Contextual novelty changes reward representations in the striatum

Reward representation in ventral striatum is boosted by perceptual novelty, although the mechanism of this effect remains elusive. Animal studies indicate a functional loop (Lisman and Grace, 2005) that includes hippocampus, ventral striatum, and midbrain as being important in regulating salience attribution within the context of novel stimuli. According to this model, reward responses in ventral striatum or midbrain should be enhanced in the context of novelty even if reward and novelty constitute unrelated, independent events. Using fMRI, we show that trials with reward-predictive cues and subsequent outcomes elicit higher responses in the striatum if preceded by an unrelated novel picture, indicating that reward representation is enhanced in the context of novelty. Notably, this effect was observed solely when reward occurrence, and hence reward-related salience, was low. These findings support a view that contextual novelty enhances neural responses underlying reward representation in the striatum and concur with the effects of novelty processing as predicted by the model of Lisman and Grace (2005)

Contextual novelty modulates the neural dynamics of reward anticipation

We investigated how rapidly the reward-predicting properties of visual cues are signaled in the human brain and the extent these reward prediction signals are contextually modifiable. In a magnetoencephalography study, we presented participants with fractal visual cues that predicted monetary rewards with different probabilities. These cues were presented in the temporal context of a preceding novel or familiar image of a natural scene. Starting at similar to 100 ms after cue onset, reward probability was signaled in the event-related fields (ERFs) over temporo-occipital sensors and in the power of theta (5-8 Hz) and beta (20-30 Hz) band oscillations over frontal sensors. While theta decreased with reward probability beta power showed the opposite effect. Thus, in humans anticipatory reward responses are generated rapidly, within 100 ms after the onset of reward-predicting cues, which is similar to the timing established in non-human primates. Contextual novelty enhanced the reward anticipation responses in both ERFs and in beta oscillations starting at similar to 100 ms after cue onset. This very early context effect is compatible with a physiological model that invokes the mediation of a hippocampal-VTA loop according to which novelty modulates neural response properties within the reward circuitry. We conclude that the neural processing of cues that predict future rewards is temporally highly efficient and contextually modifiable

MTBVAC-Based TB-HIV Vaccine Is Safe, Elicits HIV-T Cell Responses, and Protects against Mycobacterium tuberculosis in Mice

The tuberculosis (TB) vaccine MTBVAC is the only live-attenuated Mycobacterium tuberculosis (Mtb)-based vaccine in clinical development, and it confers superior protection in different animal models compared to the current vaccine, BCG (Mycobacterium bovis bacillus Calmette-Guérin). With the aim of using MTBVAC as a vector for a dual TB-HIV vaccine, we constructed the recombinant MTBVAC.HIVA 2auxo strain. First, we generated a lysine auxotroph of MTBVAC (MTBVAC¿lys) by deleting the lysA gene. Then the auxotrophic MTBVAC¿lys was transformed with the E. coli-mycobacterial vector p2auxo.HIVA, harboring the lysA-complementing gene and the HIV-1 clade A immunogen HIVA. This TB-HIV vaccine conferred similar efficacy to the parental strain MTBVAC against Mtb challenge in mice. MTBVAC.HIVA 2auxo was safer than BCG and MTBVAC in severe combined immunodeficiency (SCID) mice, and it was shown to be maintained up to 42 bacterial generations in vitro and up to 100 days after inoculation in vivo. The MTBVAC.HIVA 2auxo vaccine, boosted with modified vaccinia virus Ankara (MVA).HIVA, induced HIV-1 and Mtb-specific interferon-¿-producing T cell responses and polyfunctional HIV-1-specific CD8+ T cells producing interferon-¿ (IFN-¿), tumor necrosis factor alpha (TNF-a), and CD107a in BALB/c mice. Here we describe new tools to develop combined vaccines against TB and HIV with the potential of expansion for other infectious diseases

Informe preliminar sobre la prospección de la Vall del Barxell -Polop (Alcoi-Alcant)

Dins del projecte d'estudi del procés de neolitització a les comarques centromeridionals del País Valencià. es presenten els resultats preliminars obringuts en la prospecció sistemàtica deI la capçalera del riu Serpis, la Vall de Barxell-Polop (Alcoi-Alacant).Within the survey project of neolithization in the central and southern regions of the Valencian Country, we present herein the preliminary results achieved so far in the systematic prospecting at the source of the Serpis River, located in the Barxell-Polop Valley, within the municipal boundary of Alcoi, in the Alicante area.Dentro del proyecto de estudio del proceso de Neolitización en las comarcas centromeridionales del País Valenciano. se presentan los resultados preliminares obtenidos en la prospección sistemática de la cabecera del río Serpis, valle del Barxell-Polop (Alcoi. Alacant)

