High prevalence of patent foramen ovale in migraine with aura

In this study we evaluated the presence of patent foramen ovale (PFO) in a cohort of 25 consecutive patients suffering from migraine with aura (MA) during an attack presenting to the emergency ward of an Italian hospital. Patients underwent brain magnetic resonance imaging (MRI) with contrast medium, routine coagulation tests, contrast transcranial echocolour–coded sonography (c–TCCS) and transoesophageal echocardiography (TEE). Of the enrolled patients, 88.7% showed a PFO according to the c–TCCS test, whereas only in 72% TEE confirmed the presence of PFO. This discordance could be due to the fact that c–TCCS is more sensitive even with shunts with minimal capacity also located in the pulmonary vasculature. After surgical treatment of the PFO, MA disappeared within two months. Also, the treatment with warfarin as well as with acetylsalicylic acid and flunarizine was able to dramatically reduce the frequency of migraine attacks. These data indicate a higher prevalence of PFO in MA vs. normal population (OR=2.92) and could suggest that the presence of arteriovenous (AV) shunts could represent a trigger for MA attacks as well as for stroke, but more studies are needed to confirm this preliminary hypothesis

A new mechanism shapes the naïve CD8+ T cell repertoire: the selection for full diversity

During thymic T cell differentiation, TCR repertoires are shaped by negative, positive and agonist selection. In the thymus and in the periphery, repertoires are also shaped by strong inter-clonal and intra-clonal competition to survive death by neglect. Understanding the impact of these events on the T cell repertoire requires direct evaluation of TCR expression in peripheral naïve T cells. Several studies have evaluated TCR diversity, with contradictory results. Some of these studies had intrinsic technical limitations since they used material obtained from T cell pools, preventing the direct evaluation of clone sizes. Indeed with these approaches, identical TCRs may correspond to different cells expressing the same receptor, or to several amplicons from the same T cell. We here overcame this limitation by evaluating TCRB expression in individual naïve CD8+ T cells. Of the 2269 Tcrb sequences we obtained from 13 mice, 99% were unique. Mathematical analysis of this data showed that the average number of naïve peripheral CD8+ T cells expressing the same TCRB is 1.1 cell. Since TCRA co-expression studies could only increase repertoire diversity, these results reveal that the number of naïve T cells with unique TCRs approaches the number of naïve cells. Since thymocytes undergo multiple rounds of divisions after TCRB rearrangement; and 3–5% of thymocytes survive thymic selection events; the number of cells expressing the same TCRB was expected to be much higher. Thus, these results suggest a new repertoire selection mechanism, which strongly selects for full TCRB diversity

An Adaptive Complex Network Model for Brain Functional Networks

Brain functional networks are graph representations of activity in the brain, where the vertices represent anatomical regions and the edges their functional connectivity. These networks present a robust small world topological structure, characterized by highly integrated modules connected sparsely by long range links. Recent studies showed that other topological properties such as the degree distribution and the presence (or absence) of a hierarchical structure are not robust, and show different intriguing behaviors. In order to understand the basic ingredients necessary for the emergence of these complex network structures we present an adaptive complex network model for human brain functional networks. The microscopic units of the model are dynamical nodes that represent active regions of the brain, whose interaction gives rise to complex network structures. The links between the nodes are chosen following an adaptive algorithm that establishes connections between dynamical elements with similar internal states. We show that the model is able to describe topological characteristics of human brain networks obtained from functional magnetic resonance imaging studies. In particular, when the dynamical rules of the model allow for integrated processing over the entire network scale-free non-hierarchical networks with well defined communities emerge. On the other hand, when the dynamical rules restrict the information to a local neighborhood, communities cluster together into larger ones, giving rise to a hierarchical structure, with a truncated power law degree distribution

Mesoscopic organization reveals the constraints governing C. elegans nervous system

