Spatiotemporal insight into early pregnancy governed by immune-featured stromal cells.

Endometrial decidualization connecting embryo implantation and placentation is transient but essential for successful pregnancy, which, however, is not systematically investigated. Here, we use a scStereo-seq technology to spatially visualize and define the dynamic functional decidual hubs assembled by distinct immune, endothelial, trophoblast, and decidual stromal cells (DSCs) in early pregnant mice. We unravel the DSC transdifferentiation trajectory and surprisingly discover a dual-featured type of immune-featured DSCs (iDSCs). We find that immature DSCs attract immune cells and induce decidual angiogenesis at the mesenchymal-epithelial transition hub during decidualization initiation. iDSCs enable immune cell recruitment and suppression, govern vascularization, and promote cytolysis at immune cell assembling and vascular hubs, respectively, to establish decidual homeostasis at a later stage. Interestingly, dysfunctional and spatially disordered iDSCs cause abnormal accumulation of immune cells in the vascular hub, which disrupts decidual hub specification and eventually leads to pregnancy complications in DBA/2-mated CBA/J mice.

Low-Affinity Binding Sites and the Transcription Factor Specificity Paradox in Eukaryotes.

Eukaryotic transcription factors (TFs) from the same structural family tend to bind similar DNA sequences, despite the ability of these TFs to execute distinct functions in vivo. The cell partly resolves this specificity paradox through combinatorial strategies and the use of low-affinity binding sites, which are better able to distinguish between similar TFs. However, because these sites have low affinity, it is challenging to understand how TFs recognize them in vivo. Here, we summarize recent findings and technological advancements that allow for the quantification and mechanistic interpretation of TF recognition across a wide range of affinities. We propose a model that integrates insights from the fields of genetics and cell biology to provide further conceptual understanding of TF binding specificity. We argue that in eukaryotes, target specificity is driven by an inhomogeneous 3D nuclear distribution of TFs and by variation in DNA binding affinity such that locally elevated TF concentration allows low-affinity binding sites to be functional.

Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation.

Multi-enhancer hubs are spatial clusters of enhancers present across numerous developmental programs. Here, we studied the functional relevance of these three-dimensional structures in T cell biology. Mathematical modeling identified a highly connected multi-enhancer hub at the Ets1 locus, comprising a noncoding regulatory element that was a hotspot for sequence variation associated with allergic disease in humans. Deletion of this regulatory element in mice revealed that the multi-enhancer connectivity was dispensable for T cell development but required for CD4+ T helper 1 (Th1) differentiation. These mice were protected from Th1-mediated colitis but exhibited overt allergic responses. Mechanistically, the multi-enhancer hub controlled the dosage of Ets1 that was required for CTCF recruitment and assembly of Th1-specific genome topology. Our findings establish a paradigm wherein multi-enhancer hubs control cellular competence to respond to an inductive cue through quantitative control of gene dosage and provide insight into how sequence variation within noncoding elements at the Ets1 locus predisposes individuals to allergic responses.

Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency.

Enhancers bind transcription factors, chromatin regulators, and non-coding transcripts to modulate the expression of target genes. Here, we report 3D genome structures of single mouse ES cells as they are induced to exit pluripotency and transition through a formative stage prior to undergoing neuroectodermal differentiation. We find that there is a remarkable reorganization of 3D genome structure where inter-chromosomal intermingling increases dramatically in the formative state. This intermingling is associated with the formation of a large number of multiway hubs that bring together enhancers and promoters with similar chromatin states from typically 5-8 distant chromosomal sites that are often separated by many Mb from each other. In the formative state, genes important for pluripotency exit establish contacts with emerging enhancers within these multiway hubs, suggesting that the structural changes we have observed may play an important role in modulating transcription and establishing new cell identities.

Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer.

Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance remain largely unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation ability. Here, we show that these mutations, clustered in ENL's structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL's two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activation. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional condensates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism.

Network architecture of intrinsic connectivity in a mammalian spinal cord (the central nervous system's caudal sector).

