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Martin Ruthardt - One of the best experts on this subject based on the ideXlab platform.
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the Functional interplay between the t 9 22 associated fusion proteins bcr abl and abl bcr in philadelphia chromosome positive acute lymphatic leukemia
PLOS Genetics, 2015Co-Authors: Anahita Rafiei, Afsar Ali Mian, Anna Metodieva, Oliver G Ottmann, Claudia Doring, Claudia Oancea, Frederic B Thalheimer, Martinleo Hansmann, Martin RuthardtAbstract:The hallmark of Philadelphia chromosome positive (Ph+) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph+ leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. The co-expression of p96ABL/BCR enhanced the kinase activity and as a consequence, the transformation potential of p185BCR/ABL. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and Ph+ ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a Functional Hierarchy of p96ABL/BCR and p185BCR/ABL in hematopoietic stem cells. Co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph+ ALL.
Simon B Eickhoff - One of the best experts on this subject based on the ideXlab platform.
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ep 34 Functional Hierarchy within the neural network for optokinetic look nystagmus
Clinical Neurophysiology, 2016Co-Authors: Felix Hoffstaedter, Zu P. Eulenburg, Simon B Eickhoff, Andrew T Reid, Christian GrefkesAbstract:Key nodes of neural networks for ocular motor control and visual motion processing have been localized using saccades, smooth pursuit, and optokinetic nystagmus (OKN). Within the context of an independent fMRI study using OKN, 9 bilateral network nodes were localized comprising cortical eye fields in frontal (FEF), supplementary motor (SEF), cingulate (CEF) and parietal cortex (PEF), visual motion centers MT+ and V6, the superior colliculus (SC), the lateral geniculate nucleus (LGN) and the globus pallidus (GP). Here, we examined the network’s Functional Hierarchy as present in the structural co-variation (SCoV) and resting-state (RS) fMRI, and the effect of RS condition (eyes open/closed) on its’ Functional connectivity (FC). Two publicly available samples were analyzed consisting of the enhanced NKI sample with RS (TR 1.4s) and structural MR data (n = 124; age 46.7 ± 17.6; 40 male) and the “Beijing: eyes open eyes closed sample” measuring RS (TR 2s; n = 48; age 22.5 ± 2.2; 24 male). For the FC analysis, ICA-based denoising (FSL) was applied before spatial preprocessing (SPM) and band-pass filtering. Each bilateral ROI was represented by the first eigenvariate of the respective voxels’ time-series and partial correlation were computed using FSLNets. One group t-tests were computed over Fisher’s z transformed correlation coefficients. Each ROIs volume was approximated with voxel-based morphometry (VBM8) using non-linearly modulated gray matter density and partial correlations were computed for SCoV. Hierarchical cluster analysis was applied to determine sub-clustering within the OKN network. Edge-wise comparisons between RS conditions were performed using permutation testing and Bonferroni correction. Both FC and SCoV revealed two major subcluster. MT+ and V6 were similar to LGN and SC. The cortical eye fields clustered together with the GP. As effect of RS condition, with eyes closed the CEF switched to the visual subcluster. The edge-wise comparison revealed generally higher FC with eyes open and in particular a decrease of FC between MT+ and PEF, FEF and SEF as well as between V6 and SEF. Hierarchical clustering based on RS and structural data revealed a task-independent sub-division of the network for ocular-motor control and visual motion processing into two streams either involved in top-down (efferent voluntary) ocular-motor control (FEF, PEF, SEF, GP) and in more bottom-up visual target tracking (MT+, V6, LGN, SC) streams. This general network Hierarchy was equally present in the RS with eyes open and eyes closed, with the CEF fulfilling a condition specific role in the network. The edge-wise comparison between RS conditions strengthens the evidence for a specific influence of MT+ on the ocular-motor control subcluster. These findings indicate a systematic influence of the resting condition not only on FC of the visual system, but on the state of the whole OKN network, while a general system Hierarchy is omnipresent independent of RS condition.
