Airfall volume of the 15 January 2022 eruption of Hunga volcano estimated from ocean color changes.

On 15 January 2022, Hunga volcano erupted, creating an extensive and high-reaching umbrella cloud over the open ocean, hindering traditional isopach mapping and fallout volume estimation. In MODIS satellite imagery, ocean surface water was discolored around Hunga following the eruption, which we attribute to ash fallout from the umbrella cloud. By relating intensity of ocean discoloration to fall deposit thicknesses in the Kingdom of Tonga, we develop a methodology for estimating airfall volume over the open ocean. Ash thickness measurements from 41 locations are used to fit a linear relationship between ash thickness and ocean reflectance. This produces a minimum airfall volume estimate of 1.8-0.4+0.3 km3. The whole eruption produced > 6.3 km3 of uncompacted pyroclastic material on the seafloor and a caldera volume change of 6 km3 DRE. Our fall estimates are consistent with the interpretation that most of the seafloor deposits were emplaced by gravity currents rather than fall deposits. Our proposed method does not account for the largest grain sizes, so is thus a minimum estimate. However, this new ocean-discoloration method provides an airfall volume estimate consistent with other independent measures of the plume and is thus effective for rapidly estimating fallout volumes in future volcanic eruptions over oceans. Supplementary Information: The online version contains supplementary material available at 10.1007/s00445-024-01744-6.

Dysregulated BH4 metabolism facilitates immunosuppression in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive, malignant, and lethal cancers, displaying strong resistance to immunotherapy. In this issue of Cell Metabolism, a study by Liu et al. identifies tetrahydrobiopterin metabolic dysregulation as a key driver for the immunosuppressive PDAC environment in mouse and human.

Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism.

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of mechanisms responsible for this decline is limited. Glycerophosphocholine phosphodiesterase 1 (Gpcpd1) is a highly abundant muscle enzyme that hydrolyzes glycerophosphocholine (GPC). The physiological functions of Gpcpd1 remain largely unknown. Here we show, in mice, that the Gpcpd1-GPC metabolic pathway is perturbed in aged muscles. Further, muscle-specific, but not liver- or fat-specific, inactivation of Gpcpd1 resulted in severely impaired glucose metabolism. Western-type diets markedly worsened this condition. Mechanistically, Gpcpd1 muscle deficiency resulted in accumulation of GPC, causing an 'aged-like' transcriptomic signature and impaired insulin signaling in young Gpcpd1-deficient muscles. Finally, we report that the muscle GPC levels are markedly altered in both aged humans and patients with type 2 diabetes, displaying a high positive correlation between GPC levels and chronological age. Our findings reveal that the muscle GPCPD1-GPC metabolic pathway has an important role in the regulation of glucose homeostasis and that it is impaired during aging, which may contribute to glucose intolerance in aging.

The magmatic system under Hunga volcano before and after the 15 January 2022 eruption.

One of the largest explosive eruptions instrumentally recorded occurred at Hunga volcano on 15 January 2022. The magma plumbing system under this volcano is unexplored because of inherent difficulties caused by its submarine setting. We use marine gravity data derived from satellite altimetry combined with multibeam bathymetry to model the architecture and dynamics of the magmatic system before and after the January 2022 eruption. We provide geophysical evidence for substantial high-melt content magma accumulation in three reservoirs at shallow depths (2 to 10 kilometers) under the volcano. We estimate that less than ~30% of the existing magma was evacuated by the main eruptive phases, enough to trigger caldera collapse. The eruption and caldera collapse reorganized magma storage, resulting in an increased connectivity between the two spatially distinct reservoirs. Modeling global satellite altimetry-derived gravity data at undersea volcanoes offer a promising reconnaissance tool to probe the subsurface for eruptible magma.

Fast and destructive density currents created by ocean-entering volcanic eruptions.