The vertebrate spinal cord (SP) is the long, thin extension of the brain forming the central nervous system's caudal sector. Functionally, the SP directly mediates motor and somatic sensory interactions with most parts of the body except the face, and it is the preferred model for analyzing relatively simple reflex behaviors. Here, we analyze the organization of axonal connections between the 50 gray matter regions forming the bilaterally symmetric rat SP. The assembled dataset suggests that there are about 385 of a possible 2,450 connections between the 50 regions for a connection density of 15.7%. Multiresolution consensus cluster analysis reveals a hierarchy of structure-function subsystems in this neural network, with 4 subsystems at the top level and 12 at the bottom-level. The top-level subsystems include a) a bilateral subsystem related most clearly to somatic and autonomic motor functions and centered in the ventral horn and intermediate zone; b) a bilateral subsystem associated with general somatosensory functions and centered in the base, neck, and head of the dorsal horn; and c) a pair of unilateral, bilaterally symmetric subsystems associated with nociceptive information processing and occupying the apex of the dorsal horn. The intrinsic SP network displayed no hubs, rich club, or small-world attributes, which are common measures of global functionality. Advantages and limitations of our methodology are discussed in some detail. The present work is part of a comprehensive project to assemble and analyze the neurome of a mammalian nervous system and its interactions with the body.

Neural network architecture of a mammalian brain.

Connectomics research is making rapid advances, although models revealing general principles of connectional architecture are far from complete. Our analysis of 106 published connection reports indicates that the adult rat brain interregional connectome has about 76,940 of a possible 623,310 axonal connections between its 790 gray matter regions mapped in a reference atlas, equating to a network density of 12.3%. We examined the sexually dimorphic network using multiresolution consensus clustering that generated a nested hierarchy of interconnected modules/subsystems with three first-order modules and 157 terminal modules in females. Top-down hierarchy analysis suggests a mirror-image primary module pair in the central nervous system's rostral sector (forebrain-midbrain) associated with behavior control, and a single primary module in the intermediate sector (rhombicbrain) associated with behavior execution; the implications of these results are considered in relation to brain development and evolution. Bottom-up hierarchy analysis reveals known and unfamiliar modules suggesting strong experimentally testable hypotheses. Global network analyses indicate that all hubs are in the rostral module pair, a rich club extends through all three primary modules, and the network exhibits small-world attributes. Simulated lesions of all regions individually enabled ranking their impact on global network organization, and the visual path from the retina was used as a specific example, including the effects of cyclic connection weight changes from the endogenous circadian rhythm generator, suprachiasmatic nucleus. This study elucidates principles of interregional neuronal network architecture for a mammalian brain and suggests a strategy for modeling dynamic structural connectivity.

Extrachromosomal DNA in Cancer.

In cancer, complex genome rearrangements and other structural alterations, including the amplification of oncogenes on circular extrachromosomal DNA (ecDNA) elements, drive the formation and progression of tumors. ecDNA is a particularly challenging structural alteration. By untethering oncogenes from chromosomal constraints, it elevates oncogene copy number, drives intratumoral genetic heterogeneity, promotes rapid tumor evolution, and results in treatment resistance. The profound changes in DNA shape and nuclear architecture generated by ecDNA alter the transcriptional landscape of tumors by catalyzing new types of regulatory interactions that do not occur on chromosomes. The current suite of tools for interrogating cancer genomes is well suited for deciphering sequence but has limited ability to resolve the complex changes in DNA structure and dynamics that ecDNA generates. Here, we review the challenges of resolving ecDNA form and function and discuss the emerging tool kit for deciphering ecDNA architecture and spatial organization, including what has been learned to date about how this dramatic change in shape alters tumor development, progression, and drug resistance.

Provincial and connector qualities of somatosensory brain network hubs in bipolar disorder.

Brain network hubs are highly connected brain regions serving as important relay stations for information integration. Recent studies have linked mental disorders to impaired hub function. Provincial hubs mainly integrate information within their own brain network, while connector hubs share information between different brain networks. This study used a novel time-varying analysis to investigate whether hubs aberrantly follow the trajectory of other brain networks than their own. The aim was to characterize brain hub functioning in clinically remitted bipolar patients. We analyzed resting-state functional magnetic resonance imaging data from 96 euthymic individuals with bipolar disorder and 61 healthy control individuals. We characterized different hub qualities within the somatomotor network. We found that the somatomotor network comprised mainly provincial hubs in healthy controls. Conversely, in bipolar disorder patients, hubs in the primary somatosensory cortex displayed weaker provincial and stronger connector hub function. Furthermore, hubs in bipolar disorder showed weaker allegiances with their own brain network and followed the trajectories of the limbic, salience, dorsal attention, and frontoparietal network. We suggest that these hub aberrancies contribute to previously shown functional connectivity alterations in bipolar disorder and may thus constitute the neural substrate to persistently impaired sensory integration despite clinical remission.

Plant genetic effects on microbial hubs impact host fitness in repeated field trials.

