Simultaneous H alpha and dust reverberation mapping of 3C120: Testing the bowl-shaped torus geometry

At the Universitaetssternwarte Bochum near Cerro Armazones we have monitored the Seyfert-1 galaxy 3C 120 between September 2014 and March 2015 in BVRI and a narrow band filter covering the redshifted H alpha line; in addition we obtained a single con-temporary spectrum with FAST at Mt. Hopkins. Compared to earlier epochs 3C 120 is about a factor of three brighter, allowing us to study the shape of the broad line region (BLR) and the dust torus in a high luminosity phase. The analysis of the light curves yields that the dust echo is rather sharp and symmetric in contrast to the more complex broad H alpha BLR echo. We investigate how far this supports an optically thick bowl-shaped BLR and dust torus geometry as proposed by Kawaguchi & Mori (2010) and Goad et al. (2012). The comparison with several parameterizations of these models supports the following geometry: the BLR clouds lie inside the bowl closely above the bowl rim, up to a half covering angle 0 deg < theta < 40 deg (measured against the equatorial plane). Then the BLR is spread over many isodelay surfaces, yielding a smeared and structured echo as observed. Furthermore, if the BLR clouds shield the bottom of the bowl rim against radiation from the nucleus, the hot dust emission comes essentially from the top edge of the bowl (40 deg < theta < 45 deg). Then, for small inclinations as for 3C120, the top dust edge forms a ring which largely coincides with a narrow range of isodelay surfaces, yielding the observed sharp dust echo. The scale height of the BLR increases with radial distance from the black hole. This leads to luminosity dependent foreshortening effects of the lag. We discuss implications and possible corrections of the foreshortening for the black hole mass determination and consequences for the lag (size) - luminosity relationships and the difference to interferometric torus sizes.Comment: 17 pages, 18 figures, 3 tables, accepted for publication in in section 4. Extragalactic astronomy of Astronomy and Astrophysic

Association of age with the timing of acute spine surgery–effects on neurological outcome after traumatic spinal cord injury

Purpose: To investigate the association of age with delay in spine surgery and the effects on neurological outcome after traumatic spinal cord injury (SCI). Methods: Ambispective cohort study (2011-2017) in n = 213 patients consecutively enrolled in a Level I trauma center with SCI care in a metropolitan region in Germany. Age-related differences in the injury to surgery interval and conditions associated with its delay (> 12 h after SCI) were explored using age categories or continuous variables and natural cubic splines. Effects of delayed surgery or age with outcome were analyzed using multiple logistic regression. Results: The median age of the study population was 58.8 years (42.0-74.6 IQR). Older age (>= 75y) was associated with a prolonged injury to surgery interval of 22.8 h (7.2-121.3) compared to 6.6 h (4.4-47.9) in younger patients ( 60 h = 40y 5-20% probability). Conclusion: Older patient age complexifies surgical SCI care and research. Tackling secondary referral to Level I trauma centers and delayed spine surgery imposes as tangible opportunity to improve the outcome of older SCI patients

a clinical study protocol

Introduction The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, ‘small molecule’-mediated Rho inhibition after acute SCI warrants clinical investigation. Methods and analysis Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. Ethics and dissemination The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal. Trial registration number NCT02096913; Pre-results

Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury

BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane. METHODS: This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored. RESULTS: Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier. DISCUSSION: This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes

The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI

Up- and downstream signalling pathways of the Go2alpha-mediated regulation of vesicular monoamine storage

