Evaluating MODIS cloud-free snow cover datasets using massive spatial benchmark data in the Tibetan Plateau.

Accurate snow cover data is crucial for understanding climate change, managing water resources, and calibrating models. The MODIS (Moderate-resolution Imaging Spectroradiometer) and its cloud-free snow cover datasets are widely used, but they have not been systematically evaluated due to different benchmark data and evaluation parameters. Conventional methods using station observations as a ground truth suffer from underrepresentation and mismatches in temporal and spatial scales.

Structure-Guided Design of Partial Agonists at an Opioid Receptor.

The persistence of chronic pain and continuing overdose deaths from pain-relieving opioids targeting μ opioid receptor (μOR) have fueled the need for reliable long-term analgesics which use different targets and mechanisms. The δ opioid receptor (δOR) is a potential alternative target for non-addictive analgesics to alleviate chronic pain, made more attractive by its lack of respiratory depression associated with μOR agonists. However, early δOR full agonists were found to induce seizures, precluding clinical use.

A µ-opioid receptor modulator that works cooperatively with naloxone.

The µ-opioid receptor (µOR) is a well-established target for analgesia, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive.

Limitations and potential of κOR biased agonists for pain and itch management.

The concept of ligand bias is based on the premise that different agonists can elicit distinct responses by selectively activating the same receptor. These responses often determine whether an agonist has therapeutic or undesirable effects. Therefore, it would be highly advantageous to have agonists that specifically trigger the therapeutic response.

Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression.

While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (), possesses potent in vitro agonist activity.

Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.

The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance.

High spatial resolution elevation change dataset derived from ICESat-2 crossover points on the Tibetan Plateau.

Understanding elevation changes on the Tibetan Plateau is crucial to comprehend the changes in topography, landscape, climate, environmental conditions, and water resources. However, some of the current products that track elevation changes only cover specific surface types or limited areas, and others have low spatial resolution. We propose an algorithm to extract ICESat-2 crossover points dataset for the Tibetan Plateau, and form a dataset.

Ligand efficacy modulates conformational dynamics of the µ-opioid receptor.

The µ-opioid receptor (µOR) is an important target for pain management and molecular understanding of drug action on µOR will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of µOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex.

GPCR-G protein selectivity revealed by structural pharmacology.

Receptor-G protein promiscuity is frequently observed in class A G protein-coupled receptors (GPCRs). In particular, GPCRs can couple with G proteins from different families (Gαs, Gαq/11, Gαi/o, and Gα12/13) or the same family subtypes. The molecular basis underlying the selectivity/promiscuity is not fully revealed.

Docking for EP4R antagonists active against inflammatory pain.

The lipid prostaglandin E (PGE) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use.

Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor.

Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities.

Enhancing Leaf Area Index Estimation for Maize with Tower-Based Multi-Angular Spectral Observations.

The leaf area index (LAI) played a crucial role in ecological, hydrological, and climate models. The normalized difference vegetation index (NDVI) has been a widely used tool for LAI estimation. However, the NDVI quickly saturates in dense vegetation and is susceptible to soil background interference in sparse vegetation.

Molecular basis of opioid receptor signaling.

Opioids are used for pain management despite the side effects that contribute to the opioid crisis. The pursuit of non-addictive opioid analgesics remains unattained due to the unresolved intricacies of opioid actions, receptor signaling cascades, and neuronal plasticity. Advancements in structural, molecular, and computational tools illuminate the dynamic interplay between opioids and opioid receptors, as well as the molecular determinants of signaling pathways, which are potentially interlinked with pharmacological responses.

An RFI-suppressed SMOS L-band multi-angular brightness temperature dataset spanning over a decade (since 2010).

The Soil Moisture Ocean Salinity (SMOS) was the first mission providing L-band multi-angular brightness temperature (TB) at the global scale. However, radio frequency interferences (RFI) and aliasing effects degrade, when present SMOS TBs, and thus affect the retrieval of land parameters. To alleviate this, a refined SMOS multi-angular TB dataset was generated based on a two-step regression approach.

Conformational dynamics of the μ-opioid receptor determine ligand intrinsic efficacy.

The μ-opioid receptor (μOR) is an important target for pain management and the molecular understanding of drug action will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance (DEER) and single-molecule fluorescence resonance energy transfer (smFRET), how ligand-specific conformational changes of the μOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several cytoplasmic receptor conformations interconverting on different timescales, including a pre-activated receptor conformation which is capable of G protein binding, and a fully activated conformation which dramatically lowers GDP affinity within the ternary complex.

Ligand and G-protein selectivity in the κ-opioid receptor.

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects. The initiation of KOR signalling requires the G-family proteins including the conventional (G, G, G, G and G) and nonconventional (G and G) subtypes.

Molecular mechanism of biased signaling at the kappa opioid receptor.

The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As for most G protein-coupled receptors (GPCRs), however, the molecular mechanisms of ligand-specific signaling at KOR have remained unclear. To better understand the molecular determinants of KOR signaling bias, we apply structure determination, atomic-level molecular dynamics (MD) simulations, and functional assays.

Structure-based design of bitopic ligands for the µ-opioid receptor.

Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site found in µOR and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp residue in the Na site.

Insights into distinct signaling profiles of the µOR activated by diverse agonists.

Drugs targeting the μ-opioid receptor (μOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two μOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and β-arrestin recruitment.

Structure determination of inactive-state GPCRs with a universal nanobody.

Cryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. Despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained inaccessible for cryo-EM because their small size and membrane-embedded nature impedes projection alignment for high-resolution map reconstructions. Here we demonstrate that the same single-chain camelid antibody (nanobody) recognizing a grafted intracellular loop can be used to obtain cryo-EM structures of inactive-state GPCRs at resolutions comparable or better than those obtained by X-ray crystallography.

Bespoke library docking for 5-HT receptor agonists with antidepressant activity.

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors.

Satellite-Enabled Internet of Remote Things Network Transmits Field Data from the Most Remote Areas of the Tibetan Plateau.

In this article, we employed a satellite-enabled Internet of Remote Things (IoRT) network as a promising solution to retrieve data in the most remote areas of interest, where public networks are absent. This article presents a system network based on the satellite-enabled IoRT, a new paradigm that defines a network where each environmental monitoring device can autonomously establish a network with a remote data center. The Xingyun satellite constellation was employed for data retrieval on the Tibetan Plateau (TP).