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v11 Functional Hierarchy within an overall network for visual motion processing and ocular motor control at rest
Clinical Neurophysiology, 2015Co-Authors: Felix Hoffstaedter, Simon B Eickhoff, Zu P. EulenburgAbstract:Introduction Visual motion processing on one hand and ocular motor functions on the other are rarely studied together in vivo in humans. The interrelation of these Functional networks is rather unclear, even though their Functional dependence seems obvious. In several fMRI studies the essential nodes of both networks could be localized using voluntary optokinetic ('look') nystagmus (OKN) in the horizontal plane incorporating visual motion tracking (Dieterich et al., 2009). Here, Functional connectivity (FC) between these nodes representing both networks was studies using resting-state FC. Methods Resting-state fMRI data of 200 healthy adults (age 44.1±17.9; 79 male) were included in the cross correlation analysis of 9 bilateral nodes including frontal (FEF), supplementary (SEF), cingulate (CEF) and parietal eye fields (PEF), V5 and V6, as well as the superior colliculus (SupCol), the lateral geniculate body (CGL) and the globus pallidus (GlobPal). The necessary ROIs were obtained in a separate OKN fmri experiment with 21 healthy subjects. After spatial preprocessing and confound removal using 24 motion regression and mean signal within white matter and cerebral spinal fluid and band-pass filtering (0.01–0.08Hz), each ROI was represented by the first eigenvariate of the respective voxels' time-series. For each node pair partial correlations were computed within subjects and Fisher Z transformed for one group t -tests corrected for the influence of age and gender resulting in an 18×18 cross correlation matrix. Subsequently, hierarchical cluster analysis was applied to analyze sub-clustering within the overall network. Results The analysis showed consistent FC between each regions respective homotopical partner. Hierarchical clustering revealed an overall split between one cluster comprising SEF, FEF, CEF and GlobPal and a second including CGL, SubCol, V6 as well as PEF and V5. Conclusion This new approach revealed an observer- and task-indepedent separation of the cortical eye fields into two main groups either responsible for voluntary ocular motor control (SEF, FEF, CEF, and GlobPal) or involved in visual motion target tracking streams (CGL, SupCol, PEF, V5, and V6). The further subgrouping of PEF and V5 together with area V6 representing an isolated cluster within the second group seem to reflect their order and importance along the dorsal visual stream known from lesion studies (Pierrot-Deseilligny et al., 2004). The other subgroup of CGL and SupCol may represent the early nodes of the network involved in voluntary and reflexive ocular motor control. In sum, these neuroscientifically sound network findings for visual motion and ocular motor control derived from task-free data give a promising outlook for the novel concept of hierarchical clustering (Figs. 1 and 2).
Hannah Choi - One of the best experts on this subject based on the ideXlab platform.
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survey of spiking in the mouse visual system reveals Functional Hierarchy
Nature, 2021Co-Authors: Joshua H Siegle, Xiaoxuan Jia, Severine Durand, Sam Gale, Corbett Bennett, Nile Graddis, Greggory Heller, Tamina Ramirez, Hannah ChoiAbstract:The anatomy of the mammalian visual system, from the retina to the neocortex, is organized hierarchically1. However, direct observation of cellular-level Functional interactions across this Hierarchy is lacking due to the challenge of simultaneously recording activity across numerous regions. Here we describe a large, open dataset-part of the Allen Brain Observatory2-that surveys spiking from tens of thousands of units in six cortical and two thalamic regions in the brains of mice responding to a battery of visual stimuli. Using cross-correlation analysis, we reveal that the organization of inter-area Functional connectivity during visual stimulation mirrors the anatomical Hierarchy from the Allen Mouse Brain Connectivity Atlas3. We find that four classical hierarchical measures-response latency, receptive-field size, phase-locking to drifting gratings and response decay timescale-are all correlated with the Hierarchy. Moreover, recordings obtained during a visual task reveal that the correlation between neural activity and behavioural choice also increases along the Hierarchy. Our study provides a foundation for understanding coding and signal propagation across hierarchically organized cortical and thalamic visual areas.