Volcanic eruptions on land create hot and fast pyroclastic density currents, triggering tsunamis or surges that travel over water where they reach the ocean. However, no field study has documented what happens when large volumes of erupted volcanic material are instead delivered directly into the ocean. We show how the rapid emplacement of large volumes of erupted material onto steep submerged slopes triggered extremely fast (122 kilometers per hour) and long-runout (>100 kilometers) seafloor currents. These density currents were faster than those triggered by earthquakes, floods, or storms, and they broke seafloor cables, cutting off a nation from the rest of the world. The deep scours excavated by these currents are similar to those around many submerged volcanoes, providing evidence of large eruptions at other sites worldwide.

Mast cell-derived BH4 is a critical mediator of postoperative pain.

Postoperative pain affects most patients after major surgery and can transition to chronic pain. Here, we discovered that postoperative pain hypersensitivity correlated with markedly increased local levels of the metabolite BH4. Gene transcription and reporter mouse analyses after skin injury identified neutrophils, macrophages and mast cells as primary postoperative sources of GTP cyclohydrolase-1 (Gch1) expression, the rate-limiting enzyme in BH4 production. While specific Gch1 deficiency in neutrophils or macrophages had no effect, mice deficient in mast cells or mast cell-specific Gch1 showed drastically decreased postoperative pain after surgery. Skin injury induced the nociceptive neuropeptide substance P, which directly triggers the release of BH4-dependent serotonin in mouse and human mast cells. Substance P receptor blockade substantially ameliorated postoperative pain. Our findings underline the unique position of mast cells at the neuro-immune interface and highlight substance P-driven mast cell BH4 production as promising therapeutic targets for the treatment of postoperative pain.

Implementation of a Drug Screening Platform to TargetGch1 Expression in Injured Mouse Dorsal Root Ganglion Neurons.

Management of neuropathic pain is notoriously difficult; current analgesics, including anti-inflammatory- and opioid-based medications, are generally ineffective and can pose serious side effects. There is a need to uncover non-addictive and safe analgesics to combat neuropathic pain. Here, we describe the setup of a phenotypic screen whereby the expression of an algesic gene,Gch1, is targeted. GCH1 is the rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin (BH4), a metabolite linked to neuropathic pain in both animal models and in human chronic pain sufferers.Gch1is induced in sensory neurons after nerve injury and its upregulation is responsible for increased BH4 levels. GCH1 protein has proven to be a difficult enzyme to pharmacologically target with small molecule inhibition. Thus, by establishing a platform to monitor and target inducedGch1 expression in individual injured dorsal root ganglion (DRG) neurons in vitro, we can screen for compounds that regulate its expression levels. This approach also allows us to gain valuable biological insights into the pathways and signals regulating GCH1 and BH4 levels upon nerve injury. This protocol is compatible with any transgenic reporter system in which the expression of an algesic gene (or multiple genes) can be monitored fluorescently. Such an approach can be scaled up for high-throughput compound screening and is amenable to transgenic mice as well as human stem cell-derived sensory neurons. Graphical overview.

Peripheralized sepiapterin reductase inhibition as a safe analgesic therapy.

The development of novel analgesics for chronic pain in the last 2 decades has proven virtually intractable, typically failing due to lack of efficacy and dose-limiting side effects. Identified through unbiased gene expression profiling experiments in rats and confirmed by human genome-wide association studies, the role of excessive tetrahydrobiopterin (BH4) in chronic pain has been validated by numerous clinical and preclinical studies. BH4 is an essential cofactor for aromatic amino acid hydroxylases, nitric oxide synthases, and alkylglycerol monooxygenase so a lack of BH4 leads to a range of symptoms in the periphery and central nervous system (CNS). An ideal therapeutic goal therefore would be to block excessive BH4 production, while preventing potential BH4 rundown. In this review, we make the case that sepiapterin reductase (SPR) inhibition restricted to the periphery (i.e., excluded from the spinal cord and brain), is an efficacious and safe target to alleviate chronic pain. First, we describe how different cell types that engage in BH4 overproduction and contribute to pain hypersensitivity, are themselves restricted to peripheral tissues and show their blockade is sufficient to alleviate pain. We discuss the likely safety profile of peripherally restricted SPR inhibition based on human genetic data, the biochemical alternate routes of BH4 production in various tissues and species, and the potential pitfalls to predictive translation when using rodents. Finally, we propose and discuss possible formulation and molecular strategies to achieve peripherally restricted, potent SPR inhibition to treat not only chronic pain but other conditions where excessive BH4 has been demonstrated to be pathological.

