1,068 research outputs found
Nuclear pore assembly proceeds by an inside-out extrusion of the nuclear envelope
The nuclear pore complex (NPC) mediates nucleocytoplasmic transport through the
nuclear envelope. How the NPC assembles into this double membrane boundary has remained
enigmatic. Here, we captured temporally staged assembly intermediates by correlating live cell
imaging with high-resolution electron tomography and super-resolution microscopy. Intermediates
were dome-shaped evaginations of the inner nuclear membrane (INM), that grew in diameter and
depth until they fused with the flat outer nuclear membrane. Live and super-resolved fluorescence
microscopy revealed the molecular maturation of the intermediates, which initially contained the
nuclear and cytoplasmic ring component Nup107, and only later the cytoplasmic filament
component Nup358. EM particle averaging showed that the evagination base was surrounded by
an 8-fold rotationally symmetric ring structure from the beginning and that a growing mushroomshaped
density was continuously associated with the deforming membrane. Quantitative structural
analysis revealed that interphase NPC assembly proceeds by an asymmetric inside-out extrusion of
the INM
The barrel DIRC of PANDA
Cooled antiproton beams of unprecedented intensities in the momentum range of 1.5-15 GeV/c will be used for the PANDA experiment at FAIR to perform high precision experiments in the charmed quark sector. The PANDA detector will investigate antiproton annihilations with beams in the momentum range of 1.5 GeV/c to 15 GeV/c on a fixed target. An almost 4π acceptance double spectrometer is divided in a forward spectrometer and a target spectrometer. The charged particle identification in the latter is performed by ring imaging Cherenkov counters employing the DIRC principle
The barrel DIRC of PANDA
Cooled antiproton beams of unprecedented intensities in the momentum range of 1.5-15 GeV/c will be used for the PANDA experiment at FAIR to perform high precision experiments in the charmed quark sector. The PANDA detector will investigate antiproton annihilations with beams in the momentum range of 1.5 GeV/c to 15 GeV/c on a fixed target. An almost 4π acceptance double spectrometer is divided in a forward spectrometer and a target spectrometer. The charged particle identification in the latter is performed by ring imaging Cherenkov counters employing the DIRC principle
Status of the PANDA barrel DIRC
The PANDA experiment at the future Facility for Antiproton and Ion Research in Europe GmbH (FAIR) at GSI, Darmstadt will study fundamental questions of hadron physics and QCD using high-intensity cooled antiproton beams with momenta between 1.5 and 15 GeV/c. Hadronic PID in the barrel region of the PANDA detector will be provided by a DIRC (Detection of Internally Reflected Cherenkov light) counter. The design is based on the successful BABAR DIRC with several key improvements, such as fast photon timing and a compact imaging region. Detailed Monte Carlo simulation studies were performed for DIRC designs based on narrow bars or wide plates with a variety of focusing solutions. The performance of each design was characterized in terms of photon yield and single photon Cherenkov angle resolution and a maximum likelihood approach was used to determine the π/K separation. Selected design options were implemented in prototypes and tested with hadronic particle beams at GSI and CERN. This article describes the status of the design and R&D for the PANDA Barrel DIRC detector, with a focus on the performance of different DIRC designs in simulation and particle beams
From Demonstrations to Task-Space Specifications:Using Causal Analysis to Extract Rule Parameterization from Demonstrations
Learning models of user behaviour is an important problem that is broadly
applicable across many application domains requiring human-robot interaction.
