Valence and State-Dependent Population Coding in Dopaminergic Neurons in the Fly Mushroom Body

Neuromodulation permits flexibility of synapses, neural circuits, and ultimately behavior. One neuromodulator, dopamine, has been studied extensively in its role as a reward signal during learning and memory across animal species. Newer evidence suggests that dopaminergic neurons (DANs) can modulate sensory perception acutely, thereby allowing an animal to adapt its behavior and decision making to its internal and behavioral state. In addition, some data indicate that DANs are not homogeneous but rather convey different types of information as a heterogeneous population. We have investigated DAN population activity and how it could encode relevant information about sensory stimuli and state by taking advantage of the confined anatomy of DANs innervating the mushroom body (MB) of the fly Drosophila melanogaster. Using in vivo calcium imaging and a custom 3D image registration method, we found that the activity of the population of MB DANs encodes innate valence information of an odor or taste as well as the physiological state of the animal. Furthermore, DAN population activity is strongly correlated with movement, consistent with a role of dopamine in conveying behavioral state to the MB. Altogether, our data and analysis suggest that DAN population activities encode innate odor and taste valence, movement, and physiological state in a MB-compartment-specific manner. We propose that dopamine shapes innate perception through combinatorial population coding of sensory valence, physiological, and behavioral context

A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry Drosophila

In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive

Imaging Inter-Edge State Scattering Centers in the Quantum Hall Regime

We use an atomic force microscope tip as a local gate to study the scattering between edge channels in a 2D electron gas in the quantum Hall regime. The scattering is dominated by individual, microscopic scattering centers, which we directly image here for the first time. The tip voltage dependence of the scattering indicates that tunneling occurs through weak links and localized states.Comment: 4 pages, 5 figure

Enabling clinical development of an HIV attachment inhibitor through innovative pharmaceutical development: novel extended-release delivery of prodrug

Background: HIV-1 attachment inhibitors are a new class of viral entry inhibitors which target viral gp120 preventing attachment of virus to its host cell receptor CD4. This class presents major challenges for development based upon low solubility and short half-lives. For progression into clinical studies, requirements include reliable and reproducible absorption from a tolerable and convenient oral dosing regimen. Methods: A series of highly soluble prodrugs were designed to overcome the poor absorption caused by the low solubility of the active compounds. A regional absorption study was conducted to assess the uptake of active throughout the gastro-intestinal tract following oral prodrug delivery. An extended-release (ER) strategy was subsequently devised to optimise tolerability, decrease peak to trough ratios and reduce frequency of dosing. In silico absorption modelling was used to verify feasibility and drive in vitro testing leading to dosage form development and selection. The performance of the ER dosage form was verified in vivo prior to use in clinical studies. Results: Phosphonooxymethyl prodrugs with aqueous solubilities in excess of 250 mg/mL were synthesised and shown to be readily converted to parent compound via alkaline phosphatase in vitro. Results of regional absorption studies for the selected compound, BMS-663068, confirmed the rapid absorption but short half-life of active following oral administration of prodrug. Delivery to specific regions throughout the GI tract showed absorption of active to be subject to regional variation with an extent of colonic absorption of approximately 40% of intestinal absorption. Incorporation of this data into an in silico model guided development of an ER tablet which releases prodrug over 24 hours and achieves the required exposure, pharmacokinetics and reproducibility in vivo. Conclusions: The novel approach of combining prodrug synthesis and ER formulation has enabled clinical evaluation of a promising new class of therapeutic entity into Phase 2b studies

Earth System Model Evaluation Tool (ESMValTool) v2.0 - An extended set of large-scale diagnostics for quasi-operational and comprehensive evaluation of Earth system models in CMIP

The Earth System Model Evaluation Tool (ESMValTool) is a community diagnostics and performance metrics tool designed to improve comprehensive and routine evaluation of Earth system models (ESMs) participating in the Coupled Model Intercomparison Project (CMIP). It has undergone rapid development since the first release in 2016 and is now a well-tested tool that provides end-to-end provenance tracking to ensure reproducibility. It consists of (1) an easy-to-install, well-documented Python package providing the core functionalities (ESMValCore) that performs common preprocessing operations and (2) a diagnostic part that includes tailored diagnostics and performance metrics for specific scientific applications. Here we describe large-scale diagnostics of the second major release of the tool that supports the evaluation of ESMs participating in CMIP Phase 6 (CMIP6). ESMValTool v2.0 includes a large collection of diagnostics and performance metrics for atmospheric, oceanic, and terrestrial variables for the mean state, trends, and variability. ESMValTool v2.0 also successfully reproduces figures from the evaluation and projections chapters of the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5) and incorporates updates from targeted analysis packages, such as the NCAR Climate Variability Diagnostics Package for the evaluation of modes of variability, the Thermodynamic Diagnostic Tool (TheDiaTo) to evaluate the energetics of the climate system, as well as parts of AutoAssess that contains a mix of top-down performance metrics. The tool has been fully integrated into the Earth System Grid Federation (ESGF) infrastructure at the Deutsches Klimarechenzentrum (DKRZ) to provide evaluation results from CMIP6 model simulations shortly after the output is published to the CMIP archive. A result browser has been implemented that enables advanced monitoring of the evaluation results by a broad user community at much faster timescales than what was possible in CMIP5

Selenium and vitamin E for prevention of non–muscle-invasive bladder cancer recurrence and progression

Importance Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non–muscle-invasive bladder cancer. Objective To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC. Design, Setting, and Participants This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required. Interventions Oral selenium (200 μg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo. Main Outcome and Measures Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022). Results The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment. Conclusions and Relevance In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required

Indicators of Global Climate Change 2022: annual update of large-scale indicators of the state of the climate system and human influence

Intergovernmental Panel on Climate Change (IPCC) assessments are the trusted source of scientific evidence for climate negotiations taking place under the United Nations Framework Convention on Climate Change (UNFCCC), including the first global stocktake under the Paris Agreement that will conclude at COP28 in December 2023. Evidence-based decision-making needs to be informed by up-to-date and timely information on key indicators of the state of the climate system and of the human influence on the global climate system. However, successive IPCC reports are published at intervals of 5–10 years, creating potential for an information gap between report cycles. We follow methods as close as possible to those used in the IPCC Sixth Assessment Report (AR6) Working Group One (WGI) report. We compile monitoring datasets to produce estimates for key climate indicators related to forcing of the climate system: emissions of greenhouse gases and short-lived climate forcers, greenhouse gas concentrations, radiative forcing, surface temperature changes, the Earth's energy imbalance, warming attributed to human activities, the remaining carbon budget, and estimates of global temperature extremes. The purpose of this effort, grounded in an open data, open science approach, is to make annually updated reliable global climate indicators available in the public domain (https://doi.org/10.5281/zenodo.8000192, Smith et al., 2023a). As they are traceable to IPCC report methods, they can be trusted by all parties involved in UNFCCC negotiations and help convey wider understanding of the latest knowledge of the climate system and its direction of travel. The indicators show that human-induced warming reached 1.14 [0.9 to 1.4] ∘C averaged over the 2013–2022 decade and 1.26 [1.0 to 1.6] ∘C in 2022. Over the 2013–2022 period, human-induced warming has been increasing at an unprecedented rate of over 0.2 ∘C per decade. This high rate of warming is caused by a combination of greenhouse gas emissions being at an all-time high of 54 ± 5.3 GtCO₂e over the last decade, as well as reductions in the strength of aerosol cooling. Despite this, there is evidence that increases in greenhouse gas emissions have slowed, and depending on societal choices, a continued series of these annual updates over the critical 2020s decade could track a change of direction for human influence on climate

Indicators of Global Climate Change 2023: annual update of key indicators of the state of the climate system and human influence

