Hallmarks of criticality, such as power-laws and scale invariance, have been empirically found in cortical-network dynamics and it has been conjectured that operating at criticality entails ...functional advantages, such as optimal computational capabilities, memory and large dynamical ranges. As critical behaviour requires a high degree of fine tuning to emerge, some type of self-tuning mechanism needs to be invoked. Here we show that, taking into account the complex hierarchical-modular architecture of cortical networks, the singular critical point is replaced by an extended critical-like region that corresponds--in the jargon of statistical mechanics--to a Griffiths phase. Using computational and analytical approaches, we find Griffiths phases in synthetic hierarchical networks and also in empirical brain networks such as the human connectome and that of Caenorhabditis elegans. Stretched critical regions, stemming from structural disorder, yield enhanced functionality in a generic way, facilitating the task of self-organizing, adaptive and evolutionary mechanisms selecting for criticality.
Abstract
Network theoretical measures such as geodesic edge betweenness centrality (GEBC) have been proposed as failure predictors in network models of load-driven materials failure. Edge betweenness ...centrality ranks which links are significant, based on the fraction of shortest paths that pass through the links between network nodes. We study GEBC as a failure predictor for two-dimensional fuse network models of load transmission in structurally disordered materials. We analyze the evolution of edge betweenness centrality in the run-up to failure and the correlation between GEBC and failure propensity for both hierarchical and non-hierarchical networks exhibiting various degrees of disorder. We observe a non trivial relationship between GEBC and failure propensity, which suggests that the idea of GEBC as a useful failure predictor needs to be strongly qualified.
Creep failure of hierarchical materials is investigated by simulation of beam network models. Such models are idealizations of hierarchical fibrous materials where bundles of load-carrying fibers are ...held together by multi-level (hierarchical) cross-links. Failure of individual beams is assumed to be governed by stress-assisted thermal activation over local barriers, and beam stresses are computed by solving the global balance equations of linear and angular momentum across the network. Disorder is mimicked by a statistical distribution of barrier heights. Both initially intact samples and samples containing side notches of various length are considered. Samples with hierarchical cross-link patterns are simulated alongside reference samples where cross-links are placed randomly without hierarchical organization. The results demonstrate that hierarchical patterning may strongly increase creep strain and creep lifetime while reducing the lifetime variation. This is due to the fact that hierarchical patterning induces a failure mode that differs significantly from the standard scenario of failure by nucleation and growth of a critical crack. Characterization of this failure mode demonstrates good agreement between the present simulations and experimental findings on hierarchically patterned paper sheets.
We study precursors of failure in hierarchical random fuse network models which can be considered as idealizations of hierarchical (bio)materials where fibrous assemblies are held together by ...multi-level (hierarchical) cross-links. When such structures are loaded towards failure, the patterns of precursory avalanche activity exhibit generic scale invariance: irrespective of load, precursor activity is characterized by power-law avalanche size distributions without apparent cut-off, with power-law exponents that decrease continuously with increasing load. This failure behavior and the ensuing super-rough crack morphology differ significantly from the findings in non-hierarchical structures.
Rett syndrome, a neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2), is a leading cause of mental retardation with autistic features in ...females.
MECP2 mutations have also been identified in individuals with a variety of clinical syndromes, including mild learning-disability in females, neonatal encephalopathy in males, and psychiatric disorders, autism and X-linked mental retardation in both males and females. Furthermore,
MECP2 duplications have been shown to cause a progressive postnatal neurological disorder. MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides flanked by AT-rich segments and recruits a co-repressor complex, thereby altering chromatin structure. Subtle gene expression changes have been identified in Rett patients and mouse models; however, MeCP2 dysfunction has also been shown to cause abnormalities of RNA splicing, suggesting a complex molecular pathogenesis. Discovering which genes are misregulated in the absence of functional MeCP2 and demonstrating their role in causing neuronal dysfunction and disease manifestations are challenging but important steps for understanding the pathogenesis of Rett syndrome and related disorders.
BACKGROUNDTranscriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate ...DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq-guided method to diagnose individuals across a wide range of ages and clinical phenotypes.METHODSOne hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and skin fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network clinical site from 2014 to 2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis.RESULTSThe transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Skin fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts.CONCLUSIONSFor our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.TRIAL REGISTRATIONNot applicable.FUNDINGNIH Common Fund, BCM Intellectual and Developmental Disabilities Research Center, Eunice Kennedy Shriver National Institute of Child Health & Human Development.