"I want to be a furious leopard with magical wings and super power": developing an ethico-interpretive framework for detecting Chinese students' funds of identity

The Avatar Project was a two-week English project in which Chinese high school students in an internationalised school in Shanghai China explored the topic of cultural and individual identity. The project synthesised prospective education with the Funds of Identity approach, both of which have particular relevance within an internationalised teaching context. During the project, students created three identity texts: a written reflection, a word cloud and an avatar which were later used as data for this article. This article presents findings from the project and critically evaluates the effectiveness of avatars and word clouds as strategies for detecting students’ funds of identity. A multimodal approach to data collection and analysis was adopted in order to ensure that the interpretation of students’ work remained situated within their lived experience. The project revealed the existence of social, practical, institutional and cultural funds of identity. However, it also detected more problematic forms of funds of identity related to political and philosophical beliefs which I label ideological and existential funds of identity. While avatars and word clouds were effective in drawing out students’ out-of-school identities, the written reflections were ultimately more useful in revealing students’ funds of identity and also ensuring that any interpretations remained within the participants’ horizon of intended meaning. The project also brought about significant transformation in the way I viewed my students

Analysis of the functional roles of mammary serum amyloid A3 protein

La Serum Amiloide A3 (M-S133) mamària és una proteïna de fase aguda expressada principalment a la glàndula mamària. Els nivells d'expressió de la M-S133 varia en diferents situacions fisiològiques, el que suggereix un rol important a nivell funcional. Per tal d'analitzar les propietats de la proteïna, es van dur a terme quatre estudis. En el primer, la M-S133 va ser expressada de forma recombinant en un sistema bacterià. Aquest pas és important ja que ens proporciona una font de proteïna, en casos en que la purificació de fonts naturals representa clarament un coll d'ampolla. Es va obtenir la seqüència de dues isoformes, però només una va ser expressada recombinantment. La principal diferència entre les dues formes era una deleció en la regió del motiu SNARE, el que suggeria que aquest motiu pot estar implicat en una activitat antibacteriana directe. A més, en el primer estudi es va analitzar la primera funcionalitat. La M-S133 activava la fagocitosi mediada per macròfags, incrementant el nombre de macròfags actiu i la seva capacitat fagocítica. En el segon estudi es va analitzar l'efecte protector a nivell gastrointestinal. La M-S133 clarament reduïa la translocació de bacteris enteropatògens en cèl∙lules CaCo-2, una línia d'epiteli intestinal comercial. La M-S133 també afectava la expressió de MUC3 i IL-8, incrementant els seus nivells, el que connecta de forma directa la proteïna amb la resposta immune innata. En el tercer estudi, es va desenvolupar un model intestinal en boví a partir de cultius ex vivo de Plaques de Peyer. Aquests cultius ex vivo ofereixen un ambient únic on coexisteixen diferents tipus cel∙lulars i una aproximació més realista a la situació in vivo. En aquest context la infecció també va ser disminuïda i la M-S133 incrementava els nivells de IL-8 i INFγ. Per contra, les mucines no es van veure afectades, i la protecció va ser assolida per sobre-expressió de Occludina i Claudina- 2, proteïnes que formen les tight junctions, encarregades de segellar la barrera epitelial. A més, es va demostrar que la M-S133 activa cèl∙lules dendrítiques, incrementant l'expressió de citoquines i marcadors de maduració, migració i presentació d'antigen. En el quart i últim estudi, es va avaluar la possible aplicabilitat a nivell de la industria lletera. La M-S133 va ser infosa intra-mamàriament durant el secat, un període on es deixa de munyir les vaques per tal d'afavorir la regeneració cel∙lular i augmentar la seva productivitat. La M-S133 va incrementar paràmetres relacionats amb una activació de l'involució tals com les metaloproteinases. Els nivells de proteïna i greix també eren augmentats i es va observar un augment numèric del recompte de cèl∙lules somàtiques. També es va observar que la proteïna incrementava l'expressió de IL-8 i TNFα en cultius primaris de glàndula mamària, i també inhibia la infecció bacteriana. Finalment, les cèl∙lules dendrítiques també eren activades en absència d'infeccióMammary Serum Amyloid A3 (M-SAA3) is an acute phase protein mainly expressed in the mammary gland. The levels of the protein vary in different physiological situations, indicating that may play an important functional role. In order to analyze the protein properties four studies were performed. In the first study, the protein was recombinantly produced in a bacterial expression system. This was important, as difficulty in protein purification from natural sources is a clear bottleneck for functional studies. Two M-SAA3 isoforms were obtained, but only one succeeded in the recombinant expression. Interestingly, the main difference was in a 3 amino acid deletion in the SNARE motif, which could be implicated in the direct bacterial killing. Moreover, the first functional role was evaluated. M-SAA3 clearly enhanced macrophages phagocytosis, increasing both the number of active macrophages and the phagocytic capacity. In the second study, the protective effect at a gastrointestinal level was assessed. M-SAA3 protein inhibited the translocation of enteropathogenic bacteria in CaCo-2 cells, a commercial intestinal epithelial cell line. In addition, M-SAA3 protein increased the expression of MUC3 and IL-8, which directly connected the protein with the innate immune response activation. In the third study, a bovine intestinal model was developed using ex vivo Peyer's Patches cultures. The ex vivo methodology offered a unique environment where different cell types coexist, and indeed, represent a more similar approach to an in vivo situation. In this context, the infection was also prevented, and a clear innate immune response was activated. M-SAA3 clearly activated the expression of IL-8, INFγ but in this case, mucins were not up-regulated. The bacterial translocation was achieved by an increase in the Occludin and Claudin-2 expression, tight junction genes that directly participate in the sealing of the epithelial barrier. Furthermore, the M-SAA3 directly activated dendritic cells functions, increasing their cytokine expression profile and cellular markers related to maturation, migration and antigen presentation. In the fourth and last study, the potential applicability in dairy industry was evaluated. M-SAA3 was infused in the mammary gland at dry off, a period of milking cessation which permits the mammary gland regeneration for an optimal production in following lactations. M-SAA3 increased parameters related to an increased involution of the mammary gland, such as metalloproteinases. Also protein and fat were increased and a numerical increase in the somatic cell count was observed. In addition, M-SAA3 raised the IL-8 and TNFα levels in primary mammary gland cultures, and inhibited bacterial infection. Finally, dendritic cells were also activated by M-SAA3 in absence of infection