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a survey of spiking activity reveals a Functional Hierarchy of mouse corticothalamic visual areas
bioRxiv, 2019Co-Authors: Joshua H Siegle, Xiaoxuan Jia, Severine Durand, Sam Gale, Corbett Bennett, Nile Graddis, Greggory Heller, Tamina Ramirez, Hannah ChoiAbstract:Abstract The mammalian visual system, from retina to neocortex, has been extensively studied at both anatomical and Functional levels. Anatomy indicates the cortico-thalamic system is hierarchical, but characterization of cellular-level Functional interactions across multiple levels of this Hierarchy is lacking, partially due to the challenge of simultaneously recording activity across numerous regions. Here, we describe a large, open dataset (part of the Allen Brain Observatory) that surveys spiking from units in six cortical and two thalamic regions responding to a battery of visual stimuli. Using spike cross-correlation analysis, we find that inter-area Functional connectivity mirrors the anatomical Hierarchy from the Allen Mouse Brain Connectivity Atlas. Classical Functional measures of Hierarchy, including visual response latency, receptive field size, phase-locking to a drifting grating stimulus, and autocorrelation timescale are all correlated with the anatomical Hierarchy. Moreover, recordings during a visual task support the behavioral relevance of hierarchical processing. Overall, this dataset and the Hierarchy we describe provide a foundation for understanding coding and dynamics in the mouse cortico-thalamic visual system.
Anahita Rafiei - One of the best experts on this subject based on the ideXlab platform.
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the Functional interplay between the t 9 22 associated fusion proteins bcr abl and abl bcr in philadelphia chromosome positive acute lymphatic leukemia
PLOS Genetics, 2015Co-Authors: Anahita Rafiei, Afsar Ali Mian, Anna Metodieva, Oliver G Ottmann, Claudia Doring, Claudia Oancea, Frederic B Thalheimer, Martinleo Hansmann, Martin RuthardtAbstract:The hallmark of Philadelphia chromosome positive (Ph+) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph+ leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. The co-expression of p96ABL/BCR enhanced the kinase activity and as a consequence, the transformation potential of p185BCR/ABL. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and Ph+ ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a Functional Hierarchy of p96ABL/BCR and p185BCR/ABL in hematopoietic stem cells. Co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph+ ALL.
Pascal Fries - One of the best experts on this subject based on the ideXlab platform.
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alpha beta and gamma rhythms subserve feedback and feedforward influences among human visual cortical areas
Neuron, 2016Co-Authors: Georgios Michalareas, Henry Kennedy, Julien Vezoli, Janmathijs Schoffelen, Pascal Fries, Stan Van PeltAbstract:Primate visual cortex is hierarchically organized. Bottom-up and top-down influences are exerted through distinct frequency channels, as was recently revealed in macaques by correlating inter-areal influences with laminar anatomical projection patterns. Because this anatomical data cannot be obtained in human subjects, we selected seven homologous macaque and human visual areas, and we correlated the macaque laminar projection patterns to human inter-areal directed influences as measured with magnetoencephalography. We show that influences along feedforward projections predominate in the gamma band, whereas influences along feedback projections predominate in the alpha-beta band. Rhythmic inter-areal influences constrain a Functional Hierarchy of the seven homologous human visual areas that is in close agreement with the respective macaque anatomical Hierarchy. Rhythmic influences allow an extension of the Hierarchy to 26 human visual areas including uniquely human brain areas. Hierarchical levels of ventral- and dorsal-stream visual areas are differentially affected by inter-areal influences in the alpha-beta band.
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Inter-areal causal interactions in the gamma and beta frequency bands define a Functional Hierarchy in the primate visual system
Perception, 2013Co-Authors: Julien Vezoli, Henry Kennedy, Andre M Bastos, Conrado A Bosman, Janmathijs Schoffelen, Robert Oostenveld, P. De Weerd, Pascal FriesAbstract:Cortico-cortical connectivity has been shown to be hierarchically organized such that bottom-up and top-down information are conveyed through the well-defined feedforward and feedback counter-streams, respectively. It remains however unclear what mechanisms the cortex might use to Functionally segregate these different paths of information flow. In line with recent studies, showing that Gamma rhythms are predominantly found in the supragranular layers whereas Beta rhythms are strongest in the deep layers (Buffalo et al., 2011), we analyzed causal interactions in the Gamma and Beta frequency bands between seven visual areas of macaque monkeys performing a visuospatial attention task. LFP signals were recorded through electrocorticography and analyzed through spectrally resolved Granger causality. We show here that Gamma-band influences were predominant in the bottom-up direction, whereas Beta-band influences were predominant in the top-down direction. The Functional asymmetry we identified was significantly correlated with anatomical data and was used to build a Hierarchy model from Functional data alone, which was highly similar to anatomical models of the primate visual system. These results open the possibility for the in vivo investigation of Functional hierarchies in the healthy and diseased human brain. JV, AMB and CB contributed equally. JV was funded by the LOEWE-NeFF.
