Could an endoneurial endothelial crosstalk between Wnt/β-catenin and Sonic Hedgehog pathways underlie the early disruption of the infra-orbital blood-nerve barrier following chronic constriction injury?

BackgroundBlood–nerve barrier disruption is pivotal in the development of neuroinflammation, peripheral sensitization, and neuropathic pain after peripheral nerve injury. Activation of toll-like receptor 4 and inactivation of Sonic Hedgehog signaling pathways within the endoneurial endothelial cells are key events, resulting in the infiltration of harmful molecules and immunocytes within the nerve parenchyma. However, we showed in a previous study that preemptive inactivation of toll-like receptor 4 signaling or sustained activation of Sonic Hedgehog signaling did not prevent the local alterations observed following peripheral nerve injury, suggesting the implication of another signaling pathway.MethodsUsing a classical neuropathic pain model, the infraorbital nerve chronic constriction injury (IoN-CCI), we investigated the role of the Wnt/β-catenin pathway in chronic constriction injury-mediated blood–nerve barrier disruption and in its interactions with the toll-like receptor 4 and Sonic Hedgehog pathways. In the IoN-CCI model versus control, mRNA expression levels and/or immunochemical detection of major Wnt/Sonic Hedgehog pathway (Frizzled-7, vascular endothelial-cadherin, Patched-1 and Gli-1) and/or tight junction proteins (Claudin-1, Claudin-5, and Occludin) readouts were assessed. Vascular permeability was assessed by sodium fluorescein extravasation.ResultsIoN-CCI induced early alterations in the vascular endothelial-cadherin/β-catenin/Frizzled-7 complex, shown to participate in local blood–nerve barrier disruption via a β-catenin-dependent tight junction protein downregulation. Wnt pathway also mediated a crosstalk between toll-like receptor 4 and Sonic Hedgehog signaling within endoneurial endothelial cells. Nevertheless, preemptive inhibition of Wnt/β-catenin signaling before IoN-CCI could not prevent the downregulation of key Sonic Hedgehog pathway readouts or the disruption of the infraorbital blood–nerve barrier, suggesting that Sonic Hedgehog pathway inhibition observed following IoN-CCI is an independent event responsible for blood–nerve barrier disruption.ConclusionA crosstalk between Wnt/β-catenin- and Sonic Hedgehog-mediated signaling pathways within endoneurial endothelial cells could mediate the chronic disruption of the blood–nerve barrier following IoN-CCI, resulting in increased irreversible endoneurial vascular permeability and neuropathic pain development

The High Energy Budget Allocations in Shocks and GRB

The statistical distribution of energies among particles responsible for long Gamma Ray Burst (GRB) emission is analyzed in light of recent results of the Fermi Observatory. The allsky flux, $F_{\gamma}$, recorded by the Gamma Ray Burst Monitor (GBM) is shown, despite its larger energy range, to be not significantly larger than that reported by the Burst and Transient Explorer (BATSE), suggesting a relatively small flux in the 3 - 30 MeV energy range. The present-day energy input rate in $\gamma$-rays recorded by the GBM from long GRB is found, assuming star-formation rates in the literature, to be $\dot W(0)=0.5 F_{\gamma} H/c = 5 \times 10^{42}\ \rm{erg/Mpc^3 yr}$. The Large Area Telescope (LAT) fluence, when observed, is about 5-10\% per decade of the total, in good agreement with the predictions of saturated, non-linear shock acceleration. The high-energy component of long GRBs, as measured by Fermi, is found to contain only $\sim 10^{-2.5}$ of the energy needed to produce ultrahigh-energy cosmic rays (UHECR) above 4 Eev, assuming the latter to be extragalactic, when various numerical factors are carefully included, if the cosmic ray source spectrum has a spectral index of -2. The observed $\gamma$-ray fraction of the required UHECR energy is even smaller if the source spectrum is softer than $E^{-2}$. The AMANDA II limits rule out such a GRB origin for UHECR if much more than $10^{-2}$ of the cosmic ray energy goes into neutrinos that are within, and simultaneous with, the $\gamma$-ray beam. It is suggested that "orphan" neutrinos out of the $\gamma$-ray beam might be identifiable via orphan afterglow { or other wide angle signatures of GRB in lieu of coincidence with prompt $\gamma$-rays}, and it is recommended that feasible single neutrino trigger criteria be established to search for such coincidences.Comment: to appear in The Astrophysical Journa

Une question en débat : la transformation du monde romain et le rôle des barbares

Depuis l’histoire grecque, l’histoire de l’Europe a souvent été vécue comme celle d’une civilisation entourée (voire assiégée) de barbares. Pourtant, même la Grèce de Périclès n’était pas insensible à l’Orient ou à l’or des Scythes, et l’hellénisme est la marque d’une fusion entre les Grecs et « les autres ». Le sac de Rome (410) puis la chute de l’ancienne capitale de l’Empire romain (476) ont marqué les esprits rétrospectivement, aussi comme preuve inéluctable d’une décadence de l’Empire r..