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Erratum: Production and validation of scintillating structural components from low-background Poly(ethylene naphthalate)

[no abstract available

Mineral oil certified reference materials for the determination of polychlorinated biphenyls from the National Metrology Institute of Japan (NMIJ)

Four mineral oil certified reference materials (CRMs), NMIJ CRM 7902-a, CRM 7903-a, CRM 7904-a, and CRM 7905-a, have been issued by the National Metrology Institute of Japan, which is part of the National Institute of Advanced Industrial Science and Technology (NMIJ/AIST), for the determination of polychlorinated biphenyls (PCBs). The raw materials for the CRMs were an insulation oil (CRM 7902-a and CRM 7903-a) and a fuel oil (CRM7904-a and CRM 7905-a). A solution of PCB3, PCB8, and technical PCB products, comprising four types of Kaneclor, was added to the oil matrices. The total PCB concentrations in the PCB-fortified oils (CRM 7902-a and CRM 7904-a) are approximately 6 mg kg−1. In addition, the mineral oils which were not fortified with PCBs were also distributed as CRMs (CRM 7903-a and CRM 7905-a). Characterization of these CRMs was conducted by the NMIJ/AIST, where the mineral oils and the PCB solution were analyzed using multiple analytical methods such as dimethylsulfoxide extraction, normal-phase liquid chromatography, gel permeation chromatography, reversed-phase liquid chromatography, and chromatography using sulfoxide-bonded silica; and/or various capillary columns for gas chromatography, and two ionization modes for mass spectrometry. The target compounds in the mineral oils and those in the PCB solution were determined by one of the primary methods of measurement, isotope dilution–mass spectrometry (ID-MS). Certified values have been provided for 11 PCB congeners (PCB3, 8, 28, 52, 101, 118, 138, 153, 180, 194, and 206) in the CRMs. These CRMs have information values for PCB homologue concentrations determined by using a Japanese official method for determination of PCBs in wastes and densities determined with an oscillational density meter. Because oil samples having arbitrary PCB concentrations between respective property values of the PCB-fortified and nonfortified CRMs can be prepared by gravimetric mixing of the CRM pairs, these CRMs can be used for validation of PCB analyses using various instruments which have different sensitivities

The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax