with pre-excitation in association with OT, and in 1 case inflow tract (IT), PVCs on 12-lead surface ECG. RESULTS: Six cases displayed pre-excitation and PVCs, in 5 cases originating from the right ventricular outflow tract (RVOT) and in 1 case from the right ventricular inflow tract (RVIT). In all patients, PVCs were monomorphic and had fixed coupling intervals, in 3 cases presenting in bigeminy. Catheter ablation of the AP led to the simultaneous disappearance of PVCs in 5 of 6 cases. The sites of ablation were remote from the OTs in all these cases. In most cases, the occurrence of OT PVCs was closely associated with the presence of pre-excitation. CONCLUSION: The coexistence of pre-excitation and PVCs from the OTs and the fact that in 5 of 6 cases PVCs disappeared after AP ablation suggests a common mechanism for arrhythmia genesis.

2 H/1 H measurements of amphiboles and nominally anhydrous minerals (clinopyroxene, garnet and diamond) using high-temperature continuous flow elemental analyser/pyrolysis/isotope ratio mass spectrometry.

RATIONALE: We have used a high-precision, high-efficiency method for the measurement of the 2 H/1 H ratios of hydrous silicates (amphiboles) and nominally anhydrous minerals (NAM) such as clinopyroxene, garnet and diamond, which are usually extremely resistant to pyrolysis. This opens up new fields of investigation to better understand the conditions of formation for deep-Earth minerals. METHODS: The technique described here involves Isotope Ratio Mass Spectrometry (IRMS) on-line in continuous flow mode with an Elemental Analyser (EA) using "purge and trap" technology rather than separation by conventional packed column gas chromatography (GC). The system is equipped with a special high-temperature furnace reaching 1500°C, with a longer hot zone and improved temperature stability. Emphasis is put on the efficiency of the system to reliably pyrolyse refractory minerals difficult to analyse with other conventional systems. RESULTS: While conventional systems usually fail to generate hydrogen suitable for isotopic analyses, with the technique presented here we were able to measure 2 H/1 H ratios from four diamond samples (δ2 H = -60, -77, -84 and -79‰ V-SMOW; average SD = 4.5‰; n = 2), three garnet samples (δ2 H from -70 to -63‰), and nine clinopyroxenes (δ2 H from -92 to -58‰) associated with seven amphiboles (δ2 H from -76 to -27‰) from single mantle rock. CONCLUSIONS: The possibility of using such a system to reliably measure 2 H/1 H ratios from refractory minerals, which are usually extremely difficult to analyse, offers a new tool of investigation for providing us with unrivaled clues to study the deep interiors of Earth.

Water and its influence on the lithosphere-asthenosphere boundary.

The Earth has distinctive convective behaviour, described by the plate tectonics model, in which lateral motion of the oceanic lithosphere of basaltic crust and peridotitic uppermost mantle is decoupled from the underlying mechanically weaker upper mantle (asthenosphere). The reason for differentiation at the lithosphere-asthenosphere boundary is currently being debated with relevant observations from geophysics (including seismology) and geochemistry (including experimental petrology). Water is thought to have an important effect on mantle rheology, either by weakening the crystal structure of olivine and pyroxenes by dilute solid solution, or by causing low-temperature partial melting. Here we present a novel experimental approach to clarify the role of water in the uppermost mantle at pressures up to 6 GPa, equivalent to a depth of 190 km. We found that for lherzolite in which a water-rich vapour is present, the temperature at which a silicate melt first appears (the vapour-saturated solidus) increases from a minimum of 970 °C at 1.5 GPa to 1,350 °C at 6 GPa. We have measured the water content in lherzolite to be approximately 180 parts per million, retained in nominally anhydrous minerals at 2.5 and 4 GPa at temperatures above and below the vapour-saturated solidus. The hydrous mineral pargasite is the main water-storage site in the uppermost mantle, and the instability of pargasite at pressures greater than 3 GPa (equivalent to more than about 90 km depth) causes a sharp drop in both the water-storage capacity and the solidus temperature of fertile upper-mantle lherzolite. The presence of interstitial melt in mantle with more than 180 parts per million of water at pressures greater than 3 GPa alters mantle rheology and defines the lithosphere-asthenosphere boundary. Modern asthenospheric mantle acting as the source for mid-oceanic ridge basalts has a water content of 50-200 parts per million (refs 3-5). We show that this matches the water content of residual nominally anhydrous minerals after incipient melting of lherzolite at the vapour-saturated solidus at high pressure.

Genetic diversity and distribution patterns of diploid and polyploid hybrid water frog populations (Pelophylax esculentus complex) across Europe.