Diatoms represent the most abundant and diversified class of primary producers in present oceans; their distinctive trait is the ability to incorporate silicic acid in a silica outer shell called ...frustule. Numerous adaptative functions are ascribed to frustules, including the control of vertical movements through the water column; this indirectly determines cell access to fundamental resources such as light and nutrients, and favors diatom escape from predators. At the same time, light guides phototroph movements in the water column by affecting cell density (e.g., by modulating Si deposition in diatoms, vacuole volume, and/or solution). We investigated how the tremendous diversity in morphology and silicification that characterizes the frustule and the crucial role of light in diatom spatial distribution govern diatom sinking capacity. To test their integrative effects, we acclimated four diatoms distinguished by frustule traits (
,
,
, and
) to different light conditions and evaluated their physiological performance in terms of growth, elemental composition, morphological changes, and their
sinking capacity. What emerged from this study was that silicification, more than other morphological characteristics, controls species vertical movements, while a higher energy availability enhances cell floating independently from the silica content.
In this study, we unravel the atomic structure of a covalent resin near boundaries such as surfaces and composite constituents. For this, a molecular simulation analysis of epoxy resin hardening ...under various boundary conditions was performed. On the atomic level of detail, molecular dynamics simulations were employed to study crosslinking reactions and self-organization of the polymer network within nm scale slab models. The resulting structures were then coarsened into a graph theoretical description for connectivity analysis of the nodes and combined with characterization of the node-to-node vector orientation. On this basis, we show that the local bonding of epoxy resins near interfaces tends to avoid under-coordinated linker sites. For both epoxy–vacuum surface models and epoxy–silica/epoxy cellulose interfaces, we find almost fully cured polymer networks. These feature a local increase in network linking lateral to the surface/interface, rather than the dangling of unreacted epoxy groups. Consequently, interface tension is low (as compared to the work of separating bulk epoxy), and the reactivity of the resin surface appears negligible.
Connectivity patterns of relevance in neuroscience and systems biology can be encoded in hierarchical modular networks (HMNs). Recent studies highlight the role of hierarchical modular organization ...in shaping brain activity patterns, providing an excellent substrate to promote both segregation and integration of neural information. Here, we propose an extensive analysis of the critical spreading rate (or 'epidemic' threshold)-separating a phase with endemic persistent activity from one in which activity ceases-on diverse HMNs. By employing analytical and computational techniques we determine the nature of such a threshold and scrutinize how it depends on general structural features of the underlying HMN. We critically discuss the extent to which current graph-spectral methods can be applied to predict the onset of spreading in HMNs and, most importantly, we elucidate the role played by the network topological dimension as a relevant and unifying structural parameter, controlling the epidemic threshold.
Multicentric Carpo-Tarsal Osteolysis Syndrome (MCTO) is an autosomal dominant disease with increased bone reabsorption in the carpus and tarsus and the elbows, knees and spine. The disease is ...extremely heterogeneous and secondary and tertiary injuries vary widely and can lead to progressive disability and severe functional limitations. In addition to the available and upcoming drug therapies, physical medicine and rehabilitation are important treatment options. Currently, the indication and plan are overlooked, nonspecific and reported only for one patient.
We describe a case series of MCTO patients diagnosed and followed by a centre to identify functional deficit as a potential clinical marker of disease progression for future etiological therapies. In addition, we define a symptomatic treatment approach and specific clinical management, including a patient-centred rehabilitation approach. Functional assessments are performed independently by a multidisciplinary group to establish the functional abilities of patients and the relationship between residual motor skills and their degree of autonomy and participation. We suggest a way to identify a rehabilitation plan based on a specific disease using the International Classification of Functioning, Disability and Health Children and Youth (ICF-CY).
To define a reliable and reproducible "Function Profile", through age and over time, we used to value the disease status according to the ICF-CY domains. It could be used to determine the complexity of the illness, its overall impact on the complexity of the person and the burden on the caregiver, and an eventual short- and long-term rehabilitation plan for MCTO and other ultra-rare diseases.
Based on the MCTO experience, we suggest a way to determine a rehabilitation plan based on a specific disease and patient needs, keeping in mind that often the final point is not recovering the full function but improving or maintaining the starting point. In all cases, each patient at the time of diagnosis requires a functional assessment that must be repeated over time to adjust the course of rehabilitation. The evaluations revealed the importance of early rehabilitation management in enhancing independence, participation and control of stress deconditioning, shrinking of muscle tendons and loss of movement to immobility.
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