Die Grundlage der neuronalen Signalübertragung ist die regulierte Freisetzung vesikulärer Neurotransmitter in den synaptischen Spalt. Die synaptische Signalübertragung unterliegt dabei einer Vielzahl regulatorischer prä- und postsynaptischer Prozesse. Die Beeinflussung des vesikulären Füllungszustandes stellt dabei eine Möglichkeit dar, die synaptische Übertragung präsynaptisch zu modulieren. Vorangegangene Arbeiten konnten zeigen, dass der Füllungszustand monoaminerger Vesikel durch die Go2alpha-Untereinheit heterotrimerer G-Proteine reguliert wird. Der vesikuläre Füllungszustand ist dabei das auslösende Signal der G-Proteinregulation. Die daran beteiligten zellulären Prozesse und Signaltransduktionswege sowie die Bedeutung dieser Regulation in vivo sind aber bisher unverstanden. Ziel dieser Arbeit war es daher, vor- und nachgeschaltete Signalwege zu identifizieren und physiologische Effekte der Inaktivierung von Go2alpha zu analysieren. Monoamine werden durch zwei Isoformen des vesikulären Monoamintransporters (VMAT) in Vesikeln gespeichert. In Neurotransmitteraufnahmeexperimenten mit CHO-Zellen, die mit verschiedenen mutierten Konstrukten des VMAT2 transfiziert, als stark vereinfachtes Modellsystem dienten, konnte gezeigt werden, dass die erste intraluminale Schleife des VMAT2 an der Signaltransduktion aus dem Vesikellumen beteiligt ist. Ähnliche Untersuchungen mit dem VMAT1 legen eine vergleichbare Bedeutung der ersten intraluminalen Schleife als intravesikuläre Rezeptorstruktur nahe. Einen weiteren Schwerpunkt der Arbeit bildete die Identifikation potentieller nachgeschalteter Signalproteine. Dabei stellte sich heraus, dass die Proteine CAPS1 und CAPS2 in der Lage sind, den vesikulären Monoamintransport und die Speicherfähigkeit für Monoamine zu erhöhen. Durch systematisches Durchmustern einer cDNA-Bibliothek mit konstitutiv aktivem Go2alpha in einem Yeast-two-Hybrid-System wurden 15 Proteine identifiziert, die als potentielle Zielproteine an der G-Proteinregulation der VMAT beteiligt sind. Darüber hinaus konnten verschiedene, dabei identifizierte Go2alpha-bindende Proteine bereits im Zellkern lokalisiert bzw. assoziiert mit dem Zytoskelett nachgewiesen werden und deuten auf eine Funktion von Go2alpha an diesen Strukturen hin. In genetisch veränderten Mäusen, die nicht in der Lage sind, Go2alpha zu exprimieren, konnten im Striatum, einer Gehirnregion die besonders an der motorischen Feinregulation beteiligt ist, verminderte Dopaminspiegel festgestellt werden. Diese verminderten Monoaminspiegel korrelieren mit einer verminderten Bewegungsaktivität der Go2a-defizienten Mäuse nach Stimulation des dopaminergen Systems mittels Amphetamin und Kokain. Zusätzlich bleibt nach mehrfacher Behandlung mit Kokain die in Wildtyptieren einsetzende substanzvermittelte Sensibilisierung aus, die auf zusätzliche Störungen des dopaminergen Systems hinweist.The basic principle of neural communication involves regulated exocytosis of neurotransmitter molecules into the synaptic cleft. Neuronal communication at the synapse depends on several regulatory mechanisms which are localized pre- or postsynaptically. Vesicular filling represents one possibility of influencing synaptic transmission presynaptically. Previous experiments showed that activation of Go2alpha, a brain and neuroendocrine cell specific subunit of heterotrimeric G-proteins, modulates filling of synaptic vesicles with monoamines. Vesicular filling itself was shown to be the preceding step of the Go2alpha-regulation. Further evidence of participating intracellular signalling cascades was missing. Therefore the aim of the project was to identify possible upstream and downstream signalling molecules as well as to determine the impact of Go2alpha inactivation in vitro and in vivo. Monoamine storage in vesicles is mediated by the activity of two isoforms of the vesicular monoamine transporter (VMAT). Neurotransmitter uptake experiments using CHO-cells transfected with wildtype and mutant VMAT2-cDNA proved that the first intravesicular loop of VMAT2 is required for Go2alpha-activation. Similar experiments using VMAT1-cDNA-constructs also indicated that the first intralumenal loop of the VMAT shows receptor like properties. The investigation of potential downstream targets revealed the proteins CAPS1 and CAPS2 to enhance vesicular transport and storage capacity for monoamines. Furthermore a yeast two hybrid screening of a mouse brain cDNA-library using GTPase deficient Go2alpha as bait identified 15 potential downstream effectors. Besides a possible role in regulating vesicular filling, some of the identified proteins are localized in the nucleus or associated with the cytoskeleton. These observations point to further functions of Go2alpha at other subcellular structures.Analysis of Go2alpha-knockout mice revealed reduced dopamine-amounts in the striatum, a brain region involved in movement control. Decreased striatal dopamine levels correlate with reduced locomotor-activity of the knockout mice compared to wildtype animals after challenging the monoaminergic system using amphetamine and cocaine. Additionally knockout mice lack drug-induced sensitization after repeated application of cocaine indicating further disturbances of the dopaminergic system

Eine explizite Version der Jacquet-Langlands-Korrespondenz für den dreidimensionalen hyperbolischen Raum

Ausgehend von Eigenfunktionen des Laplace-Beltrami-Operators zu kokompakten Quaternionengruppen über einem imaginär-quadratischen Zahlkörper K, die auf dem 3-dimensionalen hyperbolischen Halbraum operieren, werden in dieser Arbeit explizit Eigenfunktionen des Laplace-Beltrami-Operators zu gewissen kofiniten Untergruppen von PSL(2;O_K) mit gleichem Eigenwert konstruiert. Dies wird dabei bewirkt durch einen Integraloperator, dessen Kern eine geeignete Siegelsche Thetafunktion bildet. Für die Transformationseigenschaften dieser Thetafunktion wird eine Verallgemeinerung eines Transformationssatzes von C.L. Siegel auf beliebige imaginär-quadratische Zahlkörper und beliebige ganze Hauptideale bewiesen. Für Klassenzahl 1 zeigt sich, dass die konstruierten Eigenfunktionen Spitzenfunktionen sind. Die Darstellung der Fourierentwicklung dieser Spitzenfunktionen kann schließlich für den Fall einer maximalen Ordnung mit Hilfe der Hecke-Theorie vereinfacht werden

Eine explizite Version der Jacquet-Langlands-Korrespondenz für den dreidimensionalen hyperbolischen Raum

Ausgehend von Eigenfunktionen des Laplace-Beltrami-Operators zu kokompakten Quaternionengruppen über einem imaginär-quadratischen Zahlkörper K, die auf dem 3-dimensionalen hyperbolischen Halbraum operieren, werden in dieser Arbeit explizit Eigenfunktionen des Laplace-Beltrami-Operators zu gewissen kofiniten Untergruppen von PSL(2;O_K) mit gleichem Eigenwert konstruiert. Dies wird dabei bewirkt durch einen Integraloperator, dessen Kern eine geeignete Siegelsche Thetafunktion bildet. Für die Transformationseigenschaften dieser Thetafunktion wird eine Verallgemeinerung eines Transformationssatzes von C.L. Siegel auf beliebige imaginär-quadratische Zahlkörper und beliebige ganze Hauptideale bewiesen. Für Klassenzahl 1 zeigt sich, dass die konstruierten Eigenfunktionen Spitzenfunktionen sind. Die Darstellung der Fourierentwicklung dieser Spitzenfunktionen kann schließlich für den Fall einer maximalen Ordnung mit Hilfe der Hecke-Theorie vereinfacht werden

Regulation of monoamine oxidase a by circadian-clock components implies clock influence on mood

SummaryThe circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3–5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6–10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors