Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1

Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal-PFC connectivity. Altered hippocampal-PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1-PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity

Post-treatment follow-up study of abdominal cystic echinococcosis in Tibetan communities of northwest Sichuan Province, China

Background: Human cystic echinococcosis (CE), caused by the larval stage of Echinococcus granulosus, with the liver as the most frequently affected organ, is known to be highly endemic in Tibetan communities of northwest Sichuan Province. Antiparasitic treatment with albendazole remains the primary choice for the great majority of patients in this resource-poor remote area, though surgery is the most common approach for CE therapy that has the potential to remove cysts and lead to complete cure. The current prospective study aimed to assess the effectiveness of community based use of cyclic albendazole treatment in Tibetan CE cases, and concurrently monitor the changes of serum specific antibody levels during treatment. Methodology/Principal Findings: Ultrasonography was applied for diagnosis and follow-up of CE cases after cyclic albendazole treatment in Tibetan communities of Sichuan Province during 2006 to 2008, and serum specific IgG antibody levels against Echinococcus granulosus recombinant antigen B in ELISA was concurrently monitored in these cases. A total of 196 CE cases were identified by ultrasound, of which 37 (18.9%) showed evidence of spontaneous healing/involution of hepatic cyst(s) with CE4 or CE5 presentations. Of 49 enrolled CE cases for treatment follow-up, 32.7% (16) were considered to be cured based on B-ultrasound after 6 months to 30 months regular albendazole treatment, 49.0% (24) were improved, 14.3% (7) remained unchanged, and 4.1% (2) became aggravated. In general, patients with CE2 type cysts (daughter cysts present) needed a longer treatment course for cure (26.4 months), compared to cases with CE1 (univesicular cysts) (20.4 months) or CE3 type (detached cyst membrane or partial degeneration of daughter cysts) (9 months). In addition, the curative duration was longer in patients with large (.10 cm) cysts (22.3 months), compared to cases with medium (5– 10 cm) cysts (17.3 months) or patients with small (,5 cm) cysts (6 months). At diagnosis, seven (53.8%) of 13 cases with CE1 type cysts without any previous intervention showed negative specific IgG antibody response to E. granulosus recombinant antigen B (rAgB). However, following 3 months to 18 months albendazole therapy, six of these 7 initially seronegative CE1 cases sero-converted to be specific IgG antibody positive, and concurrently ultrasound scan showed that cysts changed to CE3a from CE1 type in all the six CE cases. Two major profiles of serum specific IgG antibody dynamics during albendazole treatment were apparent in CE cases: (i) presenting as initial elevation followed by subsequent decline, or (ii) a persistent decline. Despite a decline, however, specific antibody levels remained positive in most improved or cured CE cases. Conclusions: This was the first attempt to follow up community-screened cystic echinococcosis patients after albendazole therapy using ultrasonography and serology in an endemic Tibetan region. Cyclic albendazole treatment proved to be effective in the great majority of CE cases in this resource-poor area, but periodic abdominal ultrasound examination was necessary to guide appropriate treatment. Oral albendazole for over 18 months was more likely to result in CE cure. Poor drug compliance resulted in less good outcomes. Serology with recombinant antigen B could provide additional limited information about the effectiveness of albendazole in CE cases. Post-treatment positive specific IgG antibody seroconversion, in initially seronegative, CE1 patients was considered a good indication for positive therapeutic efficacy of albendazole

The pains of desistance

Desistance is generally presented in a positive light, with themes of ‘making good’ and generativity recurring in the literature. This article reports on two qualitative studies exploring the desistance journeys of two different groups of ex-offenders, drawing attention to the pains of this process. It examines the possible consequences of these ‘pains of desistance’ and how they are linked to three spheres of desistance: act-desistance; identity desistance; and relational desistance. The attempt to achieve act-desistance often led to the pain of isolation for our interviewees, while the clash between the need to achieve identity desistance and a lack of relational desistance (especially on the meso- and macro-levels) meant that they suffered the pain of goal failure. The pains of isolation and goal failure combined to lead to the further pain of hopelessness. Those interviewed were indeed ‘going straight’, but taking this path led many to a limited and often diminished life

