Salience Attribution and its Relationship to Cannabis-Induced Psychotic Symptoms

BACKGROUND: Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity. METHODS: We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test (SAT), a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory (PSI). Dopamine synthesis capacity, indexed as the influx rate constant Kicer, was measured in 10 users and 6 controls with 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine positron emission tomography. RESULTS: There was no significant difference in aberrant salience between the groups (F1,32 = 1.12, p=.30 [implicit]; F1,32=1.09, p=.30 [explicit]). Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r=.61, p=.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F1,15= 5.8, p=.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r=-.91, p=.01), whereas this relationship was non-significant within users (difference between correlations: Z=-2.05, p=.04). CONCLUSIONS: Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use

MARQUIS: A multiplex method for absolute quantification of peptides and posttranslational modifications

Absolute quantification of protein expression and posttranslational modifications by mass spectrometry has been challenging due to a variety of factors, including the potentially large dynamic range of phosphorylation response. To address these issues, we have developed MARQUIS—Multiplex Absolute Regressed Quantification with Internal Standards—a novel mass spectrometry-based approach using a combination of isobaric tags and heavy-labelled standard peptides, to construct internal standard curves for peptides derived from key nodes in signal transduction networks. We applied MARQUIS to quantify phosphorylation dynamics within the ​EGFR network at multiple time points following stimulation with several ligands, enabling a quantitative comparison of ​EGFR phosphorylation sites and demonstrating that receptor phosphorylation is qualitatively similar but quantitatively distinct for each ​EGFR ligand tested. MARQUIS was also applied to quantify the effect of ​EGFR kinase inhibition on glioblastoma patient-derived xenografts. MARQUIS is a versatile method, broadly applicable and extendable to multiple mass spectrometric platforms.United States-Israel Binational Science FoundationNational Institutes of Health (U.S.) (Grant U54 CA112967)National Institutes of Health (U.S.) (Grant R01 CA118705)National Institutes of Health (U.S.) (Grant R01 CA096504)Mayo Brain Tumor SPORE CA10896

PKSB1740-517: An ALMA view of the cold gas feeding a distant interacting young radio galaxy

Cold neutral gas is a key ingredient for growing the stellar and central black hole mass in galaxies throughout cosmic history. We have used the Atacama Large Millimetre Array (ALMA) to detect a rare example of redshifted $^{12}$CO(2-1) absorption in PKS B1740-517, a young ($t \sim 1.6 \times 10^{3}$ yr) and luminous ($L_{\rm 5 GHz} \sim 6.6 \times 10^{43}$ erg s$^{-1}$ ) radio galaxy at $z = 0.44$ that is undergoing a tidal interaction with at least one lower-mass companion. The coincident HI 21-cm and molecular absorption have very similar line profiles and reveal a reservoir of cold gas ($M_{\rm gas} \sim 10^{7} - 10^{8}$ M$_{\odot}$), likely distributed in a disc or ring within a few kiloparsecs of the nucleus. A separate HI component is kinematically distinct and has a very narrow line width ($\Delta{v}_{\rm FWHM} \lesssim 5$ km s$^{-1}$), consistent with a single diffuse cloud of cold ($T_{\rm k} \sim 100$ K) atomic gas. The $^{12}$CO(2-1) absorption is not associated with this component, which suggests that the cloud is either much smaller than 100 pc along our sight-line and/or located in low-metallicity gas that was possibly tidally stripped from the companion. We argue that the gas reservoir in PKS B1740-517 may have accreted onto the host galaxy $\sim$50 Myr before the young radio AGN was triggered, but has only recently reached the nucleus. This is consistent with the paradigm that powerful luminous radio galaxies are triggered by minor mergers and interactions with low-mass satellites and represent a brief, possibly recurrent, active phase in the life cycle of massive early type galaxies.Comment: 15 pages, 7 figures, accepted for publication in MNRA

Ketamine Modulates the Neural Correlates of Reward Processing in Unmedicated Patients in Remission from Depression.

BACKGROUND: Ketamine as an antidepressant improves anhedonia as early as 2h post-infusion. These drug effects are thought to be exerted via actions on reward-related brain areas-yet, these actions remain largely unknown. Our study investigates ketamine's effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported. METHODS: We examined ketamine's effects during the anticipation and receipt of expected rewards on pre-defined brain areas, namely the dorsal and ventral striatum, the ventral tegmental area, the amygdala and the insula. We have recruited 37 male and female participants who remitted from depression and were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned, 2h after drug administration, in a double-blind cross over design (ketamine:0.5mg/kg and placebo) while performing a monetary reward task. RESULTS: A significant main effect of ketamine, across all ROIs, was observed during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, which showed increased activation upon the receipt of smaller rewards compared to neutral. The levels of (2R,6R)-HNK, 2h post-infusion, significantly correlated with the activation observed in the ventral tegmental area for that contrast. CONCLUSIONS: These findings demonstrate that ketamine can produce detectable changes in reward-related brain areas, 2h after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback

Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review

With a political debate about the potential risks and benefits of cannabis use as a backdrop, the wave of legalization and liberalization initiatives continues to spread. Four states (Colorado, Washington, Oregon, and Alaska) and the District of Columbia have passed laws that legalized cannabis for recreational use by adults, and 23 others plus the District of Columbia now regulate cannabis use for medical purposes. These policy changes could trigger a broad range of unintended consequences, with profound and lasting implications for the health and social systems in our country. Cannabis use is emerging as one among many interacting factors that can affect brain development and mental function. To inform the political discourse with scientific evidence, the literature was reviewed to identify what is known and not known about the effects of cannabis use on human behavior, including cognition, motivation, and psychosis

Selective axonal transport through branch junctions is directed by growth cone signaling and mediated by KIF1/kinesin-3 motors.

Development and function of nerve cells rely on the orchestration of microtubule-based transport from the cell body into distal axonal terminals. Neurons often have highly elaborate branches innervating multiple targets, but how protein or membrane cargos navigate through branch junctions to specific branch targets is unknown. Here, we demonstrate that anterograde transport of membrane vesicles through axonal branch junctions is highly selective, which is influenced by branch length and more strongly by growth cone motility. Using an optogenetic tool, we demonstrate that signaling from the growth cone can rapidly direct transport through branch junctions. We further demonstrate that such transport selectivity is differentially regulated for different vesicles and mediated by the KIF1/kinesin-3 family motors. We propose that this transport regulation through branch junctions could broadly impact neuronal development, function, and regeneration

Combination CTLA-4 Blockade and 4-1BB Activation Enhances Tumor Rejection by Increasing T-Cell Infiltration, Proliferation, and Cytokine Production

BACKGROUND: The co-inhibitory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) attenuates immune responses and prevent autoimmunity, however, tumors exploit this pathway to evade the host T-cell response. The T-cell co-stimulatory receptor 4-1BB is transiently upregulated on T-cells following activation and increases their proliferation and inflammatory cytokine production when engaged. Antibodies which block CTLA-4 or which activate 4-1BB can promote the rejection of some murine tumors, but fail to cure poorly immunogenic tumors like B16 melanoma as single agents.METHODOLOGY/PRINCIPAL FINDINGS: We find that combining ?CTLA-4 and ?4-1BB antibodies in the context of a Flt3-ligand, but not a GM-CSF, based B16 melanoma vaccine promoted synergistic levels of tumor rejection. 4-1BB activation elicited strong infiltration of CD8+ T-cells into the tumor and drove the proliferation of these cells, while CTLA-4 blockade did the same for CD4+ effector T-cells. Anti-4-1BB also depressed regulatory T-cell infiltration of tumors. 4-1BB activation strongly stimulated inflammatory cytokine production in the vaccine and tumor draining lymph nodes and in the tumor itself. The addition of CTLA-4 blockade further increased IFN-? production from CD4+ effector T-cells in the vaccine draining node and the tumor. Anti 4-1BB treatment, with or without CTLA-4 blockade, induced approximately 75% of CD8+ and 45% of CD4+ effector T-cells in the tumor to express the killer cell lectin-like receptor G1 (KLRG1). Tumors treated with combination antibody therapy showed 1.7-fold greater infiltration by these KLRG1+CD4+ effector T-cells than did those treated with ?4-1BB alone.CONCLUSIONS/SIGNIFICANCE: This study shows that combining T-cell co-inhibitory blockade with ?CTLA-4 and active co-stimulation with ?4-1BB promotes rejection of B16 melanoma in the context of a suitable vaccine. In addition, we identify KLRG1 as a useful marker for monitoring the anti-tumor immune response elicited by this therapy. These findings should aid in the design of future trials for the immunotherapy of melanoma

Carbon Efficiency of Humanitarian Supply Chains: Evidence from French Red Cross operations

Natural catastrophes are often amplified by man-made impact on the environment. Sustainability is identified as a major gap in humanitarian logistics research literature. Although humanitarian supply chains are designed for speed and sustainability is of minor concern, environmentally-friendly behavior (e.g. through reduction of transportation emissions and avoidance of non-degradable materials) should be a long-term concern as it may ultimately affect more vulnerable regions. The purpose of this paper is to illustrate how green house gas emissions can be measured using the supply chain of common relief items in humanitarian logistics. We analyze the CO2 emissions of selected supply chains by performing Life Cycle Assessments based on data provided by the French Red Cross. We calculate the CO2 emissions of the items from ‘cradle to grave’ including production, transportation, warehousing and disposal. Using these calculations, we show that transporting relief items causes the majority of emissions; however, transportation modes may not always be changed as the main purpose of humanitarian supply chains is speed. Nevertheless, strategic and efficient pre-positioning of main items will translate into less transportation and thus reducing the environmental impact. The study also shows that initiatives for “greening” item production and disposal can improve the overall carbon efficiency of humanitarian supply chains