Consistency and diversity of spike dynamics in the neurons of bed nucleus of Stria Terminalis of the rat: a dynamic clamp study

Neurons display a high degree of variability and diversity in the expression and regulation of their voltage-dependent ionic channels. Under low level of synaptic background a number of physiologically distinct cell types can be identified in most brain areas that display different responses to standard forms of intracellular current stimulation. Nevertheless, it is not well understood how biophysically different neurons process synaptic inputs in natural conditions, i.e., when experiencing intense synaptic bombardment in vivo. While distinct cell types might process synaptic inputs into different patterns of action potentials representing specific "motifs'' of network activity, standard methods of electrophysiology are not well suited to resolve such questions. In the current paper we performed dynamic clamp experiments with simulated synaptic inputs that were presented to three types of neurons in the juxtacapsular bed nucleus of stria terminalis (jcBNST) of the rat. Our analysis on the temporal structure of firing showed that the three types of jcBNST neurons did not produce qualitatively different spike responses under identical patterns of input. However, we observed consistent, cell type dependent variations in the fine structure of firing, at the level of single spikes. At the millisecond resolution structure of firing we found high degree of diversity across the entire spectrum of neurons irrespective of their type. Additionally, we identified a new cell type with intrinsic oscillatory properties that produced a rhythmic and regular firing under synaptic stimulation that distinguishes it from the previously described jcBNST cell types. Our findings suggest a sophisticated, cell type dependent regulation of spike dynamics of neurons when experiencing a complex synaptic background. The high degree of their dynamical diversity has implications to their cooperative dynamics and synchronization

Large rivers and orogens: the evolution of the Yarlung Tsangpo–Irrawaddy system and the eastern Himalayan syntaxis

The eastern Himalayan syntaxis has experienced some of the highest rates of deformation and erosion in the orogen during the Late Cenozoic, and the Yarlung Tsangpo, Brahmaputra, Irrawaddy, Salween, and Mekong rivers are the key erosional systems in that region. The Yarlung Tsangpo drains southern Tibet and the deep Siang River gorge through the eastern Himalayan syntaxis before joining the Brahmaputra in northeastern India. It has been proposed that the Yarlung Tsangpo drained into other large rivers of southern Asia, such as the Irrawaddy, Salween and Red River. We have used uranium/lead dating and hafnium measurements of detrital zircons from Cenozoic sedimentary deposits in Central Myanmar to demonstrate that the Yarlung Tsangpo formerly drained into the Irrawaddy River in Myanmar through the eastern syntaxis, and that this ancient river system was established by (at least) the Middle–Late Eocene. The Yarlung Tsangpo–Irrawaddy river disconnected in the Early Miocene driven by increased deformation in the eastern syntaxis and headward erosion by tributaries of the Brahmaputra. Our results highlight the significance of the sedimentary record of large orogen-parallel rivers and provide key chronological constraints on landscape evolution during the Early Miocene phase of the Himalayan orogeny

Are virtues national, supranational, or universal?

Many studies investigated cultural differences in values, most notably by Hofstede and Schwarz. Relatively few have focused on virtues, a related and important concept in contemporary social science. The present paper examines the similarities and differences between nations, or blocks of - culturally related - nations on the perceived importance of virtues. Adults (N = 2.809 students) from 14 countries were asked to freely mention which virtues they found important to practice in daily life, and next to rate a list of 15 virtues, which reflect the most frequently mentioned categories in The Netherlands, as found in a previous study. The 14 nations included the United States, Mexico, nine European and three Asian nations. For the free-listed virtues, we compared the top-ten lists of most frequently mentioned virtues across the nations. We used a correspondence analysis on the frequency table to assess the relationships between the virtues and nations. For the 15 virtues ratings, a MANOVA, and follow-up ANOVA’s were used to examine effects of nation, age, gender and religion. We found strong evidence for relationships between nations and blocks of culturally related nations and the importance attached to various virtues. There appear to be some country specific virtues, such as generosity in France, but also some relatively universal virtues, most notably honesty, respect, and kindness

Delayed Onset of Positive Feedback Activation of Rab5 by Rabex-5 and Rabaptin-5 in Endocytosis