Crucial neuroprotective roles of the metabolite BH4 in dopaminergic neurons.

Dopa-responsive dystonia (DRD) and Parkinson's disease (PD) are movement disorders caused by the dysfunction of nigrostriatal dopaminergic neurons. Identifying druggable pathways and biomarkers for guiding therapies is crucial due to the debilitating nature of these disorders. Recent genetic studies have identified variants of GTP cyclohydrolase-1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, as causative for these movement disorders. Here, we show that genetic and pharmacological inhibition of BH4 synthesis in mice and human midbrain-like organoids accurately recapitulates motor, behavioral and biochemical characteristics of these human diseases, with severity of the phenotype correlating with extent of BH4 deficiency. We also show that BH4 deficiency increases sensitivities to several PD-related stressors in mice and PD human cells, resulting in worse behavioral and physiological outcomes. Conversely, genetic and pharmacological augmentation of BH4 protects mice from genetically- and chemically induced PD-related stressors. Importantly, increasing BH4 levels also protects primary cells from PD-affected individuals and human midbrain-like organoids (hMLOs) from these stressors. Mechanistically, BH4 not only serves as an essential cofactor for dopamine synthesis, but also independently regulates tyrosine hydroxylase levels, protects against ferroptosis, scavenges mitochondrial ROS, maintains neuronal excitability and promotes mitochondrial ATP production, thereby enhancing mitochondrial fitness and cellular respiration in multiple preclinical PD animal models, human dopaminergic midbrain-like organoids and primary cells from PD-affected individuals. Our findings pinpoint the BH4 pathway as a key metabolic program at the intersection of multiple protective mechanisms for the health and function of midbrain dopaminergic neurons, identifying it as a potential therapeutic target for PD.

Pseudorabies virus hijacks DDX3X, initiating an addictive "mad itch" and immune suppression, to facilitate viral spread.

Infections with defined Herpesviruses, such as Pseudorabies virus (PRV) and Varicella zoster virus (VZV) can cause neuropathic itch, referred to as "mad itch" in multiple species. The underlying mechanisms involved in neuropathic "mad itch" are poorly understood. Here, we show that PRV infections hijack the RNA helicase DDX3X in sensory neurons to facilitate anterograde transport of the virus along axons. PRV induces re-localization of DDX3X from the cell body to the axons which ultimately leads to death of the infected sensory neurons. Inducible genetic ablation of Ddx3x in sensory neurons results in neuronal death and "mad itch" in mice. This neuropathic "mad itch" is propagated through activation of the opioid system making the animals "addicted to itch". Moreover, we show that PRV co-opts and diverts T cell development in the thymus via a sensory neuron-IL-6-hypothalamus-corticosterone stress pathway. Our data reveal how PRV, through regulation of DDX3X in sensory neurons, travels along axons and triggers neuropathic itch and immune deviations to initiate pathophysiological programs which facilitate its spread to enhance infectivity.

The 2022 Hunga-Tonga megatsunami: Near-field simulation of a once-in-a-century event.

The Hunga Tonga-Hunga Ha'apai (HTHH) volcanic eruption in January 2022 generated catastrophic tsunami and contends for the largest natural explosion in more than a century. The main island, Tongatapu, suffered waves up to 17 m, and Tofua Island suffered waves up to 45 m, comfortably placing HTHH in the "megatsunami" league. We present a tsunami simulation of the Tongan Archipelago calibrated by field observations, drone, and satellite data. Our simulation emphasizes how the complex shallow bathymetry of the area acted as a low-velocity wave trap, capturing tsunami for more than 1 hour. Despite its size and long duration, few lives were lost. Simulation suggests that HTHH's location relative to urban centers saved Tonga from a worse outcome. Whereas 2022 seems to have been a lucky escape, other oceanic volcanoes have the capacity to spawn future tsunami at HTHH scale. Our simulation amplifies the state of understanding of volcanic explosion tsunami and provides a framework for assessment of future hazards.

PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing.

Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle diseases, represents an important goal in improving human health. Here, we show that the lipid synthesis enzyme phosphatidylethanolamine cytidyltransferase (PCYT2/ECT) is critical to muscle health. Human deficiency in PCYT2 causes a severe disease with failure to thrive and progressive weakness. pcyt2-mutant zebrafish and muscle-specific Pcyt2-knockout mice recapitulate the participant phenotypes, with failure to thrive, progressive muscle weakness and accelerated ageing. Mechanistically, muscle Pcyt2 deficiency affects cellular bioenergetics and membrane lipid bilayer structure and stability. PCYT2 activity declines in ageing muscles of mice and humans, and adeno-associated virus-based delivery of PCYT2 ameliorates muscle weakness in Pcyt2-knockout and old mice, offering a therapy for individuals with a rare disease and muscle ageing. Thus, PCYT2 plays a fundamental and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2-synthesized lipids to severe muscle dystrophy and ageing.

Tsunami Runup and Inundation in Tonga from the January 2022 Eruption of Hunga Volcano.

On January 15th, 2022, at approximately 4:47 pm local time (0347 UTC), several weeks of heightened activity at the Hunga volcano 65 km northwest of Tongatapu, culminated in an 11-h long violent eruption which generated a significant near-field tsunami. Although the Kingdom of Tonga lies astride a large and tsunamigenic subduction zone, it has relatively few records of significant tsunami. Assessment activities took place both remotely and locally. Between March and June 2022, a field team quantified tsunami runup and inundation on the main populated islands Tongatapu and Eua, along with several smaller islands to the north, including the Ha'apai Group. Peak tsunami heights were ~ 19 m in western Tongatapu, ~ 20 m on south-eastern Nomuka Iki island and ~ 20 m on southern Tofua, located ~ 65 km S and E and 90 km N from Hunga volcano, respectively. In western Tongatapu, the largest tsunami surge overtopped a 13-15 m-high ridge along the narrow Hihifo peninsula in several locations. Analysis of tide gauge records from Nukualofa (which lag western Tongatapu arrivals by ~ 18-20 min), suggest that initial tsunami surges were generated prior to the largest volcanic explosions at ~ 0415 UTC. Further waves were generated by ~ 0426 UTC explosions that were accompanied by air-pressure waves. Efforts to model this event are unable to reproduce the timing of the large tsunami wave that toppled a weather station and communication tower on a 13 m-high ridge on western Tongatapu after 0500 UTC. Smaller tsunami waves continued until ~ 0900, coincident with a second energetic phase of eruption, and noted by eyewitnesses on Tungua and Mango Islands. Despite an extreme level of destruction caused by this tsunami, the death toll was extraordinarily low (4 victims). Interviews with witnesses and analysis of videos posted on social media suggest that this can be attributed to the arrival of smaller 'pre tsunami' waves that prompted evacuations, heightened tsunami awareness due to tsunami activity and advisories on the day before, the absence of tourists and ongoing tsunami education efforts since the 2009 Niuatoputapu, Tonga tsunami. This event highlights an unexpectedly great hazard from volcanic tsunami worldwide, which in Tonga's case overprints an already extreme level of tectonic tsunami hazard. Education and outreach efforts should continue to emphasize the 'natural warning signs' of strong ground shaking and unusual wave and current action, and the importance of self-evacuation from coastal areas of low-lying islands. The stories of survival from this event can be used as global best practice for personal survival strategies from future tsunami. Supplementary Information: The online version contains supplementary material available at 10.1007/s00024-022-03215-5.