Although complex interactions between hosts and microbial associates are increasingly well documented, we still know little about how and why hosts shape microbial communities in nature. In addition, host genetic effects on microbial communities vary widely depending on the environment, obscuring conclusions about which microbes are impacted and which plant functions are important. We characterized the leaf microbiota of 200 Arabidopsis thaliana genotypes in eight field experiments and detected consistent host effects on specific, broadly distributed microbial species (operational taxonomic unit [OTUs]). Host genetic effects disproportionately influenced central ecological hubs, with heritability of particular OTUs declining with their distance from the nearest hub within the microbial network. These host effects could reflect either OTUs preferentially associating with specific genotypes or differential microbial success within them. Host genetics associated with microbial hubs explained over 10% of the variation in lifetime seed production among host genotypes across sites and years. We successfully cultured one of these microbial hubs and demonstrated its growth-promoting effects on plants in sterile conditions. Finally, genome-wide association mapping identified many putatively causal genes with small effects on the relative abundance of microbial hubs across sites and years, and these genes were enriched for those involved in the synthesis of specialized metabolites, auxins, and the immune system. Using untargeted metabolomics, we corroborate the consistent association between variation in specialized metabolites and microbial hubs across field sites. Together, our results reveal that host genetic variation impacts the microbial communities in consistent ways across environments and that these effects contribute to fitness variation among host genotypes.

Emerging Features of Linear Motif-Binding Hub Proteins.

Hub proteins are important elements of interactomes within an organism; they bind diverse partners, display significant pleiotropy, and connect many cellular systems. Static hubs interact with their partners simultaneously, while dynamic hubs bind different partners at different locations and times. Although this distinguishes some features of hub protein/partner interactions, the increasing literature requires an expanded categorization of molecular and functional properties. Here, we focus on dynein light chain LC8 as a canonical example of dynamic hub proteins to develop a conceptual residue-level framework for hub-partner interactions and functions. We propose a new class of structural linear motif-binding hub proteins (LMB-hubs) with key common features. LMB-hubs have structural plasticity yet conserved interfaces, can function as integral members of large multimolecular assemblies, and are self-regulating.

Meso-scale reorganization of local-global brain networks under mild sedation of propofol anesthesia.

The fragmentation of the functional brain network has been identified through the functional connectivity (FC) analysis in studies investigating anesthesia-induced loss of consciousness (LOC). However, it remains unclear whether mild sedation of anesthesia can cause similar effects. This paper aims to explore the changes in local-global brain network topology during mild anesthesia, to better understand the macroscopic neural mechanism underlying anesthesia sedation. We analyzed high-density EEG from 20 participants undergoing mild and moderate sedation of propofol anesthesia. By employing a local-global brain parcellation in EEG source analysis, we established binary functional brain networks for each participant. Furthermore, we investigated the global-scale properties of brain networks by estimating global efficiency and modularity, and examined the changes in meso-scale properties of brain networks by quantifying the distribution of high-degree and high-betweenness hubs and their corresponding rich-club coefficients. It is evident from the results that the mild sedation of anesthesia does not cause a significant change in the global-scale properties of brain networks. However, network components centered on SomMot L show a significant decrease, while those centered on Default L, Vis L and Limbic L exhibit a significant increase during the transition from wakefulness to mild sedation (p<0.05). Compared to the baseline state, mild sedation almost doubled the number of high-degree hubs in Vis L, DorsAttn L, Limbic L, Cont L, and reduced by half the number of high-degree hubs in SomMot R, DorsAttn R, SalVentAttn R. Further, mild sedation almost doubled the number of high-betweenness hubs in Vis L, Vis R, Limbic R, Cont R, and reduced by half the number of high-betweenness hubs in SomMot L, SalVentAttn L, Default L, and SomMot R. Our results indicate that mild anesthesia cannot affect the global integration and segregation of brain networks, but influence meso-scale function for integrating different resting-state systems involved in various segregation processes. Our findings suggest that the meso-scale brain network reorganization, situated between global integration and local segregation, could reflect the autonomic compensation of the brain for drug effects. As a direct response and adjustment of the brain network system to drug administration, this spontaneous reorganization of the brain network aims at maintaining consciousness in the case of sedation.

Multimodal imaging investigation of structural rich club alterations in Alzheimer's disease and mild cognitive impairment: Amyloid deposition, structural atrophy, and functional activation differences.

