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Investigating and modelling the functionality of human neurons remains challenging due to the technical limitations, resulting in scarce and incomplete 3D anatomical reconstructions. Here we used a morphological modelling approach based on optimal wiring to repair the parts of a dendritic morphology that were lost due to incomplete tissue samples. In Drosophila, where dendritic regrowth has been studied experimentally using laser ablation, we found that modelling the regrowth reproduced a bimodal distribution between regeneration of cut branches and invasion by neighbouring branches. Interestingly, our repair model followed growth rules similar to those for the generation of a new dendritic tree. To generalise the repair algorithm from Drosophila to mammalian neurons, we artificially sectioned reconstructed dendrites from mouse and human hippocampal pyramidal cell morphologies, and showed that the regrown dendrites were morphologically similar to the original ones. Furthermore, we were able to restore their electrophysiological functionality, as evidenced by the recovery of their firing behaviour. Importantly, we show that such repairs also apply to other neuron types including hippocampal granule cells and cerebellar Purkinje cells. We then extrapolated the repair to incomplete human CA1 pyramidal neurons, where the anatomical boundaries of the particular brain areas innervated by the neurons in question were known. Interestingly, the repair of incomplete human dendrites helped to simulate the recently observed increased synaptic thresholds for dendritic NMDA spikes in human versus mouse dendrites. To make the repair tool available to the neuroscience community, we have developed an intuitive and simple graphical user interface (GUI), which is available in the TREES toolbox (www.treestoolbox.org).

Abstract Disruption of blood–brain barrier (BBB) integrity is a feature of various neurological disorders. Here we found that the BBB is differently affected during the preclinical, progression and remission phase of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We have identified an upregulation of pro-inflammatory and pro-angiogenic factors in the BBB transcriptome and down-regulation of endothelial tight junction members coinciding with elevated BBB leakage specifically during the progression phase. These changes were antagonized by blocking PDGFRα signaling with the small tyrosine kinase inhibitor imatinib. Moreover, targeting the PDGFRα ligand PDGF-CC using a neutralizing antibody, facilitated recovery of BBB integrity and improvement of EAE symptoms. Intracerebroventricular injection of PDGF-CC induced upregulation, whereas blocking PDGF-CC during EAE led to downregulation of Tnfa and Il1a at the BBB. Our findings suggest that blocking PDGF-CC counteracts fundamental aspects of endothelial cell activation and disruption of the BBB by decreasing Tnfa and Il1a expression. We also demonstrate that both PDGF-CC and its receptor PDGFRα were upregulated in MS lesions indicating that blocking PDGF-CC may be considered a novel treatment for MS.

ObjectiveFatigue in road traffic can occur after long driving times or during night-time driving and can lead to a dangerous decrease in vigilance or microsleep. As a countermeasure, the effectiveness of brain stimulation by means of frequency-modified music is investigated. Small frequency shifts between two different sounds simultaneously perceived by both ears (e.g. 400 and 418 Hz) stimulate the brain to increase activity in the stimulated range (e.g. 18 Hz).MethodsThe effects of acoustic brain entrainment (ABE) in the EEG beta range (12-20 Hz) were compared to placebo during day and night driving (n = 40 each) in 80 subjects. The effects were examined at the subjective (Karolinska Sleepiness Scale, KSS), physiological (EEG) and performance level (test battery for attention testing, TAP). The test drive took place on the motorway. Sequence of events with measurement times: Preparation in the laboratory (60 min; TAP & KSS), driving (90 min day/ 180 min night; KSS every 30 min), beta/placebo stimulation while driving (20 min), rest (20 min; TAP & KSS), driving (60 min; KSS every 30 min), end of driving (40 min; TAP & KSS). EEG was recorded continuously (Fz, Cz, Pz, C3, C4) and analyzed for 10 min time windows.ResultsThe subjective fatigue rating in the KSS decreased significantly after ABE compared to placebo. This was still significant about 100 minutes after stimulation. The ABE led to a significant increase in EEG beta activity compared to placebo. This was still significant about 80 minutes after stimulation. Furthermore, the ABE led to a significant decrease in theta activity compared to placebo. This was still significant about 70 minutes after stimulation and was more pronounced during daytime driving. Faster reaction times were observed for the ABE compared to the placebo condition during day and night driving. The faster reaction times were partly significant for the ABE still 80 minutes after stimulation.ConclusionPositive effects of ABE during driving could be demonstrated on the subjective, physiological and performance level. The effect was more pronounced during the day than at night. No negative side effects of Beta Stimulation were observed. The stimulation in the beta frequency range led to an increase of beta activity in the EEG.

Investigating and modelling the functionality of human neurons remains challenging due to the technical limitations, resulting in scarce and incomplete 3D anatomical reconstructions. Here we used a morphological modelling approach based on optimal wiring to repair the parts of a dendritic morphology that were lost due to incomplete tissue samples. In Drosophila, where dendritic regrowth has been studied experimentally using laser ablation, we found that modelling the regrowth reproduced a bimodal distribution between regeneration of cut branches and invasion by neighbouring branches. Interestingly, our repair model followed growth rules similar to those for the generation of a new dendritic tree. To generalise the repair algorithm from Drosophila to mammalian neurons, we artificially sectioned reconstructed dendrites from mouse and human hippocampal pyramidal cell morphologies, and showed that the regrown dendrites were morphologically similar to the original ones. Furthermore, we were able to restore their electrophysiological functionality, as evidenced by the recovery of their firing behaviour. Importantly, we show that such repairs also apply to other neuron types including hippocampal granule cells and cerebellar Purkinje cells. We then extrapolated the repair to incomplete human CA1 pyramidal neurons, where the anatomical boundaries of the particular brain areas innervated by the neurons in question were known. Interestingly, the repair of incomplete human dendrites helped to simulate the recently observed increased synaptic thresholds for dendritic NMDA spikes in human versus mouse dendrites. To make the repair tool available to the neuroscience community, we have developed an intuitive and simple graphical user interface (GUI), which is available in the TREES toolbox (www.treestoolbox.org). Author summary: Reconstructing neuronal dendrites by drawing their 3D branching structures in the computer has proved to be crucial for interpreting the flow of electrical signals and therefore the computations that dendrites perform on their inputs. These reconstructions are tedious and prone to disruptive limitations imposed by experimental procedures. In recent years, complementary computational procedures have emerged that reproduce the fine details of morphology in theoretical models. These models allow, for example, to populate large-scale neural networks and to study structure-function relationships. In this work we use a morphological model based on optimised wiring for signal conduction and material cost to repair faulty reconstructions, in particular those of human hippocampal dendrites, which are rare and precious but often cut due to technical limitations. Interestingly, we find that our synthetic repair mechanism reproduces the two distinct modes of repair observed in real dendrites: regeneration from the severed branch and invasion from neighbouring branches. Our model therefore provides both a useful tool for single-cell electrophysiological simulations and a useful theoretical concept for studying the biology of dendrite repair. [ABSTRACT FROM AUTHOR]

Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysema-like pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.

Novel approaches of tunable devices for millimeter wave applications based on liquid crystal (LC) are presented. In the first part of the paper, a novel concept of a tunable LC phase shifter realized in Low Temperature Cofired Ceramics technology is shown while the second part of the paper deals with a tunable high-gain antenna based on an LC tunable reflectarray. The reflectarray features continuously beam scanning in between ±25∘. Also first investigations on radiation hardness of LCs are carried out, indicating that LCs might be suitable for space applications.

Differential responses of newborn pulmonary arteries and veins to atrial and C-type natriuretic peptides. Am J Physiol Heart Circ Physiol 282: H273-H280, 2002.--Atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are important dilators of the pulmonary circulation during the perinatal period. We compared the responses of pulmonary arteries (PA) and veins (PV) of newborn lambs to these peptides. ANP caused a greater relaxation of PA than of PV, and CNP caused a greater relaxation of PV than of PA. RIA showed that ANP induced a greater increase in cGMP content of PA than CNP. In PV, ANP and CNP caused a similar moderate increase in cGMP content. Receptor binding study showed more specific binding sites for ANP than for CNP in PA and more for CNP than for ANP in PV. Relative quantitative RT-PCR for natriuretic peptide receptor A (NPR-A) and B (NPR-B) mRNAs show that, in PA, NPR-A mRNA is more prevalent than NPR-B mRNA, whereas, in PV, NPR-B mRNA is more prevalent than NPR-A mRNA. In conclusion, in the pulmonary circulation, arteries are the major site of action for ANP, and veins are the major site for CNP. Furthermore, the differences in receptor abundance and the involvement of a cGMP-independent mechanism may contribute to the heterogeneous effects of the natriuretic peptides in PA and PV of newborn lambs. smooth muscle; relaxation; natriuretic peptide receptor; perinatal; pulmonary circulation

Objective: Fatigue in road traffic can occur after long driving times or during night-time driving and can lead to a dangerous decrease in vigilance or microsleep. As a countermeasure, the effectiveness of brain stimulation by means of frequency-modified music is investigated. Small frequency shifts between two different sounds simultaneously perceived by both ears (e.g. 400 and 418 Hz) stimulate the brain to increase activity in the stimulated range (e.g. 18 Hz). Methods: The effects of acoustic brain entrainment (ABE) in the EEG beta range (12–20 Hz) were compared to placebo during day and night driving (n = 40 each) in 80 subjects. The effects were examined at the subjective (Karolinska Sleepiness Scale, KSS), physiological (EEG) and performance level (test battery for attention testing, TAP). The test drive took place on the motorway. Sequence of events with measurement times: Preparation in the laboratory (60 min; TAP & KSS), driving (90 min day/ 180 min night; KSS every 30 min), beta/placebo stimulation while driving (20 min), rest (20 min; TAP & KSS), driving (60 min; KSS every 30 min), end of driving (40 min; TAP & KSS). EEG was recorded continuously (Fz, Cz, Pz, C3, C4) and analyzed for 10 min time windows. Results: The subjective fatigue rating in the KSS decreased significantly after ABE compared to placebo. This was still significant about 100 minutes after stimulation. The ABE led to a significant increase in EEG beta activity compared to placebo. This was still significant about 80 minutes after stimulation. Furthermore, the ABE led to a significant decrease in theta activity compared to placebo. This was still significant about 70 minutes after stimulation and was more pronounced during daytime driving. Faster reaction times were observed for the ABE compared to the placebo condition during day and night driving. The faster reaction times were partly significant for the ABE still 80 minutes after stimulation. Conclusion: Positive effects of ABE during driving could be demonstrated on the subjective, physiological and performance level. The effect was more pronounced during the day than at night. No negative side effects of Beta Stimulation were observed. The stimulation in the beta frequency range led to an increase of beta activity in the EEG. [ABSTRACT FROM AUTHOR]