One of the biggest challenges in biology is to understand how activity at the cellular level of neurons, as a result of their mutual interactions, leads to the observed behavior of an organism responding to a variety of environmental stimuli. Investigating the intermediate or mesoscopic level of organization in the nervous system is a vital step towards understanding how the integration of micro-level dynamics results in macro-level functioning. In this paper, we have considered the somatic nervous system of the nematode Caenorhabditis elegans, for which the entire neuronal connectivity diagram is known. We focus on the organization of the system into modules, i.e., neuronal groups having relatively higher connection density compared to that of the overall network. We show that this mesoscopic feature cannot be explained exclusively in terms of considerations, such as optimizing for resource constraints (viz., total wiring cost) and communication efficiency (i.e., network path length). Comparison with other complex networks designed for efficient transport (of signals or resources) implies that neuronal networks form a distinct class. This suggests that the principal function of the network, viz., processing of sensory information resulting in appropriate motor response, may be playing a vital role in determining the connection topology. Using modular spectral analysis, we make explicit the intimate relation between function and structure in the nervous system. This is further brought out by identifying functionally critical neurons purely on the basis of patterns of intra- and inter-modular connections. Our study reveals how the design of the nervous system reflects several constraints, including its key functional role as a processor of information.Comment: Published version, Minor modifications, 16 pages, 9 figure

Predictive value of the CLL-IPI in CLL patients receiving chemo-immunotherapy as first-line treatment

An international collaboration has led to the development of a comprehensive tool [CLL-IPI international prognostic index for CLL] for the predicting of overall survival (OS) in chronic lymphocytic leukemia (CLL).1 CLL-IPI was based on data collected from 3500 CLL patients and was based on the following parameters: TP53 deletion and/or mutation, IGHV mutational status, \u3b22-microglobulin plasma levels, clinical stage, and age. CLL-IPI provides the means to stratify CLL patients in the daily clinical practice (Supplementary Table 1).1 Although validated for OS2-4 and time to first treatment (TTFT),5 the predictive value of CLL-IPI on progression-free survival (PFS) has until now only been demonstrated in a single study on patients treated with chlorambucil (CLB), as monotherapy, or in combination with obinutuzumab or rituximab, as a first-line approach (CLL11 study),6 and presented as a poster at the annual meeting of the American Society of Hematology (ASH) in 2016

Whole-genome sequencing analysis of semi-supercentenarians

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events

Varieties of Capitalism and the Learning Firm: Contemporary Developments in EU and German Company Law - A Comment on the Strine-Bainbridge Debate About Shared Values of Corporate Management and Labor

Research in corporate governance and in labour law has been characterized by a disjuncture in the way that scholars in each field are addressing organizational questions related to the business enterprise. While labour has eventually begun to shift perspectives from aspirations to direct employee involvement in firm management, as has been the case in Germany, to a combination of \u27exit\u27 and \u27voice\u27 strategies involving pension fund management and securities litigation, it remains to be seen whether this new stream will unfold as a viable challenge to an otherwise exclusionary shareholder value paradigm. At the same time, recent suggestions made by Delaware Chancery Court Vice Chancellor Strine, to dare think about potentially shared commitments between management and labor - and UCLA\u27s Stephen Bainbridge\u27s response - underline the viability - and, the contestedness - of attempts at moving the corporate governance debate beyond the confines of corporate law proper. While such a wider view had already famously been encouraged by Dean Clarke in his 1986 treatise on Corporate Law (p. 32), mainstream corporate law does not seem to have endorsed this perspective. This paper takes the questionable divide between management and labor within the framework of a limiting corporate governance concept as starting point to explore the institutional dynamics of the corporation, hereby building on the theory of the innovative enterprise, as developed by management theorists Mary O\u27Sullivan and William Lazonick. Largely due to the sustained distance between corporate and labour law scholars, neither group has effectively addressed their common blind spot: a better understanding of the business enterprise itself. In midst of an unceasing flow of affirmations of the finance paradigm of the corporation on the one hand and \u27voice\u27 strategies by labour on the other, it seems to fall to management theorists to draw lessons from the continuing co-existence of different forms of market organization, in which companies appear to thrive. Exploring the conundrum of \u27risky\u27 business decisions within the firm, management theorists have been arguing for the need to adopt a more sophisticated organizational perspective on companies operating on locally, regionally and transnationally shaped, often highly volatile market segments. Research by comparative political economists has revealed a high degree of connectivity between corporate governance and economic performance without, however, arriving at such favourable results only for shareholder value regimes. Such findings support the view that corporate governance regimes are embedded in differently shaped regulatory frameworks, characterized by distinct institutions, both formal and informal, and enforcement processes. As a result of these findings, arguments to disassociate issues of corporate governance from those of the firm\u27s (social) responsibility [CSR] have been losing ground. Instead, CSR can be taken to be an essential part of understanding a particular business enterprise. It is the merging of a comparative political economy perspective on the corporation with one on the organizational features, structures and processes of the corporation, which can help us better understand the distribution of power and knowledge within the \u27learning firm\u27

