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General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABA A) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABA A receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABA A receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABA A receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABA A receptors, which in turn promoted the release paracrine factors, that increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1β and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1β and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABA A receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway. Brief commentary Many older patients experience cognitive deficits after surgery. Anesthetic drugs may be a contributing factor as they cause a sustained increase in the function of "memory blocking" extrasynaptic GABA A receptors in neurons. Interestingly, astrocytes are required for this increase; however, the mechanisms underlying the astrocyte-to-neuron crosstalk remain unknown. We discovered that commonly used general anesthetic drugs stimulate GABA A receptors in astrocytes, which in turn release paracrine factors that trigger a persistent increase in extrasynaptic GABA A receptor function in neurons via p38 MAPK. This novel form of crosstalk may contribute to persistent cognitive deficits after general anesthesia and surgery. [ABSTRACT FROM AUTHOR]

Gliomas are one of the leading causes of cancer-related death in the adolescent and young adult (AYA) population. Two-thirds of AYA glioma patients are affected by low-grade gliomas (LGGs), but there are no specific treatments. Malignant progression is supported by the immunosuppressive stromal component of the tumor microenvironment (TME) exacerbated by M2 macrophages and a paucity of cytotoxic T cells. A single intravenous dose of engineered bone-marrow-derived myeloid cells that release interleukin-2 (GEMys-IL2) was used to treat mice with LGGs. Our results demonstrate that GEMys-IL2 crossed the blood-brain barrier, infiltrated the TME, and reprogrammed the immune cell composition and transcriptome. Moreover, GEMys-IL2 extended survival in an LGG immunocompetent mouse model. Here, we report the efficacy of an in vivo approach that demonstrates the potential for a cell-mediated innate immunotherapy designed to enhance the recruitment of activated effector T and natural killer cells within the glioma TME. [Display omitted] • Cytotoxic T and NK cell trafficking and activation are inhibited during glioma progression • BMDMs can be genetically engineered to release IL2 (GEMys-IL2) • GEMys-IL2 injected systemically in mice with LGG reprogram the tumor microenvironment • Mice with LGG treated with a single dose of GEMys-IL2 show a survival advantage Canella et al. tested a cellular immunotherapy for the treatment of low-grade glioma, based on the intravenous injection of bone-marrow-derived myeloid cells genetically engineered to release interleukin-2 (GEMys-IL2). The GEMys-IL2 homed to the TME and released IL2, which enhanced the trafficking and activation of cytotoxic T and NK cells. [ABSTRACT FROM AUTHOR]

Recent studies have shown the importance of the dynamic tumor microenvironment (TME) in high-grade gliomas (HGGs). In particular, myeloid cells are known to mediate immunosuppression in glioma; however, it is still unclear if myeloid cells play a role in low-grade glioma (LGG) malignant progression. Here, we investigate the cellular heterogeneity of the TME using single-cell RNA sequencing in a murine glioma model that recapitulates the malignant progression of LGG to HGG. LGGs show increased infiltrating CD4+ and CD8+ T cells and natural killer (NK) cells in the TME, whereas HGGs abrogate this infiltration. Our study identifies distinct macrophage clusters in the TME that show an immune-activated phenotype in LGG but then evolve to an immunosuppressive state in HGG. We identify CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Targeting these intra-tumoral macrophages in the LGG stage may attenuate their immunosuppressive properties and impair malignant progression. [Display omitted] • Macrophages exhibit signatures of immune activation during LGG • Macrophages evolve to an immunosuppressive state in HGG • T cell infiltration is restricted in HGG • CD74-MIF axis is upregulated in tumor-infiltrating macrophages in LGG and HGG Rajendran et al. identified distinct macrophages that show immune activation signatures in the LGG stage and immunosuppressive features in the HGG stage. The CD74-MIF axis is upregulated in the macrophages in the LGG stage and may serve as a potential target for tumor-infiltrating macrophages prior to malignant progression. [ABSTRACT FROM AUTHOR]

