A Leptin-regulated Circuit Controls Glucose Mobilization During Noxious Stimuli

Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor–expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores

Use of Avian Bornavirus Isolates to Induce Proventricular Dilatation Disease in Conures

The fulfillment of Koch’s postulates shows that the virus causes proventricular dilatation disease in parrots

Quality of Longer Term Mental Health Facilities in Europe: Validation of the Quality Indicator for Rehabilitative Care against Service Users’ Views

BACKGROUND: The Quality Indicator for Rehabilitative Care (QuIRC) is a staff rated, international toolkit that assesses care in longer term hospital and community based mental health facilities. The QuIRC was developed from review of the international literature, an international Delphi exercise with over 400 service users, practitioners, carers and advocates from ten European countries at different stages of deinstitutionalisation, and review of the care standards in these countries. It can be completed in under an hour by the facility manager and has robust content validity, acceptability and inter-rater reliability. In this study, we investigated the internal validity of the QuIRC. Our aim was to identify the QuIRC domains of care that independently predicted better service user experiences of care. METHOD: At least 20 units providing longer term care for adults with severe mental illness were recruited in each of ten European countries. Service users completed standardised measures of their experiences of care, quality of life, autonomy and the unit's therapeutic milieu. Unit managers completed the QuIRC. Multilevel modelling allowed analysis of associations between service user ratings as dependent variables with unit QuIRC domain ratings as independent variables. RESULTS: 1750/2495 (70%) users and the managers of 213 units from across ten European countries participated. QuIRC ratings were positively associated with service users' autonomy and experiences of care. Associations between QuIRC ratings and service users' ratings of their quality of life and the unit's therapeutic milieu were explained by service user characteristics (age, diagnosis and functioning). A hypothetical 10% increase in QuIRC rating resulted in a clinically meaningful improvement in autonomy. CONCLUSIONS: Ratings of the quality of longer term mental health facilities made by service managers were positively associated with service users' autonomy and experiences of care. Interventions that improve quality of care in these settings may promote service users' autonomy

A transient presence: black visitors and sojourners in Imperial Germany, 1884-1914

The onset of German colonial rule in Africa brought increasing numbers of Black men and women to Germany. Pre-1914 the vast majority of these Africans can best be described as visitors or sojourners and the Black population as a whole was a transient one. This makes recovering their presence in the archival record exceptionally difficult and it is not surprising that the existing historiography almost exclusively focuses on individual biographies of well documented lives. Through utilising a number of newly digitised archival materials, particularly the Hamburg Passenger Lists, this article draws upon a database with information on 1092 individuals from sub-Saharan Africa who spent time in Germany over the period 1884-1914 in order to add considerable bread and depth to our understanding of the Black presence as a whole. It provides increasing empirical detail about the make-up and character of this fluid population - where visitors came from, why they came to Germany, their age on arrival - as well as more accurate detail on the temporal and, to a lesser extent, spatial distribution of visitors

Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

SummaryHepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy

How Attractive Is the Girl Next Door? An Assessment of Spatial Mate Acquisition and Paternity in the Solitary Cape Dune Mole-Rat, Bathyergus suillus

Behavioural observations of reproduction and mate choice in wild fossorial rodents are extremely limited and consequently indirect methods are typically used to infer mating strategies. We use a combination of morphological, reproductive, spatial, and genetic data to investigate the reproductive strategy of a solitary endemic species, the Cape dune mole-rat Bathyergus suillus. These data provide the first account on the population dynamics of this species. Marked sexual dimorphism was apparent with males being both significantly larger and heavier than females. Of all females sampled 36% had previously reproduced and 12% were pregnant at the time of capture. Post-partum sex ratio was found to be significantly skewed in favour of females. The paternity of fifteen litters (n = 37) was calculated, with sires assigned to progeny using both categorical and full probability methods, and including a distance function. The maximum distance between progeny and a putative sire was determined as 2149 m with males moving between sub-populations. We suggest that above-ground movement should not be ignored in the consideration of mate acquisition behaviour of subterranean mammals. Estimated levels of multiple paternity were shown to be potentially as high as 26%, as determined using sibship and sire assignment methods. Such high levels of multiple paternity have not been found in other solitary mole-rat species. The data therefore suggest polyandry with no evidence as yet for polygyny

Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence

Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo. The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro, we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified αIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo. In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia

Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell

Herpes simplex type 1 (HSV1) replicates in epithelial cells and secondarily enters local sensory neuronal processes, traveling retrograde to the neuronal nucleus to enter latency. Upon reawakening newly synthesized viral particles travel anterograde back to the epithelial cells of the lip, causing the recurrent cold sore. HSV1 co-purifies with amyloid precursor protein (APP), a cellular transmembrane glycoprotein and receptor for anterograde transport machinery that when proteolyzed produces A-beta, the major component of senile plaques. Here we focus on transport inside epithelial cells of newly synthesized virus during its transit to the cell surface. We hypothesize that HSV1 recruits cellular APP during transport. We explore this with quantitative immuno-fluorescence, immuno-gold electron-microscopy and live cell confocal imaging. After synchronous infection most nascent VP26-GFP-labeled viral particles in the cytoplasm co-localize with APP (72.8+/−6.7%) and travel together with APP inside living cells (81.1+/−28.9%). This interaction has functional consequences: HSV1 infection decreases the average velocity of APP particles (from 1.1+/−0.2 to 0.3+/−0.1 µm/s) and results in APP mal-distribution in infected cells, while interplay with APP-particles increases the frequency (from 10% to 81% motile) and velocity (from 0.3+/−0.1 to 0.4+/−0.1 µm/s) of VP26-GFP transport. In cells infected with HSV1 lacking the viral Fc receptor, gE, an envelope glycoprotein also involved in viral axonal transport, APP-capsid interactions are preserved while the distribution and dynamics of dual-label particles differ from wild-type by both immuno-fluorescence and live imaging. Knock-down of APP with siRNA eliminates APP staining, confirming specificity. Our results indicate that most intracellular HSV1 particles undergo frequent dynamic interplay with APP in a manner that facilitates viral transport and interferes with normal APP transport and distribution. Such dynamic interactions between APP and HSV1 suggest a mechanistic basis for the observed clinical relationship between HSV1 seropositivity and risk of Alzheimer's disease

Legitimacy in the Multilevel European Polity

In order to be simultaneously effective and liberal, governments must normally be able to count on voluntary compliance – which, in turn, depends on the support of socially shared legitimacy beliefs. In Western constitutional democracies, such beliefs are derived from the distinct but coexistent traditions of “republican” and “liberal” political philosophy. When judged by these criteria, the European Union – if considered by itself – appears as a thoroughly liberal polity which, however, lacks all republican credentials. But this view (which seems to structure the debates about the “European democratic deficit”) ignores the multilevel nature of the European polity, where the compliance of citizens is requested, and needs to be legitimated by member states – whereas the Union appears as a “government of governments” which is entirely dependent on the voluntary compliance of its member states. What matters primarily, therefore, is the compliance-legitimacy relationship between the Union and its member states – which, however, is normatively constrained by the basic compliance-legitimacy relationship between member governments and their constituents. Given the high consensus requirements of European legislation, member governments could and should be able to assume political responsibility for European policies in which they had a voice, and to justify them in “communicative discourses” in the national public space. This is not necessarily true of “non-political” policy choices imposed by the European Court of Justice. By enforcing its “liberal” program of liberalization and deregulation, the ECJ may presently be undermining the “republican” bases of member-state legitimacy. Where this is the case, open non-compliance is a present danger, and political controls of judicial legislation may be called for.Um gleichzeitig effektiv und liberal sein zu können, ist staatliche Herrschaft auf freiwillige Folgebereitschaft angewiesen – die ihrerseits der Unterstützung durch sozial geteilte Legitimitätsüberzeugungen bedarf. In den demokratischen Verfassungsstaaten des Westens werden solche Überzeugungen aus den unterschiedlichen, aber komplementär zusammenwirkenden Traditionen der „republikanischen“ und der „liberalen“ politischen Philosophie hergeleitet. An diesen Kriterien gemessen erscheint die Europäische Union – wenn man sie für sich betrachtet – als eine „liberale“ politische Ordnung, der jedoch alle „republikanischen“ Legitimitätsmerkmale fehlen. Aber eine solche Sichtweise, die auch die derzeitige Diskussion über ein „europäisches Demokratiedefizit“ bestimmt, verkennt den Mehrebenencharakter des europäischen Gemeinwesens. In ihm sind es die Mitgliedstaaten, die Entscheidungen der Union gegenüber den eigenen Bürgern durchsetzen und auch legitimieren müssen, während es für die Union ihrerseits auf die freiwillige Folgebereitschaft ihrer Mitgliedstaaten ankommt. Dabei werden diese jedoch durch die normativen Grundlagen ihrer eigenen Legitimität begrenzt. Politische Entscheidungen auf europäischer Ebene setzen breiten Konsens voraus, und die Regierungen sollten sie deshalb auch gegenüber den eigenen Bürgern in „kommunikativen Diskursen“ vertreten und dafür die politische Verantwortung übernehmen können. Dies gilt jedoch nicht notwendigerweise auch für Entscheidungen der europäischen Politik, die im nichtpolitischen Modus ohne Beteiligung des Rates und des Parlaments vom Europäischen Gerichtshof bestimmt werden. Mit der gegenwärtigen Radikalisierung seines „liberalen“ Programms der Liberalisierung und Deregulierung des nationalen Rechts könnte der Gerichtshof in der Tat die „republikanischen“ Grundlagen der mitgliedstaatlichen Legitimität unterminieren. In diesem Falle könnte die Union sich nicht länger auf die Folgebereitschaft ihrer Mitgliedstaaten verlassen. Um diese Gefahr für die europäische Integration zu vermeiden, sollte eine stärkere politische Kontrolle der richterlichen Rechtsetzung erwogen werden.1 Legitimacy Republican and liberal legitimating discourses Constitutional democracies – and the EU? 2 Legitimacy in multilevel polities 3 Legitimating member state compliance Political modes of policy making Non-political policy making 4 The need for justification 5 The Court is pushing against the limits of justifiability 6 The liberal undermining of republican legitimacy 7 Needed: A political balance of community and autonomy Reference