The HUSH complex controls brain architecture and protocadherin fidelity.

The HUSH (human silencing hub) complex contains the H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and recruits the histone methyltransferase SETDB1 as well as Microrchidia CW-type zinc finger protein 2 (MORC2). Functional and mechanistic studies of the HUSH complex have hitherto been centered around SETDB1 while the in vivo functions of MPP8 and MORC2 remain elusive. Here, we show that genetic inactivation of Mphosph8 or Morc2a in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, in both mouse brains and human cerebral organoids, MPP8 and MORC2 suppress the repetitive-like protocadherin gene cluster in an H3K9me3-dependent manner. Our data identify MPP8 and MORC2, previously linked to silencing of repetitive elements via the HUSH complex, as key epigenetic regulators of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.

Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models.

Type 2 diabetes mellitus is one of the most prevalent metabolic diseases presenting with systemic pathologies, including reproductive disorders in male diabetic patients. However, the molecular mechanisms that contributing to spermatogenesis dysfunction in diabetic patients have not yet been fully elucidated. Here, we perform STRT-seq to examine the transcriptome of diabetic patients' testes at single-cell resolution including all major cell types of the testis. Intriguingly, whereas spermatogenesis appears largely preserved, the gene expression profiles of Sertoli cells and the blood-testis barrier (BTB) structure are dramatically impaired. Among these deregulate pathways, the Apelin (APLN) peptide/Apelin-receptor (APJ) axis is hyper-activated in diabetic patients' testes. Mechanistically, APLN is produced locally by Sertoli cells upon high glucose treatment, which subsequently suppress the production of carnitine and repress the expression of cell adhesion genes in Sertoli cells. Together, these effects culminate in BTB structural dysfunction. Finally, using the small molecule APLN receptor antagonist, ML221, we show that blocking APLN/APJ significantly ameliorate the BTB damage and, importantly, improve functional spermatogenesis in diabetic db/db mice. We also translate and validate these findings in cultured human testes. Our findings identify the APLN/APJ axis as a promising therapeutic target to improve reproduction capacity in male diabetic patients.

Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer.

Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.

Neuropeptide Neuromedin B does not alter body weight and glucose homeostasis nor does it act as an insulin-releasing peptide.

Neuromedin B (NMB) is a member of the neuromedin family of neuropeptides with a high level of region-specific expression in the brain. Several GWAS studies on non-obese and obese patients suggested that polymorphisms in NMB predispose to obesity by affecting appetite control and feeding preference. Furthermore, several studies proposed that NMB can act as an insulin releasing peptide. Since the functional study has never been done, the in vivo role of NMB as modulator of weight gain or glucose metabolism remains unclear. Here, we generated Nmb conditional mice and nervous system deficient NmB mice. We then performed olfactory and food preference analysis, as well as metabolic analysis under standard and high fat diet. Additionally, in direct islet studies we evaluated the role of NMB on basal and glucose-stimulated insulin secretion in mouse and humans.

Seismic precursors to the Whakaari 2019 phreatic eruption are transferable to other eruptions and volcanoes.

Volcanic eruptions that occur without warning can be deadly in touristic and populated areas. Even with real-time geophysical monitoring, forecasting sudden eruptions is difficult, because their precursors are hard to recognize and can vary between volcanoes. Here, we describe a general seismic precursor signal for gas-driven eruptions, identified through correlation analysis of 18 well-recorded eruptions in New Zealand, Alaska, and Kamchatka. The precursor manifests in the displacement seismic amplitude ratio between medium (4.5-8 Hz) and high (8-16 Hz) frequency tremor bands, exhibiting a characteristic rise in the days prior to eruptions. We interpret this as formation of a hydrothermal seal that enables rapid pressurization of shallow groundwater. Applying this model to the 2019 eruption at Whakaari (New Zealand), we describe pressurization of the system in the week before the eruption, and cascading seal failure in the 16 h prior to the explosion. Real-time monitoring for this precursor may improve short-term eruption warning systems at certain volcanoes.