Mentale Gehalte und erweiterter Geist: Warum das Argument der Nichtabgeleitetheit scheitert

Hundertmark F. Mentale Gehalte und erweiterter Geist: Warum das Argument der Nichtabgeleitetheit scheitert. In: Michel JG, Boström KJ, Pohl M, eds. Ist der Geist im Kopf?: Beiträge zur These des erweiterten Geistes. Münster: mentis; 2016: 133-160.Der These des erweiterten Geistes zufolge befinden sich manche mentalen Repräsentationen außerhalb der körperlichen Grenzen der Wesen, zu denen sie gehören. Einer der stärksten Einwände gegen diese These stellt das Argument der Nichtabgeleitetheit von Frederick Adams, Ken Aizawa und Jerry Fodor dar. Dieses Argument setzt voraus, dass genuine mentale Repräsentationen nichtabgeleitete Gehalte haben – ihre semantischen Eigenschaften sind also nicht durch Absichten, Wünsche oder Konventionen konstituiert. Repräsentationen mit nichtabgeleitetem Gehalt finden sich jedoch, so das Argument weiter, nur innerhalb der körperlichen Grenzen mentaler Wesen. Ich werde dafür argumentieren, dass das Argument der Nichtabgeleitetheit scheitert, da es insbesondere bei Tieren externe Repräsentationen gibt, deren Gehalt nichtabgeleitet ist. Dies folgt jedenfalls aus der aussichtsreichsten Theorie nichtabgeleiteter Repräsentationen, der Teleosemantik, und es gibt gute Gründe anzunehmen, dass auch andere naturalistische Gehaltstheorien dieselbe Implikation haben

PORTR: Pre-Operative and Post-Recurrence Brain Tumor Registration

We propose a new method for deformable registration of pre-operative and post-recurrence brain MR scans of glioma patients. Performing this type of intra-subject registration is challenging as tumor, resection, recurrence, and edema cause large deformations, missing correspondences, and inconsistent intensity profiles between the scans. To address this challenging task, our method, called PORTR, explicitly accounts for pathological information. It segments tumor, resection cavity, and recurrence based on models specific to each scan. PORTR then uses the resulting maps to exclude pathological regions from the image-based correspondence term while simultaneously measuring the overlap between the aligned tumor and resection cavity. Embedded into a symmetric registration framework, we determine the optimal solution by taking advantage of both discrete and continuous search methods. We apply our method to scans of 24 glioma patients. Both quantitative and qualitative analysis of the results clearly show that our method is superior to other state-of-the-art approaches

Endothelial dysfunction and inflammation in asymptomatic proteinuria

Background. Proteinuria is associated with vascular risk and a systemic increase in vascular permeability. Endothelial dysfunction occurs early in atherosclerosis and modulates vascular permeability. Vascular risk and chronic inflammation are associated. This study investigates whether the increased vascular permeability in proteinuria reflects systemic endothelial dysfunction and chronic inflammation. Methods. Twenty-one patients with asymptomatic proteinuria (1.29 g/24 h; range 0.18 to 3.17) and 21 matched controls were studied. Microvascular endothelial function was assessed using acetylcholine iontophoresis. Maximum microvascular hyperemia (MMH) was assessed by flux response to local skin heating. Macrovascular endothelial function was assessed by flow- associated dilation (FAD) in the brachial artery using ultrasound. von Willebrand factor (vWF) was measured as a marker of endothelial activation. Low-grade inflammation was assessed by measurement of circulating C-reactive protein (CRP) values using a high sensitivity assay. Results. FAD was impaired in proteinuric subjects (AP) compared to controls [1.8 (0.2 to 5.3) AP vs. 3.8 (1.5 to 6.2) C %; P = 0.014]. There was no significant difference between groups in MMH or in the response to acetylcholine iontophoresis. The AP group had a higher CRP [4.0 (0.5 to 39.0) AP vs. 0.2 (0.1 to 21.3) C mg/L; P lt 0.001] and tendency to higher vWF [101.5 (67.0 to 197.0) AP vs. 77.5 (45.0 to 185.0) C IU/dL; P = 0.046] compared to controls. In the AP, but not control, group there was an inverse correlation between CRP and microvascular function as determined by acetylcholine iontophoresis (r = -0.509; P = 0.018). Conclusions. In AP subjects there is evidence of macrovascular endothelial dysfunction remote from the kidney and of low-grade inflammation that is associated with microvascular endothelial dysfunction

