Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson’s disease and addiction. In contrast to the extensive ...studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.
•Astrocytes in the Nucleus Accumbens respond to synaptic dopamine in vivo•Astrocytes mediate the synaptic regulation induced by dopamine and amphetamine•Amphetamine-induced enhancement in locomotion activity is modulated by astrocytes
Corkrum et al. report that astrocyte activity is required for dopamine- and amphetamine-evoked synaptic regulation and amphetamine-induced locomotor effects. Their study reveals astrocytes as active components of dopaminergic signaling and the brain reward system.
Drosophila melanogaster tumor models are growing in popularity, driven by the high degree of genetic as well as functional conservation to humans. The most common method to measure the effects of a ...tumor on distant organs of a human cancer patient is to use computed tomography (CT), often used in diagnosing cachexia, a debilitating cancer-induced syndrome most visibly characterized by loss of muscle mass. Successful application of high resolution micro-CT scanning of D. melanogaster was recently reported and we here present the segmentation of all visible larval organs at several stages of tumor development. We previously showed the strong expected reduction in muscle mass as the tumor develops, and we here report a surprisingly strong reduction also in gut and Malpighian tubules (kidney) volume. Time-point of tumor development was found to have a stronger correlation to cachectic organ volume loss than tumor volume, giving support to the previously proposed idea that tumor size does not directly determine degree of cachexia.
During tumor growth—when nutrient and anabolic demands are high—autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras‐driven tumors ...additionally invoke non‐autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well‐characterized malignant tumor model in Drosophila melanogaster. Micro‐computed X‐ray tomography and metabolic profiling reveal that RasV12; scrib−/− tumors grow 10‐fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, ‐motility, ‐feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.
Synopsis
Autophagy maintains mitochondrial health and nutrient recycling in tumor cells, and promotes the transfer of amino acids from microenvironmental to tumor cells, thereby sustaining tumor metabolism and growth. In this study, X‐ray tomography, metabolomics and carbon tracing reveal that autophagy‐mediated wasting of distal tissues provides amino acids and sugars that increase eye tumor biomass in Drosophila melanogaster.
RasV12, scrib−/− tumors induce organ wasting and cause release of amino acids and sugar into circulation.
Systemic autophagy mediates muscle wasting and nutrient release.
Tumor biomass increasingly derive from host tissues as wasting ensues.
X‐ray tomography, metabolomics and carbon tracing reveal that autophagy‐mediated wasting of distal tissues provides amino acids and sugars that increase eye tumor biomass in Drosophila melanogaster.
Interneurons are critical for proper neural network function and can activate Ca
signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation ...remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition
potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABA
receptors, potentiation involved astrocyte GABA
receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABA
receptor (
) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.
We systematically reviewed the current knowledge on fixed-dose triple therapies for the treatment of chronic obstructive pulmonary disease (COPD), with a specific focus on its efficacy versus single ...bronchodilation, double fixed dose combinations, and open triple therapies. Articles were retrieved from PubMed, Embase, and Scopus up to 3 August 2018. We selected articles with randomized controlled or crossover design conducted in patients with COPD and published as full-length articles or scientific letters, evaluating triple therapy combinations in a single or different inhaler, and with efficacy data versus monocomponents, double combinations, or open triple therapies. Our systematic search reported 108 articles, of which 24 trials were finally selected for the analysis. A total of 7 studies with fixed dose triple therapy combinations, and 17 studies with open triple therapies combinations. Triple therapy showed improvements in lung function trough forced expiratory volume (FEV1) ranging from not significant (NS) to 147 ml, health status using the St. George’s Respiratory Questionnaire (SGRQ) from NS to 8.8 points, and exacerbations risk ratio (RR) from NS to 0.59 for all exacerbations versus single or double therapies with a variability in the response, depending the specific combination, and the comparison group. The proportion of adverse effects was similar between study groups, the exception being the increase in pneumonia for some inhaled corticosteroid (ICS) containing groups.
The reviews of this paper are available via the supplementary material section.
Abstract
Multiplanet systems are valuable arenas for investigating exoplanet architectures and comparing planetary siblings. TOI-1246 is one such system, with a moderately bright K dwarf (
V
= 11.6,
...K
= 9.9) and four transiting sub-Neptunes identified by TESS with orbital periods of 4.31, 5.90, 18.66, and 37.92 days. We collected 130 radial velocity observations with Keck/HIRES and TNG/HARPS-N to measure planet masses. We refit the 14 sectors of TESS photometry to refine planet radii (2.97 ± 0.06
R
⊕
, 2.47 ± 0.08
R
⊕
, 3.46 ± 0.09
R
⊕
, and 3.72 ± 0.16
R
⊕
) and confirm the four planets. We find that TOI-1246 e is substantially more massive than the three inner planets (8.1 ± 1.1
M
⊕
, 8.8 ± 1.2
M
⊕
, 5.3 ± 1.7
M
⊕
, and 14.8 ± 2.3
M
⊕
). The two outer planets, TOI-1246 d and TOI-1246 e, lie near to the 2:1 resonance (
P
e
/
P
d
= 2.03) and exhibit transit-timing variations. TOI-1246 is one of the brightest four-planet systems, making it amenable for continued observations. It is one of only five systems with measured masses and radii for all four transiting planets. The planet densities range from 0.70 ± 0.24 to 3.21 ± 0.44 g cm
−3
, implying a range of bulk and atmospheric compositions. We also report a fifth planet candidate found in the RV data with a minimum mass of 25.6 ± 3.6
M
⊕
. This planet candidate is exterior to TOI-1246 e, with a candidate period of 93.8 days, and we discuss the implications if it is confirmed to be planetary in nature.
The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting β
-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary ...disease (COPD). Here, we systematically review the current knowledge on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus placebo and/or monotherapy bronchodilation.
A systematic review of clinical trials investigating LABA/LAMA combination therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26, 2016. We specifically selected clinical trials with a randomized controlled or crossover design published in any scientific journal showing the following characteristics: 1) comparison of different LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in terms of lung function, respiratory symptoms, or exacerbations.
We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA combinations were consistently able to improve lung function compared with both placebo and bronchodilator monotherapy. Improvements in symptoms were also consistent versus placebo, showing some lack of correlation for some clinical end points and combinations versus monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an improvement with LABA/LAMA combinations over placebo in some trials; however, scarce information was available in comparison with bronchodilator monotherapy in most studies.
Our data show consistent improvements for LABA/LAMA combinations, albeit with some variability (depending on the clinical end point, the specific combination, and the comparison group). Clinicians should be aware that these are average differences. All treatments should be tailored at the individual level to optimize clinical outcomes.
Training in pulmonology at overseas centers may require a considerable effort, and although such an experience could even imply a financial burden for the trainee, the benefits far outweigh the ...material costs. The desire for personal and scientific growth should encourage young pulmonologists and medical residents to rotate outside Spain and become acquainted with other health care systems, customs, dynamics, and resources in order to obtain quality training and added value that will further enrich our specialty. Any pulmonologist wishing to undergo specialized training at an overseas institution will necessarily consider questions such as the relevance of the stay and its objectives, timing, availability of centers, eligibility, and funding agencies. Based on one resident's personal experience, we attempt to answer several of these questions.
Abstract
During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors ...additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12 ; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. Thus, host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.
Citation Format: Petter Holland, Todd Andrew Schoborg, Ifat Abramovich, Szabolcs Takáts, Caroline Dillard, Ashish Jain, Fergal O'Farrell, Sebastian Wolfgang Schultz, William M. Hagopian, Eduardo Martin Quintana, Rachel Ng, Nadja Sandra Katheder, Mohammed Mahidur Rahman, José Gerardo Teles Reis, Andreas Brech, Heinrich Jasper, Nasser M. Rusan, Anne Hope Jahren, Eyal Gottlieb, Tor Erik Rusten. Host autophagy mediates organ wasting and nutrient mobilization for tumor growth abstract. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA14.
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