In this work, we show that it is possible to learn generative models for
distinct user behavioural types, extracted from human demonstrations, by
enforcing clustering of preferred task solutions within the latent space. We
use these models to differentiate between user types and to find cases with
overlapping solutions. Moreover, we can alter an initially guessed solution to
satisfy the preferences that constitute a particular user type by
backpropagating through the learned differentiable models. An advantage of
structuring generative models in this way is that we can extract causal
relationships between symbols that might form part of the user's specification
of the task, as manifested in the demonstrations. We further parameterize these
specifications through constraint optimization in order to find a safety
envelope under which motion planning can be performed. We show that the
proposed method is capable of correctly distinguishing between three user
types, who differ in degrees of cautiousness in their motion, while performing
the task of moving objects with a kinesthetically driven robot in a tabletop
environment. Our method successfully identifies the correct type, within the
specified time, in 99% [97.8 - 99.8] of the cases, which outperforms an IRL
baseline. We also show that our proposed method correctly changes a default
trajectory to one satisfying a particular user specification even with unseen
objects. The resulting trajectory is shown to be directly implementable on a
PR2 humanoid robot completing the same task.Comment: arXiv admin note: substantial text overlap with arXiv:1903.0126
Theta-Burst Stimulation-Induced Plasticity over Primary Somatosensory Cortex Changes Somatosensory Temporal Discrimination in Healthy Humans
BACKGROUND: The somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Precisely how the single cerebral structures contribute in controlling the STDT is partially known and no information is available about whether STDT can be modulated by plasticity-inducing protocols. METHODOLOGY/PRINCIPAL FINDINGS: To investigate how the cortical and cerebellar areas contribute to the STDT we used transcranial magnetic stimulation and a neuronavigation system. We enrolled 18 healthy volunteers and 10 of these completed all the experimental sessions, including the control experiments. STDT was measured on the left hand before and after applying continuous theta-burst stimulation (cTBS) on the right primary somatosensory area (S1), pre-supplementary motor area (pre-SMA), right dorsolateral prefrontal cortex (DLPFC) and left cerebellar hemisphere. We then investigated whether intermittent theta-burst stimulation (iTBS) on the right S1 improved the STDT. After right S1 cTBS, STDT values increased whereas after iTBS to the same cortical site they decreased. cTBS over the DLPFC and left lateral cerebellum left the STDT statistically unchanged. cTBS over the pre-SMA also left the STDT statistically unchanged, but it increased the number of errors subjects made in distinguishing trials testing a single stimulus and those testing paired stimuli. CONCLUSIONS/SIGNIFICANCE: Our findings obtained by applying TBS to the cortical areas involved in processing sensory discrimination show that the STDT is encoded in S1, possibly depends on intrinsic S1 neural circuit properties, and can be modulated by plasticity-inducing TBS protocols delivered over S1. Our findings, giving further insight into mechanisms involved in somatosensory temporal discrimination, help interpret STDT abnormalities in movement disorders including dystonia and Parkinson's disease
Global and regional brain metabolic scaling and its functional consequences
Background: Information processing in the brain requires large amounts of
metabolic energy, the spatial distribution of which is highly heterogeneous
reflecting complex activity patterns in the mammalian brain.
Results: Here, it is found based on empirical data that, despite this
heterogeneity, the volume-specific cerebral glucose metabolic rate of many
different brain structures scales with brain volume with almost the same
exponent around -0.15. The exception is white matter, the metabolism of which
seems to scale with a standard specific exponent -1/4. The scaling exponents
for the total oxygen and glucose consumptions in the brain in relation to its
volume are identical and equal to , which is significantly larger
than the exponents 3/4 and 2/3 suggested for whole body basal metabolism on
body mass.
Conclusions: These findings show explicitly that in mammals (i)
volume-specific scaling exponents of the cerebral energy expenditure in
different brain parts are approximately constant (except brain stem
structures), and (ii) the total cerebral metabolic exponent against brain
volume is greater than the much-cited Kleiber's 3/4 exponent. The
neurophysiological factors that might account for the regional uniformity of
the exponents and for the excessive scaling of the total brain metabolism are
discussed, along with the relationship between brain metabolic scaling and
computation.Comment: Brain metabolism scales with its mass well above 3/4 exponen
The challenges of implementing packaged hospital electronic prescribing and medicine administration systems in UK hospitals: premature purchase of immature solutions?