Intergovernmental Panel on Climate Change (IPCC) assessments are the trusted source of scientific evidence for climate negotiations taking place under the United Nations Framework Convention on Climate Change (UNFCCC). Evidence-based decision-making needs to be informed by up-to-date and timely information on key indicators of the state of the climate system and of the human influence on the global climate system. However, successive IPCC reports are published at intervals of 5–10 years, creating potential for an information gap between report cycles. We follow methods as close as possible to those used in the IPCC Sixth Assessment Report (AR6) Working Group One (WGI) report. We compile monitoring datasets to produce estimates for key climate indicators related to forcing of the climate system: emissions of greenhouse gases and short-lived climate forcers, greenhouse gas concentrations, radiative forcing, the Earth's energy imbalance, surface temperature changes, warming attributed to human activities, the remaining carbon budget, and estimates of global temperature extremes. The purpose of this effort, grounded in an open data, open science approach, is to make annually updated reliable global climate indicators available in the public domain (https://doi.org/10.5281/zenodo.11064126, Smith et al., 2024a). As they are traceable to IPCC report methods, they can be trusted by all parties involved in UNFCCC negotiations and help convey wider understanding of the latest knowledge of the climate system and its direction of travel. The indicators show that, for the 2014–2023 decade average, observed warming was 1.19 [1.06 to 1.30] °C, of which 1.19 [1.0 to 1.4] °C was human-induced. For the single year average, human-induced warming reached 1.31 [1.1 to 1.7] °C in 2023 relative to 1850–1900. This is below the 2023 observed record of 1.43 [1.32 to 1.53] °C, indicating a substantial contribution of internal variability in the 2023 record. Human-induced warming has been increasing at rate that is unprecedented in the instrumental record, reaching 0.26 [0.2–0.4] °C per decade over 2014–2023. This high rate of warming is caused by a combination of greenhouse gas emissions being at an all-time high of 54 ± 5.4 GtCO2e per year over the last decade, as well as reductions in the strength of aerosol cooling. Despite this, there is evidence that the rate of increase in CO2 emissions over the last decade has slowed compared to the 2000s, and depending on societal choices, a continued series of these annual updates over the critical 2020s decade could track a change of direction for some of the indicators presented here

Indicators of Global Climate Change 2023: annual update of key indicators of the state of the climate system and human influence

Intergovernmental Panel on Climate Change (IPCC) assessments are the trusted source of scientific evidence for climate negotiations taking place under the United Nations Framework Convention on Climate Change (UNFCCC). Evidence-based decision-making needs to be informed by up-to-date and timely information on key indicators of the state of the climate system and of the human influence on the global climate system. However, successive IPCC reports are published at intervals of 5–10 years, creating potential for an information gap between report cycles. We follow methods as close as possible to those used in the IPCC Sixth Assessment Report (AR6) Working Group One (WGI) report. We compile monitoring datasets to produce estimates for key climate indicators related to forcing of the climate system: emissions of greenhouse gases and short-lived climate forcers, greenhouse gas concentrations, radiative forcing, the Earth's energy imbalance, surface temperature changes, warming attributed to human activities, the remaining carbon budget, and estimates of global temperature extremes. The purpose of this effort, grounded in an open-data, open-science approach, is to make annually updated reliable global climate indicators available in the public domain (https://doi.org/10.5281/zenodo.11388387, Smith et al., 2024a). As they are traceable to IPCC report methods, they can be trusted by all parties involved in UNFCCC negotiations and help convey wider understanding of the latest knowledge of the climate system and its direction of travel. The indicators show that, for the 2014–2023 decade average, observed warming was 1.19 [1.06 to 1.30] °C, of which 1.19 [1.0 to 1.4] °C was human-induced. For the single-year average, human-induced warming reached 1.31 [1.1 to 1.7] °C in 2023 relative to 1850–1900. The best estimate is below the 2023-observed warming record of 1.43 [1.32 to 1.53] °C, indicating a substantial contribution of internal variability in the 2023 record. Human-induced warming has been increasing at a rate that is unprecedented in the instrumental record, reaching 0.26 [0.2–0.4] °C per decade over 2014–2023. This high rate of warming is caused by a combination of net greenhouse gas emissions being at a persistent high of 53±5.4 Gt CO2e yr−1 over the last decade, as well as reductions in the strength of aerosol cooling. Despite this, there is evidence that the rate of increase in CO2 emissions over the last decade has slowed compared to the 2000s, and depending on societal choices, a continued series of these annual updates over the critical 2020s decade could track a change of direction for some of the indicators presented here