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The white matter architecture of the brain imparts a distinct signature on neuronal coactivation patterns. Interregional projections promote synchrony among distant neuronal populations, giving rise to richly patterned functional networks. A variety of statistical, communication, and biophysical models have been proposed to study the relationship between brain structure and function, but the link is not yet known. In the present report we seek to relate the structural and functional connection profiles of individual brain areas. We apply a simple multilinear model that incorporates information about spatial proximity, routing, and diffusion between brain regions to predict their functional connectivity. We find that structure–function relationships vary markedly across the neocortex. Structure and function correspond closely in unimodal, primary sensory, and motor regions, but diverge in transmodal cortex, particularly the default mode and salience networks. The divergence between structure and function systematically follows functional and cytoarchitectonic hierarchies. Altogether, the present results demonstrate that structural and functional networks do not align uniformly across the brain, but gradually uncouple in higher-order polysensory areas.

The human brain is a complex network of anatomically segregated regions interconnected by white matter pathways, known as the human connectome. Diffusion tensor imaging can be used to reconstruct this structural brain network in vivo and noninvasively. However, due to a wide variety of influences, both false positive and false negative connections may occur. By choosing a ‘group threshold’, brain networks of multiple subjects can be combined into a single reconstruction, affecting the occurrence of these false positives and negatives. In this case, only connections that are detected in a large enough percentage of the subjects, specified by the group threshold, are considered to be present. Although this group threshold has a substantial impact on the resulting reconstruction and subsequent analyses, it is often chosen intuitively. Here, we introduce a model to estimate how the choice of group threshold influences the presence of false positives and negatives. Based on our findings, group thresholds should preferably be chosen between 30% and 90%. Our results further suggest that a group threshold of circa 60% is a suitable setting, providing a good balance between the elimination of false positives and false negatives. ► The impact of the group threshold on false positives and negatives is modeled. ► The group threshold has a substantial impact on network metrics and errors. ► Group thresholds should preferably be chosen between 30% and 90%. ► A group threshold of circa 60% appears to be appropriate for most applications.

Large-scale biophysical circuit models provide mechanistic insights into the micro-scale and macro-scale properties of brain organization that shape complex patterns of spontaneous brain activity. We developed a spatially heterogeneous large-scale dynamical circuit model that allowed for variation in local synaptic properties across the human cortex. Here we show that parameterizing local circuit properties with both anatomical and functional gradients generates more realistic static and dynamic resting-state functional connectivity (FC). Furthermore, empirical and simulated FC dynamics demonstrates remarkably similar sharp transitions in FC patterns, suggesting the existence of multiple attractors. Time-varying regional fMRI amplitude may track multi-stability in FC dynamics. Causal manipulation of the large-scale circuit model suggests that sensory-motor regions are a driver of FC dynamics. Finally, the spatial distribution of sensory-motor drivers matches the principal gradient of gene expression that encompasses certain interneuron classes, suggesting that heterogeneity in excitation-inhibition balance might shape multi-stability in FC dynamics. Spontaneous fluctuations in brain activity exhibit complex spatiotemporal patterns across animal species. Here the authors show that sensory-motor regions and spatial heterogeneity in excitation-inhibition balance might shape multi-stability in brain dynamics.

Network-based analysis of structural and functional connections has provided a new technique to study the brains of healthy people and patients with neurological and psychiatric disorders. Graph theory provides a powerful method to quantitatively describe the topological organisation of brain connectivity. With such a framework, the brain can be depicted as a set of nodes connected by edges. Distinct modifications of network topological organisation in the brain have been identified during development and normal ageing, whereas disrupted functional and structural connectivities have been associated with several neurological and psychiatric disorders, including dementia, amyotrophic lateral sclerosis, multiple sclerosis, and schizophrenia. These assessments have improved understanding of the clinical manifestations noted in these patients, including disability and cognitive impairment. Future network-based research might enable indentification of different stages of disorders, subtypes for cognitive impairment, and connectivity profiles associated with different clinical outcomes.

Advanced glycation endproducts (AGEs) may be involved in the development of atherosclerosis, beyond diabetes and renal disease. Skin autofluorescence (AF) is a non-invasive marker for AGEs. We examined whether skin AF is increased in (subclinical) atherosclerosis and associated with the degree of atherosclerosis independent of diabetes and renal function. A cross-sectional study of 223 patients referred for primary (n = 163) or secondary (n = 60) prevention between 2006 and 2012 was performed. Skin AF was measured using the AGE-Reader. Ultrasonography was used to assess plaques in carotid and femoral arteries and computed tomography for the calculation of the coronary artery calcium score (CACS; in primary prevention only). Primary prevention patients were divided into a group with subclinical atherosclerosis defined as >1 plaque or CACS>100 (n = 67; age 53 year [interquartile range 48-56]; 49% male) and without (controls; 96; 43 [38-51]; 55%). Secondary prevention were patients with peripheral arterial disease (60; 64 [58-70]; 73%). Skin AF was higher in subclinical and clinical atherosclerosis compared with controls (skin AF 2.11 [interquartile range 1.83-2.46] and 2.71 [2.15-3.27] vs. 1.87 [1.68-2.12] respectively; P = 0.005 and <0.001). In a multivariate analysis, the association of skin AF with the atherosclerosis categories was independent of age, sex, diabetes, presence of the metabolic syndrome, Framingham Risk Score, and renal function. Skin AF correlated with most cardiovascular risk factors, Framingham risk score, and IMT and CACS. Skin AF is increased in documented subclinical and clinical atherosclerosis, independent of known risk factors such as diabetes and renal disease. These data suggest that AGEs may be associated with the burden of atherosclerosis and warrant a prospective study to investigate its clinical usability as a risk assessment tool for primary prevention.

Cells employ global genome nucleotide excision repair (GGR) to eliminate a broad spectrum of DNA lesions, including those induced by UV light. The lesion-recognition factor XPC initiates repair of helix-destabilizing DNA lesions, but binds poorly to lesions such as CPDs that do not destabilize DNA. How difficult-to-repair lesions are detected in chromatin is unknown. Here, we identify the poly-(ADP-ribose) polymerases PARP1 and PARP2 as constitutive interactors of XPC. Their interaction results in the XPC-stimulated synthesis of poly-(ADP-ribose) (PAR) by PARP1 at UV lesions, which in turn enables the recruitment and activation of the PAR-regulated chromatin remodeler ALC1. PARP2, on the other hand, modulates the retention of ALC1 at DNA damage sites. Notably, ALC1 mediates chromatin expansion at UV-induced DNA lesions, leading to the timely clearing of CPD lesions. Thus, we reveal how chromatin containing difficult-to-repair DNA lesions is primed for repair, providing insight into mechanisms of chromatin plasticity during GGR. Cells employ global genome nucleotide excision repair to repair a broad spectrum of genomic DNA lesions. Here, the authors reveal how chromatin is primed for repair, providing insight into mechanisms of chromatin plasticity during DNA repair.

Receptor-mediated endocytosis, involving megalin and cubilin, mediates renal proximal-tubular reabsorption and is decreased in Dent disease because of mutations of the chloride/proton antiporter, chloride channel-5 (CLC-5), resulting in low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. To facilitate studies of receptor-mediated endocytosis and the role of CLC-5, we established conditionally immortalized proximal-tubular epithelial cell lines (ciPTECs) from three patients with CLC-5 mutations (30:insH, R637X, and del132-241) and a normal male. Confocal microscopy using the tight junction marker zona occludens-1 (ZO-1) and end-binding protein-1 (EB-1), which is specific for the plus end of microtubules demonstrated that the ciPTECs polarized. Receptor-mediated endocytic uptake of fluorescent albumin and transferrin in 30:insH and R637X ciPTECs was significantly decreased, compared with normal ciPTECs, and could be further reduced by competition with 10-fold excess of unlabeled albumin and transferrin, whereas in the del132-241 ciPTEC, receptor-mediated endocytic uptake was abolished. Investigation of endosomal acidification by live-cell imaging of pHluorin-VAMP2 (vesicle-associated membrane protein-2), a pH-sensitive-GFP construct, revealed that the endosomal pH in normal and 30:insH ciPTECs was similar, whereas in del132-241 and R637X ciPTECs, it was significantly more alkaline, indicating defective acidification in these ciPTECs. The addition of bafilomycin-A1, a V-ATPase inhibitor, raised the pH significantly in all ciPTECs, demonstrating that the differences in acidification were not due to alterations in the V-ATPase, but instead to abnormalities of CLC-5. Thus, our studies, which have established human Dent disease ciPTECs that will facilitate studies of mechanisms in renal reabsorption, demonstrate that Dent disease-causing CLC-5 mutations have differing effects on endosomal acidification and receptor-mediated endocytosis that may not be coupled.

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) – a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date – of schizophrenia and major depression – ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others11Abbreviations: ADNI, Alzheimer's Disease Neuroimaging Initiative (http://www.adni-info.org); CHARGE, the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (http://www.chargeconsortium.com); IMAGEN, IMAging GENetics Consortium (http://www.imagen-europe.com)., ENIGMA's genomic screens – now numbering over 30,000 MRI scans – have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants – and genetic variants in general – may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures – from tens of thousands of people – that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

The rate of directional environmental change may have profound consequences for evolutionary dynamics and outcomes. Yet, most evolution experiments impose a sudden large change in the environment, after which the environment is kept constant. We previously cultured replicate Saccharomyces cerevisiae populations for 500 generations in the presence of either gradually increasing or constant high concentrations of the heavy metals cadmium, nickel, and zinc. Here, we investigate how each of these treatments affected genomic evolution. Whole-genome sequencing of evolved clones revealed that adaptation occurred via a combination of SNPs, small indels, and whole-genome duplications and other large-scale structural changes. In contrast to some theoretical predictions, gradual and abrupt environmental change caused similar numbers of genomic changes. For cadmium, which is toxic already at comparatively low concentrations, mutations in the same genes were used for adaptation to both gradual and abrupt increase in concentration. Conversely, for nickel and zinc, which are toxic at high concentrations only, mutations in different genes were used for adaptation depending on the rate of change. Moreover, evolution was more repeatable following a sudden change in the environment, particularly for nickel and zinc. Our results show that the rate of environmental change and the nature of the selection pressure are important drivers of evolutionary dynamics and outcomes, which has implications for a better understanding of societal problems such as climate change and pollution.

Post-mortem magnetic resonance imaging (MRI) provides the opportunity to acquire high-resolution datasets to investigate neuroanatomy and validate the origins of image contrast through microscopy comparisons. We introduce the Digital Brain Bank ( open.win.ox.ac.uk/DigitalBrainBank ), a data release platform providing open access to curated, multimodal post-mortem neuroimaging datasets. Datasets span three themes —Digital Neuroanatomist : datasets for detailed neuroanatomical investigations; Digital Brain Zoo : datasets for comparative neuroanatomy; and Digital Pathologist : datasets for neuropathology investigations. The first Digital Brain Bank data release includes 21 distinctive whole-brain diffusion MRI datasets for structural connectivity investigations, alongside microscopy and complementary MRI modalities. This includes one of the highest-resolution whole-brain human diffusion MRI datasets ever acquired, whole-brain diffusion MRI in fourteen nonhuman primate species, and one of the largest post-mortem whole-brain cohort imaging studies in neurodegeneration. The Digital Brain Bank is the culmination of our lab’s investment into post-mortem MRI methodology and MRI-microscopy analysis techniques. This manuscript provides a detailed overview of our work with post-mortem imaging to date, including the development of diffusion MRI methods to image large post-mortem samples, including whole, human brains. Taken together, the Digital Brain Bank provides cross-scale, cross-species datasets facilitating the incorporation of post-mortem data into neuroimaging studies.