The UK National Health Service is making major efforts to implement Hospital Electronic Prescribing and Medicine Administration (HEPMA) to improve patient safety and quality of care. Substantial public investments have attracted a wide range of UK and overseas suppliers offering Commercial-Off –The-Shelf (COTS) solutions. A lack of (UK) implementation experience and weak supplier-user relationships are reflected in systems with limited configurability, poorly matched to the needs and practices of English hospitals. This situation echoes the history of comparable corporate information infrastructures - Enterprise Resource Planning systems - in the 1980s/1990s. UK government intervention prompted a similar swarming of immature, often unfinished, products into the market. This resulted, in both cases, in protracted and difficult implementation processes as vendors and adopters struggled to get the systems to work and match the circumstances of the adopting organisations. An analysis of the influence of the Installed Base on Information Infrastructures should explore how the evolution of COTS solutions is conditioned by the structure of adopter and vendor ‘communities’
The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53
Desmoglein-3 (Dsg3), the Pemphigus Vulgaris (PV) antigen (PVA), plays an essential role in keratinocyte cell–cell
adhesion and regulates various signaling pathways involved in the progression and metastasis of cancer where it is
upregulated. We show here that expression of Dsg3 impacts on the expression and function of p53, a key transcription
factor governing the responses to cellular stress. Dsg3 depletion increased p53 expression and activity, an effect
enhanced by treating cells with UVB, mechanical stress and genotoxic drugs, whilst increased Dsg3 expression
resulted in the opposite effects. Such a pathway in the negative regulation of p53 by Dsg3 was Dsg3 specific since
neither E-cadherin nor desmoplakin knockdown caused similar effects. Analysis of Dsg3−/− mouse skin also indicated
an increase of p53/p21WAF1/CIP1 and cleaved caspase-3 relative to Dsg3+/− controls. Finally, we evaluated whether this
pathway was operational in the autoimmune disease PV in which Dsg3 serves as a major antigen involved in blistering
pathogenesis. We uncovered increased p53 with diffuse cytoplasmic and/or nuclear staining in the oral mucosa of
patients, including cells surrounding blisters and the pre-lesional regions. This finding was verified by in vitro studies
where treatment of keratinocytes with PV sera, as well as a characterized pathogenic antibody specifically targeting
Dsg3, evoked pronounced p53 expression and activity accompanied by disruption of cell–cell adhesion. Collectively,
our findings suggThe study was supported by the Barts and The London School of Medicine and Dentistry and Guizhou Medical University, China. The animal work was supported by Deutsche Forschungsgemeinschaft (TR-SFB 156). Jutamas Uttagomol was supported by a scholarship from Naresuan University, Thailand
Identification of novel target genes of nerve growth factor (NGF) in human mastocytoma cell line (HMC-1 (V560G c-Kit)) by transcriptome analysis
<p>Abstract</p> <p>Background</p> <p>Nerve growth factor (NGF) is a potent growth factor that plays a key role in neuronal cell differentiation and may also play a role in hematopoietic differentiation. It has been shown that NGF induced synergistic action for the colony formation of CD34 positive hematopoietic progenitor cells treated with macrophage-colony stimulating factor (M-CSF or CSF-1), or stem cell factor (SCF). However, the exact role of NGF in hematopoietic system is unclear. It is also not clear whether NGF mediated signals in hematopoietic cells are identical to those in neuronal cells.</p> <p>Results</p> <p>To study the signal transduction pathways induced by NGF treatment in hematopoietic cells, we utilized the mastocytoma cell line HMC-1(V560G c-Kit) which expresses the NGF receptor, tropomyosin-receptor-kinase (Trk)A, as well as the constitutively activated SCF receptor, V560G c-Kit, which can be inhibited completely by treatment with the potent tyrosine kinase inhibitor imatinib mesylate (imatinib). NGF rescues HMC-1(V560G c-Kit) cells from imatinib mediated cell death and promotes proliferation. To examine the NGF mediated proliferation and survival in these cells, we compared the NGF mediated upregulated genes (30 and 120 min after stimulation) to the downregulated genes by imatinib treatment (downregulation of c-Kit activity for 4 h) by transcriptome analysis. The following conclusions can be drawn from the microarray data: Firstly, gene expression profiling reveals 50% overlap of genes induced by NGF-TrkA with genes expressed downstream of V560G c-Kit. Secondly, NGF treatment does not enhance expression of genes involved in immune related functions that were down regulated by imatinib treatment. Thirdly, more than 55% of common upregulated genes are involved in cell proliferation and survival. Fourthly, we found Kruppel-like factor (KLF) 2 and Smad family member 7 (SMAD7) as the NGF mediated novel downstream genes in hematopoietic cells. Finally, the downregulation of KLF2 gene enhanced imatinib induced apoptosis.</p> <p>Conclusion</p> <p>NGF does not induce genes which are involved in immune related functions, but induces proliferation and survival signals in HMC-1(V560G c-Kit) cells. Furthermore, the current data provide novel candidate genes, KLF2 and SMAD7 which are induced by NGF/TrkA activation in hematopoietic cells. Since the depletion of KLF2 causes enhanced apoptosis of HMC-1(V560G c-Kit), KLF2 may play a role in the NGF mediated survival signal.</p
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