Colorectal tumors require NUAK1 for protection from oxidative stress

The authors wish to thank the staff of the CRUK Beatson Institute Biological Services Unit for animal husbandry and assistance with in vivo experiments; the staff of the CRUK BI Histology core facility and William Clark of the NGS core facility; David McGarry, Rene Jackstadt, Jiska Van der Reest, Justin Bower and Heather McKinnon for many helpful discussions, and countless colleagues at the CRUK BI and Glasgow Institute of Cancer Sciences for support; Prem Premsrirut & Mirimus Inc. for design and generation of dox-inducible Nuak1 shRNA expressing mice Nathanael Gray for initial provision of NUAK1 inhibitors. Funding was provided by the University of Glasgow and the CRUK Beaton Institute. J.P. was supported by European Commission Marie Curie actions C.I.G. 618448 “SERPLUC” to D.J.M.; N.M. was supported through Worldwide Cancer (formerly AICR) grant 15-0279 to O.J.S. & D.J.M.; B.K. was funded through EC Marie Curie actions mobility award 705190 “NuSiCC”; T.M. was funded through British Lung Foundation grant APHD13-5. The laboratories of S.R.Z. (A12935), O.J.S. (A21139) and M.D. (A17096) are funded by Cancer Research UK. O.J.S. was additionally supported by European Research Council grant 311301 “ColoCan”.Peer reviewedPostprin

Under-regulated and unaccountable?:Explaining variation in stop and search rates in Scotland, England and Wales

From a position of near parity in 2005/6, by 2012/13 recorded search rates in Scotland exceeded those in England/Wales seven times over. This divergence is intriguing given the demands placed on the police, and the legal capacity to deal with these are broadly similar across the two jurisdictions. The aim of this paper is to unpack this variation. Using a comparative casestudy approach, the paper examines the role of structural ‘top-down’ determinants of policing: substantive powers of search, rules and regulations, and scrutiny. Two arguments are presented. First, we argue that the remarkable rise of stop and search in Scotland has been facilitated by weak regulation and safeguards. Second, we argue that divergence between the two jurisdictions can also be attributed to varying levels of political and public scrutiny, caused, in part, by viewing stop and search almost exclusively through the prism of ‘race’. In Scotland, the significance of these factors is made evident by dint of organisational developments within the last decade; by the introduction of a target driven high-volume approach to stop and search in Strathclyde police force circa 1997 onwards; and the national roll-out of this approach following the single service merger in April 2013. The salient point is that the Strathclyde model was not hindered by legal rules and regulations, nor subject to policy and political challenge; rather a high discretion environment enabled a high-volume approach to stop and search to flourish

Glucose Transporter 1 and Monocarboxylate Transporters 1, 2, and 4 Localization within the Glial Cells of Shark Blood-Brain-Barriers

Although previous studies showed that glucose is used to support the metabolic activity of the cartilaginous fish brain, the distribution and expression levels of glucose transporter (GLUT) isoforms remained undetermined. Optic/ultrastructural immunohistochemistry approaches were used to determine the expression of GLUT1 in the glial blood-brain barrier (gBBB). GLUT1 was observed solely in glial cells; it was primarily located in end-feet processes of the gBBB. Western blot analysis showed a protein with a molecular mass of 50 kDa, and partial sequencing confirmed GLUT1 identity. Similar approaches were used to demonstrate increased GLUT1 polarization to both apical and basolateral membranes in choroid plexus epithelial cells. To explore monocarboxylate transporter (MCT) involvement in shark brain metabolism, the expression of MCTs was analyzed. MCT1, 2 and 4 were expressed in endothelial cells; however, only MCT1 and MCT4 were present in glial cells. In neurons, MCT2 was localized at the cell membrane whereas MCT1 was detected within mitochondria. Previous studies demonstrated that hypoxia modified GLUT and MCT expression in mammalian brain cells, which was mediated by the transcription factor, hypoxia inducible factor-1. Similarly, we observed that hypoxia modified MCT1 cellular distribution and MCT4 expression in shark telencephalic area and brain stem, confirming the role of these transporters in hypoxia adaptation. Finally, using three-dimensional ultrastructural microscopy, the interaction between glial end-feet and leaky blood vessels of shark brain was assessed in the present study. These data suggested that the brains of shark may take up glucose from blood using a different mechanism than that used by mammalian brains, which may induce astrocyte-neuron lactate shuttling and metabolic coupling as observed in mammalian brain. Our data suggested that the structural conditions and expression patterns of GLUT1, MCT1, MCT2 and MCT4 in shark brain may establish the molecular foundation of metabolic coupling between glia and neurons