The acid β-glucosidase (glucocerbrosidase (GCase)) binding sequence to LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome, has been identified. Heterologous expression of deletion constructs, the available GCase crystal structures, and binding and co-localization of identified peptides or mutant GCases were used to identify and characterize a highly conserved 11-amino acid sequence, DSPIIVDITKD, within human GCase. The binding to LIMP-2 is not dependent upon a single amino acid, but the interactions of GCase with LIMP-2 are heavily influenced by Asp399 and the di-isoleucines, Ile402 and Ile403. A single alanine substitution at any of these decreases GCase binding to LIMP-2 and alters its pH-dependent binding as well as diminishing the trafficking of GCase to the lysosome and significantly increasing GCase secretion. Enterovirus 71 also binds to LIMP-2 (also known as SCARB2) on the external surface of the plasma membrane. However, the LIMP-2/SCARB2 binding sequences for enterovirus 71 and GCase are not similar, indicating that LIMP- 2/SCARB2 may have multiple or overlapping binding sites with differing specificities. These findings have therapeutic implications for the production of GCase and the distribution of this enzyme that is delivered to various organs. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: This study is a review of our series of pediatric patients with unilateral sensorineural hearing loss (USNHL) to report abnormalities on imaging studies, review genetic and ophthalmologic results, and survey audiometric findings. Methods: This study is a retrospective chart review of all pediatric patients with USNHL seen between 1/1/03 and 12/31/08 at our institution. The study was approved by the institutional review board. Results: Eighty-nine cases were identified with audiometric findings confirming unilateral hearing thresholds greater than 20dBHL with no conductive component. There were 48 males and 41 females. Average age of diagnosis was 7 years. One audiogram showed low-frequency loss, 17 mid-frequency, 29 high-frequency, and 32 flat. Ten patients were diagnosed by auditory brainstem response testing at another institution, with thresholds not available for review. Eleven percent of patients progressed to bilateral loss. Sixty-one patients underwent computed tomography of temporal bones (CTTB). Twenty of 61 scans identified 34 anomalies including 15 enlarged vestibular aqueducts (EVAs), 8 Mondini, and 3 superior semicircular canal dehiscences (SSCDs). Thirty-one of 89 patients underwent magnetic resonance imaging (MRI). Three of these 31 patients had positive findings including 1 EVA, 1 Mondini, and 1 asymmetric internal auditory canal. When CTTB was positive, no additional lesions were detected on MRI. When CTTB was negative and MRI was done in 20 patients, 2 additional lesions were detected by MRI. Fourteen patients had genetics evaluation of which 6 had positive findings, including CHARGE, VACTERL, Goldenhar, and 3 were heterozygous for a Connexin mutation. Conclusions: CTTB is an effective diagnostic tool for USNHL. MRI should be considered in patients with negative CTTB. Genetics and ophthalmologic evaluations are recommended for patients with risk factors or an abnormal clinical examination. Close follow-up is essential due to high rate of hearing loss progression. [Copyright &y& Elsevier]

• Recently-burned area in southwestern US forests is increasing. • Landscape context, values, and future trajectories of change can inform management. • Postfire forest patches can be managed for resilience to future fires. • Novel reforestation practices may help adapt to future climate and fire in some areas. The increasing incidence of wildfires across the southwestern United States (US) is altering the contemporary forest management template within historically frequent-fire conifer forests. An increasing fraction of southwestern conifer forests have recently burned, and many of these burned landscapes contain complex mosaics of surviving forest and severely burned patches without surviving conifer trees. These heterogeneous burned landscapes present unique social and ecological challenges. Severely burned patches can present numerous barriers to successful conifer regeneration, and often contain heavy downed fuels which have cascading effects on future fire behavior and conifer regeneration. Conversely, surviving forest patches are increasingly recognized for their value in postfire reforestation but often are overlooked from a management perspective. Here we present a decision-making framework for landscape-scale management of complex postfire landscapes that allows for adaptation to a warming climate and future fire. We focus specifically on historically frequent-fire forests of the southwestern US but make connections to other forest types and other regions. Our framework depends on a spatially-explicit assessment of the mosaic of conifer forest and severely burned patches in the postfire landscape, evaluates likely vegetation trajectories, and identifies critical decision points to direct vegetation change via manipulations of fuels and live vegetation. This framework includes detailed considerations for postfire fuels management (e.g., edge hardening within live forest patches and repeat burning) and for reforestation (e.g., balancing tradeoffs between intensive and extensive planting strategies, establishing patches of seed trees, spatial planning to optimize reforestation success, and improving nursery capacity). In a future of increasing fire activity in forests where repeated low- to moderate-severity fire is essential to ecosystem resilience, the decision-making framework developed here can easily be integrated with existing postfire management strategies to optimize allocation of limited resources and more actively manage burned landscapes. [ABSTRACT FROM AUTHOR]