A novel brain partition highlights the modular skeleton shared by structure and function

Elucidating the intricate relationship between brain structure and function, both in healthy and pathological conditions, is a key challenge for modern neuroscience. Recent progress in neuroimaging has helped advance our understanding of this important issue, with diffusion images providing information about structural connectivity (SC) and functional magnetic resonance imaging shedding light on resting state functional connectivity (rsFC). Here, we adopt a systems approach, relying on modular hierarchical clustering, to study together SC and rsFC datasets gathered independently from healthy human subjects. Our novel approach allows us to find a common skeleton shared by structure and function from which a new, optimal, brain partition can be extracted. We describe the emerging common structure-function modules (SFMs) in detail and compare them with commonly employed anatomical or functional parcellations. Our results underline the strong correspondence between brain structure and resting-state dynamics as well as the emerging coherent organization of the human brain.Work supported by Ikerbasque: The Basque Foundation for Science, Euskampus at UPV/EHU, Gobierno Vasco (Saiotek SAIO13-PE13BF001) and Junta de Andalucía (P09-FQM-4682) to JMC; Ikerbasque Visiting Professor to SS; Junta de Andalucía (P09-FQM-4682) and Spanish Ministry of Economy and Competitiveness (FIS2013-43201-P) to MAM; the European Union’s Seventh Framework Programme (ICT-FET FP7/2007-2013, FET Young Explorers scheme) under grant agreement n. 284772 BRAIN BOW (www.brainbowproject.eu) and by the Joint Italy—Israel Laboratory on Neuroscience to PB. For results validation (figure S8), data were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University

Driving and Driven Architectures of Directed Small-World Human Brain Functional Networks

Recently, increasing attention has been focused on the investigation of the human brain connectome that describes the patterns of structural and functional connectivity networks of the human brain. Many studies of the human connectome have demonstrated that the brain network follows a small-world topology with an intrinsically cohesive modular structure and includes several network hubs in the medial parietal regions. However, most of these studies have only focused on undirected connections between regions in which the directions of information flow are not taken into account. How the brain regions causally influence each other and how the directed network of human brain is topologically organized remain largely unknown. Here, we applied linear multivariate Granger causality analysis (GCA) and graph theoretical approaches to a resting-state functional MRI dataset with a large cohort of young healthy participants (n = 86) to explore connectivity patterns of the population-based whole-brain functional directed network. This directed brain network exhibited prominent small-world properties, which obviously improved previous results of functional MRI studies showing weak small-world properties in the directed brain networks in terms of a kernel-based GCA and individual analysis. This brain network also showed significant modular structures associated with 5 well known subsystems: fronto-parietal, visual, paralimbic/limbic, subcortical and primary systems. Importantly, we identified several driving hubs predominantly located in the components of the attentional network (e.g., the inferior frontal gyrus, supplementary motor area, insula and fusiform gyrus) and several driven hubs predominantly located in the components of the default mode network (e.g., the precuneus, posterior cingulate gyrus, medial prefrontal cortex and inferior parietal lobule). Further split-half analyses indicated that our results were highly reproducible between two independent subgroups. The current study demonstrated the directions of spontaneous information flow and causal influences in the directed brain networks, thus providing new insights into our understanding of human brain functional connectome