The ventral tegmental area (VTA) is a heterogeneous midbrain structure, containing neurons and astrocytes, that coordinates behaviors by integrating activity from numerous afferents. Within ...neuron-astrocyte networks, astrocytes control signals from distinct afferents in a circuit-specific manner, but whether this capacity scales up to drive motivated behavior has been undetermined. Using genetic and optical dissection strategies we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance. In this circuit, astrocytes facilitate excitation of VTA GABA neurons to increase inhibition of dopamine neurons, eliciting real-time and learned avoidance behavior that is sufficient to impede expression of preference for reward. Loss of one glutamate transporter (GLT-1) from VTA astrocytes selectively blocks these avoidance behaviors and spares preference for reward. Thus, VTA astrocytes selectively regulate excitation of local GABA neurons to drive a distinct avoidance circuit that opposes approach behavior.
Abstract
The dynamics of a nuclear open quantum system could be revealed in the correlations between the breakup fragments of halo nuclei. The breakup mechanism of a proton halo nuclear system is of ...particular interest as the Coulomb polarization may play an important role, which, however, remains an open question. Here we use a highly efficient silicon detector array and measure the correlations between the breakup fragments of
8
B incident on
120
Sn at near-barrier energies. The energy and angular correlations can be explained by a fully quantum mechanical method based on the state-of-the-art continuum discretized coupled channel calculations. The results indicate that, compared to the neutron halo nucleus
6
He,
8
B presents distinctive reaction dynamics: the dominance of the elastic breakup. This breakup occurs mainly via the short-lived continuum states, almost exhausts the
7
Be yield, indicating the effect of Coulomb polarization on the proton halo state. The correlation information reveals that the prompt breakup mechanism dominates, occurring predominantly on the outgoing trajectory. We also show that, as a large environment, the continuum of
8
B breakup may not significantly influence elastic scattering and complete fusion.
The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental ...courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.
We present the main findings of the 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia (AAGA). Incidences were estimated using reports of accidental awareness as the ...numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ∼1:19 600 anaesthetics (95% confidence interval 1:16 700–23 450). However, there was considerable variation across subtypes of techniques or subspecialities. The incidence with neuromuscular block (NMB) was ∼1:8200 (1:7030–9700), and without, it was ∼1:135 900 (1:78 600–299 000). The cases of AAGA reported to NAP5 were overwhelmingly cases of unintended awareness during NMB. The incidence of accidental awareness during Caesarean section was ∼1:670 (1:380–1300). Two-thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental, rapid sequence induction, obesity, difficult airway management, NMB, and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One-third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, mostly due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex, age (younger adults, but not children), obesity, anaesthetist seniority (junior trainees), previous awareness, out-of-hours operating, emergencies, type of surgery (obstetric, cardiac, thoracic), and use of NMB. The following factors were not risk factors for accidental awareness: ASA physical status, race, and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from NAP5—the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home.
The relation between ices in the envelopes and disks surrounding young stellar objects (YSOs) and those in the quiescent interstellar medium (ISM) is investigated. For a sample of 31 stars behind ...isolated dense cores, ground-based and Spitzer spectra and photometry in the 1-25 Delta *mm wavelength range are combined. The baseline for the broad and overlapping ice features is modeled, using calculated spectra of giants, H2O ice and silicates. The adopted extinction curve is derived empirically. Its high resolution allows for the separation of continuum and feature extinction. The extinction between 13 and 25 Delta *mm is ~50% relative to that at 2.2 Delta *mm. The strengths of the 6.0 and 6.85 Delta *mm absorption bands are in line with those of YSOs. Thus, their carriers, which, besides H2O and CH3OH, may include NH+ 4, HCOOH, H2CO, and NH3, are readily formed in the dense core phase, before stars form. The 3.53 Delta *mm C-H stretching mode of solid CH3OH was discovered. The CH3OH/H2O abundance ratios of 5%-12% are larger than upper limits in the Taurus molecular cloud. The initial ice composition, before star formation occurs, therefore depends on the environment. Signs of thermal and energetic processing that were found toward some YSOs are absent in the ices toward background stars. Finally, the peak optical depth of the 9.7 Delta *mm band of silicates relative to the continuum extinction at 2.2 Delta *mm is significantly shallower than in the diffuse ISM. This extends the results of Chiar et al. to a larger sample and higher extinctions.
Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain ...injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, suggesting that the vasculature is particularly vulnerable. Brain endothelial cells and their supporting glial and neuronal elements constitute a neurovascular unit (NVU). Blast injury disrupts gliovascular and neurovascular connections in addition to damaging endothelial cells, basal laminae, smooth muscle cells, and pericytes as well as causing extracellular matrix reorganization. Perivascular pathology becomes associated with phospho-tau accumulation and chronic perivascular inflammation. Disruption of the NVU should impact activity-dependent regulation of cerebral blood flow, blood-brain barrier permeability, and glymphatic flow. Here, we review work in an animal model of low-level blast injury that we have been studying for over a decade. We review work supporting the NVU as a locus of low-level blast injury. We integrate our findings with those from other laboratories studying similar models that collectively suggest that damage to astrocytes and other perivascular cells as well as chronic immune activation play a role in the persistent neurobehavioral changes that follow blast injury.
Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson's disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative ...regulatory function of nuclear factor of activated T cells implicates leucine-rich repeat kinase 2 in the development of the inflammatory environment characteristic of Parkinson's disease. The aim of this study was to determine the expression pattern of leucine-rich repeat kinase 2 in immune cell subsets and correlate it with the immunophenotype of cells from Parkinson's disease and healthy subjects. For immunophenotyping, blood cells from 40 Parkinson's disease patients and 32 age and environment matched-healthy control subjects were analyzed by flow cytometry. Multiplexed immunoassays were used to measure cytokine output of stimulated cells. Leucine-rich repeat kinase 2 expression was increased in B cells (
= 0.0095), T cells (
= 0.029), and CD16
monocytes (
= 0.01) of Parkinson's disease patients compared to healthy controls. Leucine-rich repeat kinase 2 induction was also increased in monocytes and dividing T cells in Parkinson's disease patients compared to healthy controls. In addition, Parkinson's disease patient monocytes secreted more inflammatory cytokines compared to healthy control, and cytokine expression positively correlated with leucine-rich repeat kinase 2 expression in T cells from Parkinson's disease but not healthy controls. Finally, the regulatory surface protein that limits T-cell activation signals, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), was decreased in Parkinson's disease compared to HC in T cells (
= 0.029). In sum, these findings suggest that leucine-rich repeat kinase 2 has a regulatory role in immune cells and Parkinson's disease. Functionally, the positive correlations between leucine-rich repeat kinase 2 expression levels in T-cell subsets, cytokine expression and secretion, and T-cell activation states suggest that targeting leucine-rich repeat kinase 2 with therapeutic interventions could have direct effects on immune cell function.
There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint ...inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma.
DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415.
Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5–30·2). 31 (57%; 95% CI 44–70) of 54 patients were alive and progression-free at 6 months. The most common grade 3–4 adverse events were neutropenia (seven 13% patients), nausea (six 11%), and anaemia (four 7%). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment.
The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial.
AstraZeneca.
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a ...multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
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