Effects of Immunization With the Soil-Derived Bacterium Mycobacterium vaccae on Stress Coping Behaviors and Cognitive Performance in a "Two Hit" Stressor Model

Previous studies demonstrate that Mycobacterium vaccae NCTC 11659 (M. vaccae), a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, is a potentially useful countermeasure against negative outcomes to stressors. Here we used male C57BL/6NCrl mice to determine if repeated immunization with M. vaccae is an effective countermeasure in a "two hit" stress exposure model of chronic disruption of rhythms (CDR) followed by acute social defeat (SD). On day -28, mice received implants of biotelemetric recording devices to monitor 24-h rhythms of locomotor activity. Mice were subsequently treated with a heat-killed preparation of M. vaccae (0.1 mg, administered subcutaneously on days -21, -14, -7, and 27) or borate-buffered saline vehicle. Mice were then exposed to 8 consecutive weeks of either stable normal 12:12 h light:dark (LD) conditions or CDR, consisting of 12-h reversals of the LD cycle every 7 days (days 0-56). Finally, mice were exposed to either a 10-min SD or a home cage control condition on day 54. All mice were exposed to object location memory testing 24 h following SD. The gut microbiome and metabolome were assessed in fecal samples collected on days -1, 48, and 62 using 16S rRNA gene sequence and LC-MS/MS spectral data, respectively; the plasma metabolome was additionally measured on day 64. Among mice exposed to normal LD conditions, immunization with M. vaccae induced a shift toward a more proactive behavioral coping response to SD as measured by increases in scouting and avoiding an approaching male CD-1 aggressor, and decreases in submissive upright defensive postures. In the object location memory test, exposure to SD increased cognitive function in CDR mice previously immunized with M. vaccae. Immunization with M. vaccae stabilized the gut microbiome, attenuating CDR-induced reductions in alpha diversity and decreasing within-group measures of beta diversity. Immunization with M. vaccae also increased the relative abundance of 1-heptadecanoyl-sn-glycero-3-phosphocholine, a lysophospholipid, in plasma. Together, these data support the hypothesis that immunization with M. vaccae stabilizes the gut microbiome, induces a shift toward a more proactive response to stress exposure, and promotes stress resilience. &nbsp;</p

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Two models of inescapable stress increase tph2 mRNA expression in the anxiety-related dorsomedial part of the dorsal raphe nucleus

Expression of TPH2, the rate-limiting enzyme for brain serotonin synthesis, is elevated in the dorsal raphe nucleus (DR) of depressed suicide victims. One hypothesis is that this increase in TPH2 expression is stress-induced. Here, we used an established animal model to address whether exposure to an acute stressor, inescapable tail shock (IS), increases tph2 mRNA and Tph2 protein expression, and if IS sensitizes the DR to a subsequent, heterotypic stressor. In Experiment 1, we measured tph2 mRNA expression 4 h after IS or home cage (HC) control conditions in male rats, using in situ hybridization histochemistry. In Experiment 2, we measured Tph2 protein expression 12 h or 24 h after IS using western blot. In Experiment 3, we measured tph2 mRNA expression following IS on Day 1, and cold swim stress (10 min, 15 °C) on Day 2. Inescapable tail shock was sufficient to increase tph2 mRNA expression 4 h and 28 h later, selectively in the dorsomedial DR (caudal aspect of the dorsal DR, cDRD; an area just rostral to the caudal DR, DRC) and increased Tph2 protein expression in the DRD (rostral and caudal aspects of the dorsal DR combined) 24 h later. Cold swim increased tph2 mRNA expression in the dorsomedial DR (cDRD) 4 h later. These effects were associated with increased immobility during cold swim, elevated plasma corticosterone, and a proinflammatory plasma cytokine milieu (increased interleukin (IL)-6, decreased IL-10). Our data demonstrate that two models of inescapable stress, IS and cold swim, increase tph2 mRNA expression selectively in the anxiety-related dorsomedial DR (cDRD). Keywords: Anxiety, Dorsal raphe nucleus, Inescapable stress, Inflammation, Tryptophan hydroxylas

Property Rights, Taxpayer Rights, and the Multiscalar Attack on the State: Consequences for Regionalism in the United States