Intoxicação espontânea por Cestrum intermedium em bovinos de leite

Acute hepatotoxicity caused by plants poisoning is responsible for economic losses in farm animals in Brazil. Reports of Cestrum intermedium natural poisoning in cattle are not commonly described in Rio Grande do Sul (RS). This study aimed to document an outbreak of spontaneous C. intermedium poisoning in dairy cattle in the Central-Eastern Mesoregion of RS. Three nine-month-old Holstein and Jersey heifers were affected after they were placed in a small paddock with shortage forage. In this area, specimens of C. intermedium Sendtn with signs of consumption were observed. Morbidity and lethality rates were 100% and clinical courses ranged from 9 to 12 hours. At post mortem examination of the three heifers, there was predominance of acute liver lesions. The liver was moderately enlarged and on the cut surface there was a marked accentuation of the lobular pattern and hemorrhage. Inside the rumen, partially digested C. intermedium Sendtn leaves were observed. The histological aspects of the liver were mostly centrilobular coagulative necrosis and hemorrhage, frequently extended to the midzonal region. The immunohistochemistry technique was performed, in which the polyclonal antibody caspase 3 was used in liver fragments. Moderate to marked immunolabeling was observed in the cytoplasm and nucleus of hepatocytes, predominantly on the periphery of areas of hepatic necrosis indicating cell apoptosis. The diagnosis of C. intermedium Sendtn poisoning in dairy cattle in this study was based on epidemiological, clinical and anatomopathological findings. Since the C. intermedium poisoning is uncommon in dairy cattle, we are describing it for the first time in the Central-Eastern Mesoregion of RS, and represents a differential diagnosis of other acute toxic liver diseases in cattle.Intoxicações por plantas que causam hepatotoxicidade aguda são responsáveis por prejuízos econômicos em animais de produção no Brasil. Relatos de intoxicações naturais por Cestrum intermedium em bovinos não são comumente descritos no Rio Grande do Sul (RS). Este trabalho teve como objetivo documentar um surto de intoxicação espontânea por C. intermedium em bovinos leiteiros ocorrido na região Centro-Oriental do RS. Três bovinos com nove meses de idade, das raças Holandês e Jersey, foram acometidos depois de serem introduzidos em um pequeno piquete com escassez de forragem. Nessa área foram observados exemplares de Cestrum intermedium Sendtn com sinais de consumo. As taxas de morbidade e letalidade foram de 100% e os cursos clínicos variaram de 9 a 12 horas. Na necropsia dos três bovinos, observou-se predomínio de lesões hepáticas agudas. O fígado dos animais acometidos estava moderadamente aumentado de tamanho e na superfície de corte havia marcada acentuação do padrão lobular e hemorragia. Na abertura do rúmen, foram observadas folhas de Cestrum intermedium Sendtn parcialmente digeridas. Histologicamente, o fígado apresentava necrose coagulativa centrolobular e hemorragia. Frequentemente, essas alterações se estendiam para a região mediozonal. Foi realizada a técnica de imuno-histoquímica, na qual utilizou-se o anticorpo policlonal caspase 3 em fragmentos de fígado. Notou-se marcação moderada a acentuada em citoplasma e núcleo de hepatócitos, predominantemente na periferia das áreas de necrose hepática indicando apoptose celular. O diagnóstico de intoxicação por Cestrum intermedium Sendtn nos bovinos leiteiros desse estudo, foi realizado com base nos achados epidemiológicos, clínicos e anatomopatológicos. A intoxicação por C. intermedium é incomum em bovinos leiteiros, sendo descrita pela primeira vez na região centro oriental do RS e representa um diagnóstico diferencial de outras hepatopatias tóxicas agudas

Signatures of minor mergers in the Milky Way disc I: The SEGUE stellar sample

It is now known that minor mergers are capable of creating structure in the phase-space distribution of their host galaxy's disc. In order to search for such imprints in the Milky Way, we analyse the SEGUE F/G-dwarf and the Schuster et al. (2006) stellar samples. We find similar features in these two completely independent stellar samples, consistent with the predictions of a Milky Way minor-merger event. We next apply the same analyses to high-resolution, idealised N-body simulations of the interaction between the Sagittarius dwarf galaxy and the Milky Way. The energy distributions of stellar particle samples in small spatial regions in the host disc reveal strong variations of structure with position. We find good matches to the observations for models with a mass of Sagittarius' dark matter halo progenitor $\lessapprox 10^{11}$ M$_{\odot}$. Thus, we show that this kind of analysis could be used to provide unprecedentedly tight constraints on Sagittarius' orbital parameters, as well as place a lower limit on its mass.Comment: 14 pages, 9 figures, 2 tables. Revised to reflect accepted versio

The Outer Tracker Detector of the HERA-B Experiment. Part II: Front-End Electronics

The HERA-B Outer Tracker is a large detector with 112674 drift chamber channels. It is exposed to a particle flux of up to 2x10^5/cm^2/s thus coping with conditions similar to those expected for the LHC experiments. The front-end readout system, based on the ASD-8 chip and a customized TDC chip, is designed to fulfil the requirements on low noise, high sensitivity, rate tolerance, and high integration density. The TDC system is based on an ASIC which digitizes the time in bins of about 0.5 ns within a total of 256 bins. The chip also comprises a pipeline to store data from 128 events which is required for a deadtime-free trigger and data acquisition system. We report on the development, installation, and commissioning of the front-end electronics, including the grounding and noise suppression schemes, and discuss its performance in the HERA-B experiment