Alzheimer's disease (AD) is characterized by significant cerebral dysfunction, including increased amyloid deposition, gray matter atrophy, and changes in brain function. The involvement of highly connected network hubs, known as the "rich club," in the pathology of the disease remains inconclusive despite previous research efforts. In this study, we aimed to systematically assess the link between the rich club and AD using a multimodal neuroimaging approach. We employed network analyses of diffusion magnetic resonance imaging (MRI), longitudinal assessments of gray matter atrophy, amyloid deposition measurements using positron emission tomography (PET) imaging, and meta-analytic data on functional activation differences. Our study focused on evaluating the role of both the structural brain network's core and extended rich club regions in individuals with mild cognitive impairment (MCI) and those diagnosed with AD. Our findings revealed that structural rich club regions exhibited accelerated gray matter atrophy and increased amyloid deposition in both MCI and AD. Importantly, these regions remained unaffected by altered functional activation patterns observed outside the core rich club regions. These results shed light on the connection between two major AD biomarkers and the rich club, providing valuable insights into AD as a potential disconnection syndrome.

Network medicine in ovarian cancer: topological properties to drug discovery.

Network medicine provides network theoretical tools, methods and properties to study underlying laws governing human interactome to identify disease states and disease complexity leading to drug discovery. Within this framework, we investigated the topological properties of ovarian cancer network (OCN) and the roles of hubs to understand OCN organization to address disease states and complexity. The OCN constructed from the experimentally verified genes exhibits fractal nature in the topological properties with deeply rooted functional communities indicating self-organizing behavior. The network properties at all levels of organization obey one parameter scaling law which lacks centrality lethality rule. We showed that $\langle k\rangle $ can be taken as a scaling parameter, where, power law exponent can be estimated from the ratio of network diameters. The betweenness centrality $C_B$ shows two distinct behaviors one shown by high degree hubs and the other by segregated low degree nodes. The $C_B$ power law exponent is found to connect the exponents of distributions of high and low degree nodes. OCN showed the absence of rich-club formation which leads to the missing of a number of attractors in the network causing formation of weakly tied diverse functional modules to keep optimal network efficiency. In OCN, provincial and connector hubs, which includes identified key regulators, take major responsibility to keep the OCN integrity and organization. Further, most of the key regulators are found to be over expressed and positively correlated with immune infiltrates. Finally, few potential drugs are identified related to the key regulators.

Imaging extrachromosomal DNA (ecDNA) in cancer.

Extrachromosomal DNA (ecDNA) are circular regions of DNA that are found in many cancers. They are an important means of oncogene amplification, and correlate with treatment resistance and poor prognosis. Consequently, there is great interest in exploring and targeting ecDNA vulnerabilities as potential new therapeutic targets for cancer treatment. However, the biological significance of ecDNA and their associated regulatory control remains unclear. Light microscopy has been a central tool in the identification and characterisation of ecDNA. In this review we describe the different cellular models available to study ecDNA, and the imaging tools used to characterise ecDNA and their regulation. The insights gained from quantitative imaging are discussed in comparison with genome sequencing and computational approaches. We suggest that there is a crucial need for ongoing innovation using imaging if we are to achieve a full understanding of the dynamic regulation and organisation of ecDNA and their role in tumourigenesis.

Hub and Spoke: Next level in regional networks for infection prevention.

The threat of multidrug-resistant organisms (MDROs) and antimicrobial resistance (AMR) are real and increasing every day. They affect not only healthcare systems but also communities, causing economic and public health concerns. Governments must take action to tackle AMR and prevent the spread of MDROs and regional hubs have a critical role to play in achieving this outcome. Furthermore, bacteria have no borders, consequently, cooperation networks should be extended between countries as a crucial strategy for achieving the success of infection control. Euregions, which are a specific form of cooperation between local authorities of two or more bordering European countries, can help solve common problems and improve the lives of people living on both sides of the border. Regional collaboration strategies can enhance infection control and build resilience against antimicrobial resistance. This review identifies risk factors and the correct approaches to infection prevention and control, including education and awareness programs for healthcare professionals, appropriate prescribing practices, and infection prevention control measures. These measures can help reduce the incidence of antimicrobial resistance in the region and save lives. It is therefore essential to take concrete actions and foster the creation of more effective regional and cross-border centers to ensure the success of infection control policies and the management of healthcare-associated infections. This work sheds light on the issue of MDRO infections within healthcare settings, while also acknowledging the crucial role of the One Health concept in understanding the broader context of these infections. By recognizing the interdependence of human and animal health and the environment, we can take constructive steps toward mitigating the risks of these infections and promoting better health outcomes for all.

Moving restoration ecology forward with combinatorial approaches.