BACKGROUND: Rabex-5 is a guanine nucleotide exchange factor (GEF) that specifically activates Rab5, i.e., converting Rab5-GDP to Rab5-GTP, through two distinct pathways to promote endosome fusion and endocytosis. The direct pathway involves a pool of membrane-associated Rabex-5 that targets to the membrane via an early endosomal targeting (EET) domain. The indirect pathway, on the other hand, involves a cytosolic pool of Rabex-5/Rabaptin-5 complex. The complex is recruited to the membrane via Rabaptin-5 binding to Rab5-GTP, suggesting a positive feedback mechanism. The relationship of these two pathways for Rab5 activation in the cell is unclear. METHODOLOGY/PRINCIPAL FINDINGS: We dissect the relative contribution of each pathway to Rab5 activation via mathematical modeling and kinetic analysis in the cell. These studies show that the indirect pathway constitutes a positive feedback loop for converting Rab5-GDP to Rab5-GTP on the endosomal membrane and allows sensitive regulation of endosome fusion activity by the levels of Rab5 and Rabex-5 in the cell. The onset of this positive feedback effect, however, contains a threshold, which requires above endogenous levels of Rab5 or Rabex-5 in the cell. We term this novel phenomenon "delayed response". The presence of the direct pathway reduces the delay by increasing the basal level of Rab5-GTP, thus facilitates the function of the Rabex-5/Rabaptin-5-mediated positive feedback loop. CONCLUSION: Our data support the mathematical model. With the model's guidance, the data reveal the affinity of Rabex-5/Rabaptin-5/Rab5-GTP interaction in the cell, which is quantitatively related to the Rabex-5 concentration for the onset of the indirect positive feedback pathway. The presence of the direct pathway and increased Rab5 concentration can reduce the Rabex-5 concentration required for the onset of the positive feedback loop. Thus the direct and indirect pathways cooperate in the regulation of early endosome fusion

Infrastructure for Detector Research and Development towards the International Linear Collider

The EUDET-project was launched to create an infrastructure for developing and testing new and advanced detector technologies to be used at a future linear collider. The aim was to make possible experimentation and analysis of data for institutes, which otherwise could not be realized due to lack of resources. The infrastructure comprised an analysis and software network, and instrumentation infrastructures for tracking detectors as well as for calorimetry.Comment: 54 pages, 48 picture

Parallel algebraic multilevel Schwarz preconditioners for a class of elliptic PDE systems

Algebraic multilevel preconditioners for algebraic problems arising from the discretization of a class of systems of coupled elliptic partial differential equations (PDEs) are presented. These preconditioners are based on modifications of Schwarz methods and of the smoothed aggregation technique, where the coarsening strategy and the restriction and prolongation operators are defined using a point-based approach with a primary matrix corresponding to a single PDE. The preconditioners are implemented in a parallel computing framework and are tested on two representative PDE systems. The results of the numerical experiments show the effectiveness and the scalability of the proposed methods. A convergence theory for the twolevel case is presented

Association between germline variants and somatic mutations in colorectal cancer

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n similar or equal to 125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC

Graphical Approach to Model Reduction for Nonlinear Biochemical Networks

Model reduction is a central challenge to the development and analysis of multiscale physiology models. Advances in model reduction are needed not only for computational feasibility but also for obtaining conceptual insights from complex systems. Here, we introduce an intuitive graphical approach to model reduction based on phase plane analysis. Timescale separation is identified by the degree of hysteresis observed in phase-loops, which guides a “concentration-clamp” procedure for estimating explicit algebraic relationships between species equilibrating on fast timescales. The primary advantages of this approach over Jacobian-based timescale decomposition are that: 1) it incorporates nonlinear system dynamics, and 2) it can be easily visualized, even directly from experimental data. We tested this graphical model reduction approach using a 25-variable model of cardiac β1-adrenergic signaling, obtaining 6- and 4-variable reduced models that retain good predictive capabilities even in response to new perturbations. These 6 signaling species appear to be optimal “kinetic biomarkers” of the overall β1-adrenergic pathway. The 6-variable reduced model is well suited for integration into multiscale models of heart function, and more generally, this graphical model reduction approach is readily applicable to a variety of other complex biological systems