Polyploidization is a rare yet sometimes successful way for animals to rapidly create geno- and phenotypes that may colonize new habitats and quickly adapt to environmental changes. In this study, we use water frogs of the Pelophylax esculentus complex, comprising two species (Pelophylax lessonae, genotype LL; Pelophylax ridibundus, RR) and various diploid (LR) and triploid (LLR, LRR) hybrid forms, summarized as P. esculentus, as a model for studying recent hybridization and polyploidization in the context of speciation. Specifically, we compared the geographic distribution and genetic diversity of diploid and triploid hybrids across Europe to understand their origin, maintenance and potential role in hybrid speciation. We found that different hybrid and parental genotypes are not evenly distributed across Europe. Rather, their genetic diversity is structured by latitude and longitude and the presence/absence of parental species but not of triploids. Highest genetic diversity was observed in central and eastern Europe, the lowest in the northwestern parts of Europe. This gradient can be explained by the decrease in genetic diversity during postglacial expansion from southeastern glacial refuge areas. Genealogical relationships calculated on the basis of microsatellite data clearly indicate that hybrids are of multiple origin and include a huge variety of parental genomes. Water frogs in mixed-ploidy populations without any parental species (i.e. all-hybrid populations) can be viewed as evolutionary units that may be on their way towards hybrid speciation. Maintenance of such all-hybrid populations requires a continuous exchange of genomes between diploids and triploids, but scenarios for alternative evolutionary trajectories are discussed.

Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells.

During cell division, the activation of glycolysis is tightly regulated by the action of two ubiquitin ligases, anaphase-promoting complex/cyclosome-Cdh1 (APC/C-Cdh1) and SKP1/CUL-1/F-box protein-ß-transducin repeat-containing protein (SCF-ß-TrCP), which control the transient appearance and metabolic activity of the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3). We now demonstrate that the breakdown of PFKFB3 during S phase occurs specifically via a distinct residue (S(273)) within the conserved recognition site for SCF-ß-TrCP. Glutaminase 1 (GLS1), the first enzyme in glutaminolysis, is also targeted for destruction by APC/C-Cdh1 and, like PFKFB3, accumulates after the activity of this ubiquitin ligase decreases in mid-to-late G1. However, our results show that GLS1 differs from PFKFB3 in that its recognition by APC/C-Cdh1 requires the presence of both a Lys-Glu-Asn box (KEN box) and a destruction box (D box) rather than a KEN box alone. Furthermore, GLS1 is not a substrate for SCF-ß-TrCP and is not degraded until cells progress from S to G2/M. The presence of PFKFB3 and GLS1 coincides with increases in generation of lactate and in utilization of glutamine, respectively. The contrasting posttranslational regulation of PFKFB3 and GLS1, which we have verified by studies of ubiquitination and protein stability, suggests the different roles of glucose and glutamine at distinct stages in the cell cycle. Indeed, experiments in which synchronized cells were deprived of either of these substrates show that both glucose and glutamine are required for progression through the restriction point in mid-to-late G1, whereas glutamine is the only substrate essential for the progression through S phase into cell division.

[Applicability of laser-based geological techniques in bone research: analysis of calcium oxide distribution in thin-cut animal bones]. / Lézeralapú geológiai technikák felhasználhatósága a csontkutatásban: kalcium-oxid-eloszlás vizsgálata állati csont vékonycsiszolatain.

The structural similarities between the inorganic component of bone tissue and geological formations make it possible that mathematic models may be used to determine weight percentage composition of different mineral element oxides constituting the inorganic component of bone tissue. The determined weight percentage composition can be verified with the determination of element oxide concentration values by laser induced plasma spectroscopy and inductively coupled plasma optical emission spectrometry. It can be concluded from calculated weight percentage composition of the inorganic component of bone tissue and laboratory analyses that the properties of bone tissue are determined primarily by hydroxylapatite. The inorganic bone structure can be studied well by determining the calcium oxide concentration distribution using the laser induced plasma spectroscopy technique. In the present study, thin polished bone slides prepared from male bovine tibia were examined with laser induced plasma spectroscopy in a regular network and combined sampling system to derive the calculated calcium oxide concentration distribution. The superficial calcium oxide concentration distribution, as supported by "frequency distribution" curves, can be categorized into a number of groups. This, as such, helps in clearly demarcating the cortical and trabecular bone structures. Following analyses of bovine tibial bone, the authors found a positive association between the attenuation value, as determined by quantitative computer tomography and the "ρ" density, as used in geology. Furthermore, the calculated "ρ" density and the measured average calcium oxide concentration values showed inverse correlation.

[The role of aspiration cytology in tumor diagnostics]. / Az aspirációs citológia szerepe a daganatdiagnosztikában.

Fine needle aspiration biopsy (FNAB) of focal lesions is a quick, relatively simple and cost-effective diagnostic method. However, performing aspirations and interpreting smears require skill and experience. Before initiating an aspiration the doctor needs to be aware of the limits of cytology as it is vital to know what kind of diagnostic issues can be answered upon a smear and what kind of questions cannot. Traditionally FNAB was performed without radiologic guidance, and therefore almost only palpable lesions were aspirated. Since ultrasound (US) has become widely used in medicine, it is axiomatical that FNAB is ideally performed with US guidance not only for the protection of the patients but also for targeting the lesion more safely. Several cytologists find US guidance unnecessary as a routinely used examination, which may lead to unsatisfactory smears and false negative results. This means not only a loss for the patient, but leads to a negative judgement of this diagnostic method. Our interventional cytology diagnostic team developed a working method resulting in excellent statistical results. In the followings we would like to share our experience refined the past two decades to restore the reputation of this diagnostic method.

Proper network randomization is key to assessing social balance.

Social ties, either positive or negative, lead to signed network patterns, the subject of balance theory. For example, strong balance introduces cycles with even numbers of negative edges. The statistical significance of such patterns is routinely assessed by comparisons to null models. Yet, results in signed networks remain controversial. Here, we show that even if a network exhibits strong balance by construction, current null models can fail to identify it. Our results indicate that matching the signed degree preferences of the nodes is a critical step and so is the preservation of network topology in the null model. As a solution, we propose the STP null model, which integrates both constraints within a maximum entropy framework. STP randomization leads to qualitatively different results, with most social networks consistently demonstrating strong balance in three- and four-node patterns. On the basis our results, we present a potential wiring mechanism behind the observed signed patterns and outline further applications of STP randomization.

Utilizing the open-source programming language Python to create interactive Quality Assurance dashboards for diagnostic and screening performance in Cytology.

INTRODUCTION: Effective feedback on cytology performance relies on navigating complex laboratory information system data, which is prone to errors and lacks flexibility. As a comprehensive solution, we used the Python programming language to create a dashboard application for screening and diagnostic quality metrics. MATERIALS AND METHODS: Data from the 5-year period (2018-2022) were accessed. Versatile open-source Python libraries (user developed program code packages) were used from the first step of LIS data cleaning through the creation of the application. To evaluate performance, we selected 3 gynecologic metrics: the ASC/LSIL ratio, the ASC-US/ASC-H ratio, and the proportion of cytologic abnormalities in comparison to the total number of cases (abnormal rate). We also evaluated the referral rate of cytologists/cytotechnologists (CTs) and the ratio of thyroid AUS interpretations by cytopathologists (CPs). These were formed into colored graphs that showcase individual results in established, color-coded laboratory "goal," "borderline," and "attention" zones based on published reference benchmarks. A representation of the results distribution for the entire laboratory was also developed. RESULTS: We successfully created a web-based test application that presents interactive dashboards with different interfaces for the CT, CP, and laboratory management (https://drkvcsstvn-dashboards.hf.space/app). The user can choose to view the desired quality metric, year, and the anonymized CT or CP, with an additional automatically generated written report of results. CONCLUSIONS: Python programming proved to be an effective toolkit to ensure high-level data processing in a modular and reproducible way to create a personalized, laboratory specific cytology dashboard.

CT-Assessment of Epicardial Fat Identifies Increased Inflammation at the Level of the Left Coronary Circulation in Patients with Atrial Fibrillation.

Background: Atrial fibrillation (AF) can often be triggered by an inflammatory substrate. Perivascular inflammation may be assessed nowadays using coronary computed tomography angiography (CCTA) imaging. The new pericoronary fat attenuation index (FAI HU) and the FAI Score have prognostic value for predicting future cardiovascular events. Our purpose was to investigate the correlation between pericoronary fat inflammation and the presence of AF among patients with coronary artery disease. Patients and methods: Eighty-one patients (mean age 64.75 ± 7.84 years) who underwent 128-slice CCTA were included in this study and divided into two groups: group 1 comprised thirty-six patients with documented AF and group 2 comprised forty-five patients without a known history of AF. Results: There were no significant differences in the absolute value of fat attenuation between the study groups (p > 0.05). However, the mean FAI Score was significantly higher in patients with AF (15.53 ± 10.29 vs. 11.09 ± 6.70, p < 0.05). Regional analysis of coronary inflammation indicated a higher level of this process, especially at the level of the left anterior descending artery (13.17 ± 7.91 in group 1 vs. 8.80 ± 4.75 in group 2, p = 0.008). Conclusions: Patients with AF present a higher level of perivascular inflammation, especially in the region of the left coronary circulation, and this seems to be associated with a higher risk of AF development.