Dopaminergic neurons inhibit striatal output via non-canonical release of GABA

The substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) contain the two largest populations of dopamine (DA)-releasing neurons in the mammalian brain. These neurons extend elaborate projections in striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output via the release of DA to promote and reinforce motor action1–4. Here we show that activation of DA neurons in striatal slices rapidly inhibits action potential firing in both direct-and indirect-pathway striatal projection neurons (SPNs) through vesicular release of the inhibitory transmitter γ-aminobutyric acid (GABA). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for DA. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms employed by DA neurons to influence basal ganglia circuits, reveal a novel substrate whose transport is dependent on VMAT2, and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons

Simultaneous multi-band detection of Low Surface Brightness galaxies with Markovian modelling

We present an algorithm for the detection of Low Surface Brightness (LSB) galaxies in images, called MARSIAA (MARkovian Software for Image Analysis in Astronomy), which is based on multi-scale Markovian modeling. MARSIAA can be applied simultaneously to different bands. It segments an image into a user-defined number of classes, according to their surface brightness and surroundings - typically, one or two classes contain the LSB structures. We have developed an algorithm, called DetectLSB, which allows the efficient identification of LSB galaxies from among the candidate sources selected by MARSIAA. To assess the robustness of our method, the method was applied to a set of 18 B and I band images (covering 1.3 square degrees in total) of the Virgo cluster. To further assess the completeness of the results of our method, both MARSIAA, SExtractor, and DetectLSB were applied to search for (i) mock Virgo LSB galaxies inserted into a set of deep Next Generation Virgo Survey (NGVS) gri-band subimages and (ii) Virgo LSB galaxies identified by eye in a full set of NGVS square degree gri images. MARSIAA/DetectLSB recovered ~20% more mock LSB galaxies and ~40% more LSB galaxies identified by eye than SExtractor/DetectLSB. With a 90% fraction of false positives from an entirely unsupervised pipeline, a completeness of 90% is reached for sources with r_e > 3" at a mean surface brightness level of mu_g=27.7 mag/arcsec^2 and a central surface brightness of mu^0 g=26.7 mag/arcsec^2. About 10% of the false positives are artifacts, the rest being background galaxies. We have found our method to be complementary to the application of matched filters and an optimized use of SExtractor, and to have the following advantages: it is scale-free, can be applied simultaneously to several bands, and is well adapted for crowded regions on the sky.Comment: 39 pages, 18 figures, accepted for publication in A

Recurrent network activity drives striatal synaptogenesis

Neural activity during development critically shapes postnatal wiring of the mammalian brain. This is best illustrated by the sensory systems, in which the patterned feed-forward excitation provided by sensory organs and experience drives the formation of mature topographic circuits capable of extracting specific features of sensory stimuli1,2. In contrast, little is known about the role of early activity in the development of the basal ganglia, a phylogenetically ancient group of nuclei fundamentally important for complex motor action and reward-based learning3,4. These nuclei lack direct sensory input and are only loosely topographically organized5,6, forming interlocking feed-forward and feed-back inhibitory circuits without laminar structure. Here we use transgenic mice and viral gene transfer methods to modulate neurotransmitter release and neuronal activity in vivo in the developing striatum. We find that the balance of activity among the two inhibitory and antagonist pathways in the striatum regulates excitatory innervation of the basal ganglia during development. These effects indicate that the propagation of activity through a multi-stage network regulates the wiring of the basal ganglia, revealing an important role of positive feedback in driving network maturation

Potenciales presas zooplanctónicas (Copepoda y Appendicularia) para Engraulis anchoita en relación con las distribuciones de larvas tempranas y de desove en la región frontal patagónica (océano Atlántico sudoccidental)

We investigated the spatial distribution of the abundance, biomass and size of zooplankton (nauplii, calanoids, cyclopoids and appendicularians) in relation to the distribution of first-feeding larvae and eggs of Engraulis anchoita across the frontal system of Peninsula Valdés. Twelve samples of zooplankton and ichthyoplankton were taken with small Bongo (67 μm) and Pairovet (200 μm) nets during the spring of 2004 along two transects. The total abundance of zooplankton and the chlorophyll a concentration were higher in homogeneous waters, while total biomasses were higher in stratified waters. Temperature was negatively correlated with biological variables and was the main factor affecting the zooplankton distribution. In both transects, abundance peaks of first-feeding larvae were detected at coastal stations along with the smallest fraction of zooplankton ( < 500 μm), while the largest fraction was dominant at the external stations, coinciding with the highest egg abundance. The physical structure of this front generates different levels of food availability for first-feeding larvae. Calanoids (southern transect) and cyclopoids (northern transect) are predominant followed by nauplii and appendicularians. The biomass of zooplankton preys contributes to the carbon transfer to the upper trophic levels and is probably important for the survival and growth of anchovy larvae in this frontal system.Se investigó la distribución espacial de la abundancia, biomasa y las tallas del zooplancton (nauplii, calanoideos, ciclopoideos y apendicularias) en relación con la distribución de las larvas en estadio de primera alimentación y los huevos de Engraulis anchoita en el sistema frontal de Península Valdés. Se tomaron 12 muestras de zooplancton e ictioplancton durante la primavera de 2004 a lo largo de dos transectos, mediante una red Minibongo (67 μm) y una Pairovet (200 μm) respectivamente. La abundancia total del zooplancton y la concentración de clorofila fue mayor en aguas homogéneas, mientras que la biomasa fue mayor en aguas estratificadas. La temperatura se correlacionó negativamente con las variables biológicas siendo ésta el principal factor que afectó la distribución del zooplancton. En las estaciones costeras de ambos transectos, se encontró la mayor abundancia de larvas en coincidencia con la fracción más pequeña de zooplancton ( < 500 μm), mientras que la fracción más grande fue dominante en las estaciones externas, en coincidencia con la mayor abundancia de huevos. La estructura física de este frente genera diferente disponibilidad de alimento para las larvas siendo los calanoideos (transecto sur) y los ciclopoideos (transecto norte) predominantes, seguidos por nauplii y apendicularias. La biomasa de dicho alimento zooplanctónico podría contribuir a la transferencia de carbono a los niveles tróficos superiores y esto sería importante para la supervivencia y crecimiento de la anchoita en este sistema frontal