Our current planetary crisis, including multiple jointly acting factors of global change, moves the need for effective ecosystem restoration center stage and compels us to explore unusual options. We here propose exploring combinatorial approaches to restoration practices: management practices are drawn at random and combined from a locally relevant pool of possible management interventions, thus creating an experimental gradient in the number of interventions. This will move the current degree of interventions to higher dimensionality, opening new opportunities for unlocking unknown synergistic effects. Thus, the high dimensionality of global change (multiple jointly acting factors) would be more effectively countered by similar high-dimensionality in solutions. In this concept, regional restoration hubs play an important role as guardians of locally relevant information and sites of experimental exploration. Data collected from such studies could feed into a global database, which could be used to learn about general principles of combined restoration practices, helping to refine future experiments. Such combinatorial approaches to exploring restoration intervention options may be our best hope yet to achieve decisive progress in ecological restoration at the timescale needed to mitigate and reverse the most severe losses caused by global environmental change.

Desiderata for discoverability and FAIR adoption of health data hubs.

BACKGROUND: The future European Health Research and Innovation Cloud (HRIC), as fundamental part of the European Health Data Space (EHDS), will promote the secondary use of data and the capabilities to push the boundaries of health research within an ethical and legally compliant framework that reinforces the trust of patients and citizens. OBJECTIVE: This study aimed to analyse health data management mechanisms in Europe to determine their alignment with FAIR principles and data discovery generating best. practices for new data hubs joining the HRIC ecosystem. In this line, the compliance of health data hubs with FAIR principles and data discovery were assessed, and a set of best practices for health data hubs was concluded. METHODS: A survey was conducted in January 2022, involving 99 representative health data hubs from multiple countries, and 42 responses were obtained in June 2022. Stratification methods were employed to cover different levels of granularity. The survey data was analysed to assess compliance with FAIR and data discovery principles. The study started with a general analysis of survey responses, followed by the creation of specific profiles based on three categories: organization type, function, and level of data aggregation. RESULTS: The study produced specific best practices for data hubs regarding the adoption of FAIR principles and data discoverability. It also provided an overview of the survey study and specific profiles derived from category analysis, considering different types of data hubs. CONCLUSIONS: The study concluded that a significant number of health data hubs in Europe did not fully comply with FAIR and data discovery principles. However, the study identified specific best practices that can guide new data hubs in adhering to these principles. The study highlighted the importance of aligning health data management mechanisms with FAIR principles to enhance interoperability and reusability in the future HRIC.

Diverse functional interaction driven by control-default network hubs supports creative thinking.

Complex cognitive processes, like creative thinking, rely on interactions among multiple neurocognitive processes to generate effective and innovative behaviors on demand, for which the brain's connector hubs play a crucial role. However, the unique contribution of specific hub sets to creative thinking is unknown. Employing three functional magnetic resonance imaging datasets (total N = 1,911), we demonstrate that connector hub sets are organized in a hierarchical manner based on diversity, with "control-default hubs"-which combine regions from the frontoparietal control and default mode networks-positioned at the apex. Specifically, control-default hubs exhibit the most diverse resting-state connectivity profiles and play the most substantial role in facilitating interactions between regions with dissimilar neurocognitive functions, a phenomenon we refer to as "diverse functional interaction". Critically, we found that the involvement of control-default hubs in facilitating diverse functional interaction robustly relates to creativity, explaining both task-induced functional connectivity changes and individual creative performance. Our findings suggest that control-default hubs drive diverse functional interaction in the brain, enabling complex cognition, including creative thinking. We thus uncover a biologically plausible explanation that further elucidates the widely reported contributions of certain frontoparietal control and default mode network regions in creativity studies.

Altered development of structural MRI connectome hubs at near-term age in very and moderately preterm infants.

Preterm infants may exhibit altered developmental patterns of the brain structural network by endogenous and exogenous stimuli, which are quantifiable through hub and modular network topologies that develop in the third trimester. Although preterm brain networks can compensate for white matter microstructural abnormalities of core connections, less is known about how the network developmental characteristics of preterm infants differ from those of full-term infants. We identified 13 hubs and 4 modules and revealed subtle differences in edgewise connectivity and local network properties between 134 preterm and 76 full-term infants, identifying specific developmental patterns of the brain structural network in preterm infants. The modules of preterm infants showed an imbalanced composition. The edgewise connectivity in preterm infants showed significantly decreased long- and short-range connections and local network properties in the dorsal superior frontal gyrus. In contrast, the fusiform gyrus and several nonhub regions showed significantly increased wiring of short-range connections and local network properties. Our results suggested that decreased local network in the frontal lobe and excessive development in the occipital lobe may contribute to the understanding of brain developmental deviances in preterm infants.