Quantitative Analysis of Myelin and Axonal Remodeling in the Uninjured Motor Network After Stroke.

Contralesional brain connectivity plasticity was previously reported after stroke. This study aims at disentangling the biological mechanisms underlying connectivity plasticity in the uninjured motor network after an ischemic lesion. In particular, we measured generalized fractional anisotropy (GFA) and magnetization transfer ratio (MTR) to assess whether poststroke connectivity remodeling depends on axonal and/or myelin changes. Diffusion-spectrum imaging and magnetization transfer MRI at 3T were performed in 10 patients in acute phase, at 1 and 6 months after stroke, which was affecting motor cortical and/or subcortical areas. Ten age- and gender-matched healthy volunteers were scanned 1 month apart for longitudinal comparison. Clinical assessment was also performed in patients prior to magnetic resonance imaging (MRI). In the contralesional hemisphere, average measures and tract-based quantitative analysis of GFA and MTR were performed to assess axonal integrity and myelination along motor connections as well as their variations in time. Mean and tract-based measures of MTR and GFA showed significant changes in a number of contralesional motor connections, confirming both axonal and myelin plasticity in our cohort of patients. Moreover, density-derived features (peak height, standard deviation, and skewness) of GFA and MTR along the tracts showed additional correlation with clinical scores than mean values. These findings reveal the interplay between contralateral myelin and axonal remodeling after stroke.

Making SENSE - Sustained Effort Network for treatment of Status Epilepticus as a multicenter prospective registry.

BACKGROUND: Evidence regarding the different treatment options of status epilepticus (SE) in adults is scarce. Large randomized trials cover only one treatment at early stage and suggest the superiority of benzodiazepines over placebo, of intravenous lorazepam over intravenous diazepam or over intravenous phenytoin alone, and of intramuscular midazolam over intravenous lorazepam. However, many patients will not be treated successfully with the first treatment step. A large randomized trial covering the treatment of established status (ESETT) has just been funded recently by the NIH and will not start before 2015, with expected results in 2018; a trial on the treatment of refractory status with general anesthetics was terminated early due to insufficient recruitment. Therefore, a prospective multicenter observational registry was set up; this may help in clinical decision-making until results from randomized trials are available. METHODS/DESIGN: SENSE is a prospective, multicenter registry for patients treated for SE. The primary objective is to document patient characteristics, treatment modalities and in-house outcome of consecutive adults admitted for SE treatment in each of the participating centres and to identify predictors of outcome. Pre-treatment, treatment-related and outcome variables are documented systematically. To allow for meaningful multivariate analysis in the patient subgroups with refractory SE, a cohort size of 1000 patients is targeted. DISCUSSION: The results of the study will provide information about risks and benefits of specific treatment steps in different patient groups with SE at different points of time. Thus, it will support clinical decision-making and, furthermore, it will be helpful in the planning of treatment trials. TRIAL REGISTRATION: DRKS00000725.

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

Interactome analysis reveals that FAM161A, deficient in recessive retinitis pigmentosa, is a component of the Golgi-centrosomal network.

Defects in FAM161A, a protein of unknown function localized at the cilium of retinal photoreceptor cells, cause retinitis pigmentosa, a form of hereditary blindness. By using different fragments of this protein as baits to screen cDNA libraries of human and bovine retinas, we defined a yeast two-hybrid-based FAM161A interactome, identifying 53 bona fide partners. In addition to statistically significant enrichment in ciliary proteins, as expected, this interactome revealed a substantial bias towards proteins from the Golgi apparatus, the centrosome and the microtubule network. Validation of interaction with key partners by co-immunoprecipitation and proximity ligation assay confirmed that FAM161A is a member of the recently recognized Golgi-centrosomal interactome, a network of proteins interconnecting Golgi maintenance, intracellular transport and centrosome organization. Notable FAM161A interactors included AKAP9, FIP3, GOLGA3, KIFC3, KLC2, PDE4DIP, NIN and TRIP11. Furthermore, analysis of FAM161A localization during the cell cycle revealed that this protein followed the centrosome during all stages of mitosis, likely reflecting a specific compartmentalization related to its role at the ciliary basal body during the G0 phase. Altogether, these findings suggest that FAM161A's activities are probably not limited to ciliary tasks but also extend to more general cellular functions, highlighting possible novel mechanisms for the molecular pathology of retinal disease.

An affected core drives network integration deficits of the structural connectome in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is a genetic disease known to lead to cerebral structural alterations, which we study using the framework of the macroscopic white-matter connectome. We create weighted connectomes of 44 patients with 22q11DS and 44 healthy controls using diffusion tensor magnetic resonance imaging, and perform a weighted graph theoretical analysis. After confirming global network integration deficits in 22q11DS (previously identified using binary connectomes), we identify the spatial distribution of regions responsible for global deficits. Next, we further characterize the dysconnectivity of the deficient regions in terms of sub-network properties, and investigate their relevance with respect to clinical profiles. We define the subset of regions with decreased nodal integration (evaluated using the closeness centrality measure) as the affected core (A-core) of the 22q11DS structural connectome. A-core regions are broadly bilaterally symmetric and consist of numerous network hubs - chiefly parietal and frontal cortical, as well as subcortical regions. Using a simulated lesion approach, we demonstrate that these core regions and their connections are particularly important to efficient network communication. Moreover, these regions are generally densely connected, but less so in 22q11DS. These specific disturbances are associated to a rerouting of shortest network paths that circumvent the A-core in 22q11DS, "de-centralizing" the network. Finally, the efficiency and mean connectivity strength of an orbito-frontal/cingulate circuit, included in the affected regions, correlate negatively with the extent of negative symptoms in 22q11DS patients, revealing the clinical relevance of present findings. The identified A-core overlaps numerous regions previously identified as affected in 22q11DS as well as in schizophrenia, which approximately 30-40% of 22q11DS patients develop.

NG2 glia are required for vessel network formation during embryonic development.

The NG2(+) glia, also known as polydendrocytes or oligodendrocyte precursor cells, represent a new entity among glial cell populations in the central nervous system. However, the complete repertoire of their roles is not yet identified. The embryonic NG2(+) glia originate from the Nkx2.1(+) progenitors of the ventral telencephalon. Our analysis unravels that, beginning from E12.5 until E16.5, the NG2(+) glia populate the entire dorsal telencephalon. Interestingly, their appearance temporally coincides with the establishment of blood vessel network in the embryonic brain. NG2(+) glia are closely apposed to developing cerebral vessels by being either positioned at the sprouting tip cells or tethered along the vessel walls. Absence of NG2(+) glia drastically affects the vascular development leading to severe reduction of ramifications and connections by E18.5. By revealing a novel and fundamental role for NG2(+) glia, our study brings new perspectives to mechanisms underlying proper vessels network formation in embryonic brains.

A Social Network Analysis of Twitter: Mapping the Digital Humanities Community

Defining digital humanities might be an endless debate if we stick to the discussion about the boundaries of this concept as an academic "discipline". In an attempt to concretely identify this field and its actors, this paper shows that it is possible to analyse them through Twitter, a social media widely used by this "community of practice". Based on a network analysis of 2,500 users identified as members of this movement, the visualisation of the "who's following who?" graph allows us to highlight the structure of the network's relationships, and identify users whose position is particular. Specifically, we show that linguistic groups are key factors to explain clustering within a network whose characteristics look similar to a small world.