Associations of awareness of age-related change with emotional and physical well-being: a systematic review and meta-analysis

This is the final version. Available on open access from OUP via the DOI in this recordBACKGROUND AND OBJECTIVES: This systematic review aimed to synthesize and quantify the associations of awareness of age-related change (AARC) with emotional well-being, physical well-being, and cognitive functioning. RESEARCH DESIGN AND METHODS: We conducted a systematic review with a correlational random effects meta-analysis. We included quantitative studies, published from January 1, 2009 to October 3, 2018, exploring associations between AARC and one or more of the following outcomes: emotional well-being, physical well-being, and cognitive functioning. We assessed heterogeneity (I2) and publication bias. RESULTS: We included 12 studies in the review, 9 exploring the association between AARC and emotional well-being and 11 exploring the association between AARC and physical well-being. No study explored the association between AARC and cognitive functioning. Six articles were included in the meta-analysis. We found a moderate association between a higher level of AARC gains and better emotional well-being (r = .33; 95% CI 0.18, 0.47; p <.001; I2 = 76.01) and between a higher level of AARC losses and poorer emotional (r = -.31; 95% CI -0.38, -0.24; p < .001; I2 = 0.00) and physical well-being (r = -.38; 95% CI -0.51, -0.24; p < .001; I2 = 83.48). We found a negligible association between AARC gains and physical well-being (r = .08; 95% CI 0.02, 0.14; p < .122; I2 = 0.00). Studies were of medium to high methodological quality. DISCUSSION AND IMPLICATIONS: There is some indication that AARC gains and losses can play a role in emotional well-being and that AARC losses are associated with physical well-being. However, the number of included studies is limited and there was some indication of heterogeneity. PROSPERO REGISTRATION: CRD42018111472.University of Exeter College of Life and Environmental Sciences (School of Psychology)University of Exeter College of Medicine and Healt

ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP

Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell-targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors.National Institutes of Health (U.S.) (Grant R01CA103866)National Institutes of Health (U.S.) (Grant AI47389

Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase

During antibody affinity maturation, germinal center (GC) B cells cycle between affinity-driven selection in the light zone (LZ) and proliferation and somatic hypermutation in the dark zone (DZ). Although selection of GC B cells is triggered by antigen-dependent signals delivered in the LZ, DZ proliferation occurs in the absence of such signals. We show that positive selection triggered by T cell help activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes the anabolic program that supports DZ proliferation. Blocking mTORC1 prior to growth prevented clonal expansion, whereas blockade after cells reached peak size had little to no effect. Conversely, constitutively active mTORC1 led to DZ enrichment but loss of competitiveness and impaired affinity maturation. Thus, mTORC1 activation is required for fueling B cells prior to DZ proliferation rather than for allowing cell-cycle progression itself and must be regulated dynamically during cyclic re-entry to ensure efficient affinity-based selection

Architecture of human Rag GTPase heterodimers and their complex with mTORC1

© 2019 American Association for the Advancement of Science. All rights reserved. The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo–electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDPnucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes

An Analysis of the Atmospheric Propagation of Underground-Explosion-Generated Infrasonic Waves Based on the Equations of Fluid Dynamics: Ground Recordings

An investigation on the propagation of underground-explosion-generated infrasonic waves is carried out via numerical simulations of the equations of fluid dynamics. More specifically, the continuity, momentum, and energy conservation equations are solved along with the Herzfeld-Rice equations in order to take into account the effects of vibrational relaxation phenomena. The radiation of acoustic energy by the ground motion caused by underground explosions is initiated by enforcing the equality, at ground level, between the component of the air velocity normal to the Earth\u27s surface and the normal velocity of the ground layer. The velocity of the ground layer is defined semi-empirically as a function of the depth of burial and of the yield. The effects of the depth and of the source energy on the signals recorded in the epicentral zone are first discussed. The tropospheric and stratospheric infrasonic phases traveling at a long-range are then analyzed and explained. Synthesized ground waveforms are finally discussed and compared to those recorded at the I45RU station of the International Monitoring System after the 2013 North-Korean test. Good agreement is found between numerical results and experimental data, which motivates the use of infrasound technologies alongside seismic techniques for the characterization of underground explosions

Factors associated with failed treatment : an analysis of 121,744 women embarking on their first IVF cycles

Peer reviewedPublisher PD