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.
A deadly cascade
A catastrophic landslide in Uttarakhand state in India on February 2021 damaged two hydropower plants, and more than 200 people were killed or are missing. Shugar
et al.
describe the ...cascade of events that led to this disaster. A massive rock and ice avalanche roared down a Himalayan valley, turning into a deadly debris flow upstream from the first of the two hydropower plants. The sequence of events highlights the increasing risk in the Himalayas caused by increased warming and development.
Science
, abh4455, this issue p.
300
A cascade of events starting with a massive avalanche eventually triggered a deadly debris flow in the Indian Himalaya.
On 7 February 2021, a catastrophic mass flow descended the Ronti Gad, Rishiganga, and Dhauliganga valleys in Chamoli, Uttarakhand, India, causing widespread devastation and severely damaging two hydropower projects. More than 200 people were killed or are missing. Our analysis of satellite imagery, seismic records, numerical model results, and eyewitness videos reveals that ~27 × 10
6
cubic meters of rock and glacier ice collapsed from the steep north face of Ronti Peak. The rock and ice avalanche rapidly transformed into an extraordinarily large and mobile debris flow that transported boulders greater than 20 meters in diameter and scoured the valley walls up to 220 meters above the valley floor. The intersection of the hazard cascade with downvalley infrastructure resulted in a disaster, which highlights key questions about adequate monitoring and sustainable development in the Himalaya as well as other remote, high-mountain environments.
For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, ...an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin “burn propagation” into surrounding cold fuel, enabling the possibility of high energy gain. While “scientific breakeven” (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this work reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.
Warming experiments are increasingly relied on to estimate plant responses to global climate change. For experiments to provide meaningful predictions of future responses, they should reflect the ...empirical record of responses to temperature variability and recent warming, including advances in the timing of flowering and leafing. We compared phenology (the timing of recurring life history events) in observational studies and warming experiments spanning four continents and 1,634 plant species using a common measure of temperature sensitivity (change in days per degree Celsius). We show that warming experiments underpredict advances in the timing of flowering and leafing by 8.5-fold and 4.0-fold, respectively, compared with long-term observations. For species that were common to both study types, the experimental results did not match the observational data in sign or magnitude. The observational data also showed that species that flower earliest in the spring have the highest temperature sensitivities, but this trend was not reflected in the experimental data. These significant mismatches seem to be unrelated to the study length or to the degree of manipulated warming in experiments. The discrepancy between experiments and observations, however, could arise from complex interactions among multiple drivers in the observational data, or it could arise from remediable artefacts in the experiments that result in lower irradiance and drier soils, thus dampening the phenological responses to manipulated warming. Our results introduce uncertainty into ecosystem models that are informed solely by experiments and suggest that responses to climate change that are predicted using such models should be re-evaluated.
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.
Various studies have documented the effects of modern day irrigation on regional and global climate, but none, to date, have considered the time varying impact of steadily increasing irrigation rates ...on climate during the 20th century. We investigate the impacts of observed irrigation changes over this century with two ensemble simulations using an atmosphere general circulation model. Both ensembles are forced with transient climate forcings and observed sea surface temperatures from 1902 to 2000; one ensemble includes irrigation specified by a time varying data set of irrigation water withdrawals. Early in the century, irrigation is primarily localized over southern and eastern Asia, leading to significant cooling in boreal summer (June.August) over these regions. This cooling spreads and intensifies by century fs end, following the rapid expansion of irrigation over North America, Europe, and Asia. Irrigation also leads to boreal winter (December.February) warming over parts of North America and Asia in the latter part of the century, due to enhanced downward longwave fluxes from increased near surface humidity. Precipitation increases occur primarily downwind of the major irrigation areas, although precipitation in parts of India decreases due to a weaker summer monsoon. Irrigation begins to significantly reduce temperatures and temperature trends during boreal summer over the Northern Hemisphere midlatitudes and tropics beginning around 1950; significant increases in precipitation occur in these same latitude bands. These trends reveal the varying importance of irrigation climate interactions and suggest that future climate studies should account for irrigation, especially in regions with unsustainable irrigation resources.
Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous ...cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST). We also examined the effects of GLO1 inhibition in three models of antidepressant onset: the chronic FST (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy (OBX). Genetic knockdown of Glo1 or pharmacological inhibition using two structurally distinct GLO1 inhibitors (S-bromobenzylglutathione cyclopentyl diester (pBBG) or methyl-gerfelin (MeGFN)) reduced immobility in the TST and acute FST. Both GLO1 inhibitors also reduced immobility in the cFST after 5 days of treatment. In contrast, the serotonin reuptake inhibitor fluoxetine (FLX) reduced immobility after 14, but not 5 days of treatment. Furthermore, 5 days of treatment with either GLO1 inhibitor blocked the depression-like effects induced by CMS on the FST and coat state, and attenuated OBX-induced locomotor hyperactivity. Finally, 5 days of treatment with a GLO1 inhibitor (pBBG), but not FLX, induced molecular markers of the antidepressant response including brain-derived neurotrophic factor (BDNF) induction and increased phosphorylated cyclic-AMP response-binding protein (pCREB) to CREB ratio in the hippocampus and medial prefrontal cortex (mPFC). Our findings indicate that GLO1 inhibitors may provide a novel and fast-acting pharmacotherapy for depression.
Since its discovery in 2008, the Andromeda galaxy nova M31N 2008-12a has been observed in eruption every single year. This unprecedented frequency indicates an extreme object, with a massive white ...dwarf and a high accretion rate, which is the most promising candidate for the single-degenerate progenitor of a Type Ia supernova known to date. The previous three eruptions of M31N 2008-12a have displayed remarkably homogeneous multiwavelength properties: (i) from a faint peak, the optical light curve declined rapidly by two magnitudes in less than two days, (ii) early spectra showed initial high velocities that slowed down significantly within days and displayed clear He/N lines throughout, and (iii) the supersoft X-ray source (SSS) phase of the nova began extremely early, six days after eruption, and only lasted for about two weeks. In contrast, the peculiar 2016 eruption was clearly different. Here we report (i) the considerable delay in the 2016 eruption date, (ii) the significantly shorter SSS phase, and (iii) the brighter optical peak magnitude (with a hitherto unobserved cusp shape). Early theoretical models suggest that these three different effects can be consistently understood as caused by a lower quiescence mass accretion rate. The corresponding higher ignition mass caused a brighter peak in the free-free emission model. The less massive accretion disk experienced greater disruption, consequently delaying the re-establishment of effective accretion. Without the early refueling, the SSS phase was shortened. Observing the next few eruptions will determine whether the properties of the 2016 outburst make it a genuine outlier in the evolution of M31N 2008-12a.
The history, current situation and control measures for infectious bronchitis virus (IBV) variants are reviewed. A large number of IBV variants exist worldwide; some being unique to a particular ...area, others having a more general distribution. The possible reasons why some strains spread readily over major parts of the world, whereas other strains stay more localized are discussed. The advantages and disadvantages of strain classification by protectotyping, serotyping and genotyping are discussed in relation to in vivo protection. The different vaccination strategies are also considered.
Clinical evidence indicates that positive allosteric modulators (PAMs) of GABA
receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABA
receptor ...PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABA
receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzofimidazo1,5-a1,4diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABA
receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED
of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABA
receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABA
receptor PAMs offer an additional inroad into the management of pain.
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