Objective The best imaging study for evaluation of pediatric hearing loss is debated and it is well known magnetic resonance imaging is more costly than computed tomography. The objective of this study is to evaluate charges of computed tomography temporal bone (CTTB) versus magnetic resonance imaging brain, internal auditory canal/cerebellopontine angle (MRI IAC/CPA), with and without sedation in the pediatric population in order to assess to what extent the charges for the procedure are increased. In addition, differences in need for sedation and duration of sedation will be evaluated. Methods All patients, 0–18 years that underwent CTTB or MRI IAC/CPA, between January 2013 through December 2014 within department of otolaryngology. Results 120 CTTBs (118 non-sedated and 2 sedated) and 51 MRI IAC/CPAs (32 non-sedated and 19 sedated) were performed. Average charge for non-sedated CTTB was $1856. CTTB scan under sedation incurred total additional charges of $2385. Average charges for non-sedated MRI IAC/CPA was $3770. Technical charges for sedated MRI IAC/CPA was $151 lower ($2858) but had additional sedation charges of $2256, a recovery room charge of $250, and additional professional fees of $1496 for total charges of $7621. 37% of MRI IAC/CPAs needed sedation to be completed in comparison to 1.6% of CTTB. Conclusion MRI IAC/CPAs are, on average, twice as costly as CTTBs. Almost 40% of patients need sedation to complete MRI IAC/CPA. These considerations may factor into decision making when choosing imaging modality in evaluation of pediatric hearing loss. [ABSTRACT FROM AUTHOR]

High-throughput and deep DNA sequencing, particularly amplicon sequencing, is being increasingly utilized to reveal spatial and temporal dynamics of bacterial communities in drinking water systems. Whilst the sampling and methodological biases associated with PCR and sequencing have been studied in other environments, they have not been quantified for drinking water. These biases are likely to have the greatest effect on the ability to characterize subtle spatio-temporal patterns influenced by process/environmental conditions. In such cases, intra-sample variability may swamp any underlying small, systematic variation. To evaluate this, we undertook a study with replication at multiple levels including sampling sites, sample collection, PCR amplification, and high throughput sequencing of 16S rRNA amplicons. The variability inherent to the PCR amplification and sequencing steps is significant enough to mask differences between bacterial communities from replicate samples. This was largely driven by greater variability in detection of rare bacteria (relative abundance <0.01%) across PCR/sequencing replicates as compared to replicate samples. Despite this, we captured significant changes in bacterial community over diurnal time-scales and find that the extent and pattern of diurnal changes is specific to each sampling location. Further, we find diurnal changes in bacterial community arise due to differences in the presence/absence of the low abundance bacteria and changes in the relative abundance of dominant bacteria. Finally, we show that bacterial community composition is significantly different across sampling sites for time-periods during which there are typically rapid changes in water use. This suggests hydraulic changes (driven by changes in water demand) contribute to shaping the bacterial community in bulk drinking water over diurnal time-scales. [ABSTRACT FROM AUTHOR]

Exercise programs have shown great potential for both the prevention and treatment of substance use disorder (SUD). As exercise has been shown to have potent effects on physical and psychological health, it is reasonable to examine the mechanism of how exercise can be used as an adjunct treatment for addiction. The present study examined the effects of chronic aerobic (treadmill) exercise on both GABA(a) and mu-opioid receptor levels in the brains of male and female rats. GABA(a) receptor binding, measured by [3H] Flunitrazepam, was increased in the cingulate cortex following exercise, but only in females. Mu-opioid receptor expression, measured by [3H] ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin) (DAMGO), showed no effect of exercise while showing an effect of sex, with increased [3H] DAMGO binding in the brains of sedentary males compared to that of sedentary females. Our findings support the potential role for GABA(a) signaling in the cingulate cortex as part of the mechanism of action of aerobic exercise. These data, along with prior reports, aid our understanding of the neurochemical impact and mechanism of chronic aerobic exercise on neuropsychiatric disease, particularly regarding addiction. • Chronic aerobic exercise effects on GABA(a) and mu-opioid receptor levels in the brains of rats. • GABA(a) receptor binding, was increased in the cingulate cortex following exercise, but only in females. • Mu-opioid receptor (MOR) levels did not change with exercise, sex effect, increased MOR in sedentary males compared to females. • Neurochemical impact and mechanism of chronic aerobic exercise on implications for neuropsychiatric disease. [ABSTRACT FROM AUTHOR]