Niedt C. and Weir M. Property rights, taxpayer rights, and the multiscalar attack on the state: consequences for regionalism in the United States, Regional Studies. Studies of 'new regionalism' often focus on the new actors or goals characteristic of contemporary regional coalitions, at the cost of recognizing how competing social movements might constrain regional policy. This paper considers the recent evolution of the property rights and taxpayer movements in the United States, and how their attacks on state regulatory and tax capacity have affected regional governance. The development and strategic use of 'scalar repertoires' and framing strategies has enabled these movements to take advantage of political opportunities at different scales. Regionalists have been slow to build the versatile scalar repertoires needed to respond to these challenges. [image omitted] Niedt C. et Weir M. Les droits de propriete, les droits des contribuables, et l'attaque contre l'Etat de tous cotes: les consequences pour le regionalisme aux Etats-Unis, Regional Studies. Les etudes a propos du 'nouveau regionalisme' portent souvent sur les nouveaux acteurs ou les buts qui caracterisent des coalitions regionales contemporaines, au prix d'une reconnaissance de la facon dont les mouvements sociaux qui se rivalisent risquent de limiter la politique regionale. Cet article cherche a examiner l'evolution recente des groupes de pression aux Etats-Unis qui soutiennent les droits de propriete et les droits des contribuables, et comment leurs attaques sur la capacite reglementaire et fiscale de l'Etat ont influe sur la gouvernance regionale. Le developpement et l'emploi strategique des 'repertoires scalaires' et des strategies-cadres ont permis a ces mouvements de profiter des possibilites politiques a divers niveaux. Les regionalistes ont tarde a construire les repertoires scalaires polyvalents necessaires pour repondre a ces defis. Mouvements sociaux Regionalisme Droits de propriete Limites fiscales Recettes fiscales Etude de cas Kelo Niedt C. und Weir M. Die Rechte von Eigentumern und Steuerzahlern und der multiskalare Angriff auf den Staat: Konsequenzen fur den Regionalismus in den USA, Regional Studies. In vielen Studien uber den 'neuen Regionalismus' liegt der Augenmerk auf den neuen, fur zeitgenossische regionale Koalitionen charakteristischen Akteuren oder Zielen, wobei jedoch verkannt wird, wie sich miteinander konkurrierende Gesellschaftsbewegungen einengend auf die Regionalpolitik auswirken konnen. In diesem Beitrag werden die in letzter Zeit entstandenen Bewegungen fur die Rechte von Eigentumern und Steuerzahlern in den USA untersucht, und es wird die Frage erortert, wie sich aufgrund der Angriffe dieser Bewegungen auf die regulative und fiskale Kapazitat des Staates die regionale Regierungsfuhrung verandert hat. Die Entwicklung und der strategische Einsatz von 'skalaren Repertoires' und Rahmenstrategien haben es diesen Bewegungen ermoglicht, politische Chancen auf verschiedenen Ebenen zu nutzen. Seitens der Regionalisten wurden nur zogerlich die erforderlichen vielseitigen skalaren Repertoires aufgebaut, um diesen Herausforderungen zu begegnen. Gesellschaftsbewegungen Regionalismus Eigentumsrechte Steuerliche Einschrankungen Staatliche Enteignungen Fall Kelo Niedt C. y Weir M. Derechos de propiedad, derechos del contribuyente y el ataque multiescalar al Estado: consecuencias para el regionalismo en los Estados Unidos, Regional Studies. Los estudios sobre el 'nuevo regionalismo' se centran muchas veces en los nuevos protagonistas u objetivos caracteristicos de las coaliciones regionales contemporaneas, sin reconocer como pueden los movimientos sociales competitivos limitar la politica regional. En este articulo analizamos la reciente evolucion de los derechos de propiedad y movimientos de los contribuyentes en los Estados Unidos y como sus ataques a las normas y la capacidad impositiva estatales han afectado al gobierno regional. El desarrollo y uso estrategico de los 'repertorios escalares' y las estrategias enmarcadas han permitido que estos movimientos se aprovechen de las oportunidades politicas en diferentes escalas. Los regionalistas han construido muy lentamente los repertorios escalares versatiles necesarios para responder a estos retos. Movimientos sociales Regionalismo Derechos de propiedad Limitaciones fiscales Expropiaciones regulatorias El caso KeloSocial movements, Regionalism, Property rights, Tax limitations, Regulatory takings, Kelo case,