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At the eastern boundary of the south Taupo Rift, the NE-striking, rift-bounding Rangipo and the ENE-striking Wahianoa active normal faults intersect. We investigate their intersection at the Upper Waikato Stream to understand the kinematics of a rift termination in an active volcanic area. The Upper Waikato Stream Fault is a previously unrecognised seismogenic source also at the eastern boundary, capable of producing aMW6.5 and up toMW7.1 earthquake if it ruptures in conjunction with the Rangipo or Wahianoa faults. We found a minimum of 12 surface-rupturing earthquakes in the last 45.16 ka on the Upper Waikato Stream Fault (mean slip-rate c. 0.5 mm/yr), and a minimum of nine surface-rupturing earthquakes in the last 133 ka on the Wahianoa Fault (mean slip-rate c. 0.2 mm/yr). Periods of highest slip-rate on these faults may coincide in time with Taupo, Ruapehu or Tongariro eruptions, but, despite their intersection, movement was not coincident across all faults. The Upper Waikato Stream Fault responded to a major Taupo Volcano eruption, the Wahianoa to a major eruptive sequence from Mt Tongariro and the Rangipo to major explosive events from Mt Ruapehu. [ABSTRACT FROM PUBLISHER]

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 km 3 . The whole eruption produced > 6.3 km 3 of uncompacted pyroclastic material on the seafloor and a caldera volume change of 6 km 3 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., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

The 15 January 2022 submarine eruption at Hunga volcano was the most explosive volcanic eruption in 140 years. It involved exceptional magma and seawater interaction throughout the entire submarine caldera collapse. The submarine volcanic jet breached the sea surface and formed a subaerial eruptive plume that transported volcanic ash, gas, sea salts and seawater up to ~ 57 km, reaching into the mesosphere. We document high concentrations of sea salts in tephra (volcanic ash) collected shortly after deposition. We also discuss the potential climatic consequences of large-scale injection of salts into the upper atmosphere during submarine eruptions. Sodium chloride in these volcanic plumes can reach extreme concentrations, and dehalogenation of chlorides and bromides poses the risk of long-term atmospheric and weather impact. Salt content in rapidly collected tephra samples may also be used as a proxy to estimate the water:magma ratio during eruption, with implications for quantification of fragmentation efficiency in submarine breaching events. The balance between salt loading into the atmosphere versus deposition in ash aggregates is a key factor in understanding the atmospheric and climatic consequences of submarine eruptions., (© 2023. Springer Nature Limited.)

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.

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., Competing Interests: Conflict of InterestThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s) 2022.)

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNγ and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo., Competing Interests: RG, PS, LP, AH, KL, FO, SC, AO, BA, LE, TC, JP, DC, RK, AH, NM, AM, LB, HS, AB, CO, SK No competing interests declared, GW is an employee of Apeiron Biologics. Apeiron holds a patent on the use of ACE2 for the treatment of lung, heart, or kidney injury and is currently testing soluble ACE2 for treatment in COVID-19 patients, JP declares a conflict of interest as a founder and shareholder of Apeiron Biologics. Apeiron holds a patent on the use of ACE2 for the treatment of lung, heart, or kidney injury and is currently testing soluble ACE2 for treatment in COVID-19 patients.(patent #WO2021191436A1), (© 2022, Gawish et al.)

Sudden steam-driven eruptions strike without warning and are a leading cause of fatalities at touristic volcanoes. Recent deaths following the 2019 Whakaari eruption in New Zealand expose a need for accurate, short-term forecasting. However, current volcano alert systems are heuristic and too slowly updated with human input. Here, we show that a structured machine learning approach can detect eruption precursors in real-time seismic data streamed from Whakaari. We identify four-hour energy bursts that occur hours to days before most eruptions and suggest these indicate charging of the vent hydrothermal system by hot magmatic fluids. We developed a model to issue short-term alerts of elevated eruption likelihood and show that, under cross-validation testing, it could provide advanced warning of an unseen eruption in four out of five instances, including at least four hours warning for the 2019 eruption. This makes a strong case to adopt real-time forecasting models at active volcanoes.

Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a Kras G12D -driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of Kras G12D -driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout Kras G12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.

Background: Patients with 'suspected viral encephalitis' are frequently empirically treated with intravenous aciclovir. Increasing urea and creatinine are 'common', but rapidly progressive renal failure is reported to be 'very rare'., Aims: To describe the clinical course and outcome of cases of aciclovir-induced acute kidney injury (AKI) encountered by the Liaison Neurology Service at AMNCH and to highlight the importance of surveillance and urgent treatment of this iatrogenic complication., Methods: Retrospectively and prospectively collected data from the Liaison Neurology Service at AMNCH on patients who received IV aciclovir for suspected viral encephalitis and developed AKI were analysed. Aciclovir-induced AKI was defined by a consultant nephrologist in all cases as a rise in serum creatinine of > 26 μmol/L in 48 h or by ≥ 1.5 times the baseline value. Renal function, haematocrit, and fluid balance were monitored following AKI onset., Results: Data from 10 patients were analysed. Median time to AKI onset was 3.5 days (range: 1-6 days). Aciclovir was stopped or the dose adjusted. All patients recovered with IV normal saline, aiming for a urine output > 100-150 ml/h. The interval between first rise in creatinine and return to normal levels varied between 5 and 19 days., Conclusions: Liaison neurologists and general physicians need to be aware that aciclovir may cause AKI attributed to distal intra-tubular crystal nephropathy. Daily fluid balance and renal function monitoring are essential because AKI may arise even with intensive pre-hydration. Prognosis is good if identified early and actively treated.

Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas G12D in mouse lung epithelial cells markedly impairs the progression of KRas G12D -driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas G12D -driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer., (© 2017 Rao et al.; Published by Cold Spring Harbor Laboratory Press.)

Sigma-1 antagonism potentiates the antinociceptive effects of opioid drugs, so sigma-1 receptors constitute a biological brake to opioid drug-induced analgesia. The pathophysiological role of this process is unknown. We aimed to investigate whether sigma-1 antagonism reduces inflammatory pain through the disinhibition of the endogenous opioidergic system in mice. The selective sigma-1 antagonists BD-1063 and S1RA abolished mechanical and thermal hyperalgesia in mice with carrageenan-induced acute (3 h) inflammation. Sigma-1-mediated antihyperalgesia was reversed by the opioid antagonists naloxone and naloxone methiodide (a peripherally restricted naloxone analog) and by local administration at the inflamed site of monoclonal antibody 3-E7, which recognizes the pan-opioid sequence Tyr-Gly-Gly-Phe at the N terminus of most endogenous opioid peptides (EOPs). Neutrophils expressed pro-opiomelanocortin, the precursor of β-endorphin (a known EOP), and constituted the majority of the acute immune infiltrate. β-endorphin levels increased in the inflamed paw, and this increase and the antihyperalgesic effects of sigma-1 antagonism were abolished by reducing the neutrophil load with in vivo administration of an anti-Ly6G antibody. The opioid-dependent sigma-1 antihyperalgesic effects were preserved 5 d after carrageenan administration, where macrophages/monocytes were found to express pro-opiomelanocortin and to now constitute the majority of the immune infiltrate. These results suggest that immune cells harboring EOPs are needed for the antihyperalgesic effects of sigma-1 antagonism during inflammation. In conclusion, sigma-1 receptors curtail immune-driven peripheral opioid analgesia, and sigma-1 antagonism produces local opioid analgesia by enhancing the action of EOPs of immune origin, maximizing the analgesic potential of immune cells that naturally accumulate in painful inflamed areas., Competing Interests: The authors declare no conflict of interest.

Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation, we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8(+) sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large-pore ion channels to specifically block nociceptors, substantially reduced ovalbumin- or house-dust-mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce the release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4(+) and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Human genetic studies have revealed an association between GTP cyclohydrolase 1 polymorphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients. We now show that excessive BH4 is produced in mice by both axotomized sensory neurons and macrophages infiltrating damaged nerves and inflamed tissue. Constitutive BH4 overproduction in sensory neurons increases pain sensitivity, whereas blocking BH4 production only in these cells reduces nerve injury-induced hypersensitivity without affecting nociceptive pain. To minimize risk of side effects, we targeted sepiapterin reductase (SPR), whose blockade allows minimal BH4 production through the BH4 salvage pathways. Using a structure-based design, we developed a potent SPR inhibitor and show that it reduces pain hypersensitivity effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neurons and macrophages, with no development of tolerance or adverse effects. Finally, we demonstrate that sepiapterin accumulation is a sensitive biomarker for SPR inhibition in vivo., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The objective of this study is to describe the presentation and management of a rare site of cholesteatoma recurrence at the bony-cartilaginous junction after intact canal wall (ICW) mastoidectomy., Study Design: Retrospective case series, Setting: Tertiary referral center, Patients: Patients with cholesteatoma formation arising from the bony-cartilaginous (BC) junction of the external auditory canal (EAC) requiring surgical intervention were retrospectively identified across a 5-year period., Intervention(s): All patients were treated surgically to eradicate the disease and reconstruct the bony defect when possible., Main Outcome Measure(s): This observational study details the presentation, risk factors, and management of a rare site of cholesteatoma recurrence after ICW mastoidectomy., Results: After ICW mastoidectomy, eight patients were identified with fistulae in the lateral EAC near the BC junction. Seven patients had associated iatrogenic cholesteatomas arising at this site, and one patient had a dry fistula with bony stenosis of the EAC. All patients had a history of chronic otitis media and previous surgery. Patients averaged 9 years between surgery and recidivism. Reconstruction of the bony defect was completed using hydroxyapatite reconstruction plates in four patients with 75% success, soft wall reconstruction in two patients using temporalis muscle, and canal wall down mastoidectomy in two patients who had extensive disease and exposed dura. No recurrent disease was evident during an average follow-up of 16 months. EAC reconstruction was successful in 83% of cases., Conclusion: This case series reports a novel pattern of iatrogenic cholesteatoma formation near the BC junction of the EAC that can occur years after ICW mastoidectomy. In properly selected cases, this condition can be managed with revision ICW mastoidectomy and reconstruction.

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

Tullio phenomenon refers to eye movements induced by sound.(1) This unusual examination finding may be seen in superior semicircular canal dehiscence (SSCD) syndrome.(2) This disorder is due to absent bone over the superior semicircular canal (figure). Patients complain of dizziness triggered by loud sound, aural fullness, autophony, and pulsatile tinnitus. When Tullio phenomenon exists in SSCD syndrome, the patient develops a mixed vertical-torsional nystagmus in which the slow phase rotates up and away from the affected ear (video on the Neurology® Web site at Neurology.org). This pattern of nystagmus aligns in the plane of the dehiscent semicircular canal and is due to excitation of its afferent nerves.

γδ T cells respond rapidly to keratinocyte damage, providing essential contributions to the skin wound healing process. The molecular interactions regulating their response are unknown. Here, we identify a role for interaction of plexin B2 with the CD100 receptor in epithelial repair. In vitro blocking of plexin B2 or CD100 inhibited γδ T cell activation. Furthermore, CD100 deficiency in vivo resulted in delayed repair of cutaneous wounds due to a disrupted γδ T cell response to keratinocyte damage. Ligation of CD100 in γδ T cells induced cellular rounding via signals through ERK kinase and cofilin. Defects in this rounding process were evident in the absence of CD100-mediated signals, thereby providing a mechanistic explanation for the defective wound healing in CD100-deficient animals. The discovery of immune functions for plexin B2 and CD100 provides insight into the complex cell-cell interactions between epithelial resident γδ T cells and the neighboring cells they support., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Ambrym in Vanuatu is a persistently degassing island volcano whose inhabitants harvest rainwater for their potable water needs. The findings from this study indicate that dental fluorosis is prevalent in the population due to fluoride contamination of rainwater by the volcanic plume. A dental survey was undertaken of 835 children aged 6-18 years using the Dean's Index of Fluorosis. Prevalence of dental fluorosis was found to be 96% in the target area of West Ambrym, 71% in North Ambrym, and 61% in Southeast Ambrym. This spatial distribution appears to reflect the prevailing winds and rainfall patterns on the island. Severe cases were predominantly in West Ambrym, the most arid part of the island, and the most commonly affected by the volcanic plume. Over 50 km downwind, on a portion of Malakula Island, the dental fluorosis prevalence was 85%, with 36% prevalence on Tongoa Island, an area rarely affected by volcanic emissions. Drinking water samples from West Ambrym contained fluoride levels from 0.7 to 9.5 ppm F (average 4.2 ppm F, n = 158) with 99% exceeding the recommended concentration of 1.0 ppm F. The pathway of fluoride-enriched rainwater impacting upon human health as identified in this study has not previously been recognised in the aetiology of fluorosis. This is an important consideration for populations in the vicinity of degassing volcanoes, particularly where rainwater comprises the primary potable water supply for humans or animals.

Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the α2δ family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (α2δ3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, α2δ3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in α2δ3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in α2δ3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Over 1 billion people are estimated to be overweight, placing them at risk for diabetes, cardiovascular disease, and cancer. We performed a systems-level genetic dissection of adiposity regulation using genome-wide RNAi screening in adult Drosophila. As a follow-up, the resulting approximately 500 candidate obesity genes were functionally classified using muscle-, oenocyte-, fat-body-, and neuronal-specific knockdown in vivo and revealed hedgehog signaling as the top-scoring fat-body-specific pathway. To extrapolate these findings into mammals, we generated fat-specific hedgehog-activation mutant mice. Intriguingly, these mice displayed near total loss of white, but not brown, fat compartments. Mechanistically, activation of hedgehog signaling irreversibly blocked differentiation of white adipocytes through direct, coordinate modulation of early adipogenic factors. These findings identify a role for hedgehog signaling in white/brown adipocyte determination and link in vivo RNAi-based scanning of the Drosophila genome to regulation of adipocyte cell fate in mammals.

The activation of resting T cells is crucial to most immune processes. Recognition of foreign antigen by T-cell receptors has to be correctly translated into signal transduction events necessary for the induction of an effective immune response. In this review, we discuss the essential signals, molecules, and processes necessary to achieve full T-cell activation. In addition to describing these key biological events, we also discuss how T-cell receptor signaling may be harnessed to yield new therapeutic targets for a next generation of anti-cancer drugs.

Continuous low-level basaltic volcanic activity, from Yasur Volcano in Tanna, and Marum and Benbow vents on Ambrym, occurred for as long as records have been kept in Vanuatu. The potential chronic health implications for the inhabitants of these two areas were investigated in a preliminary environmental sampling program. The focus was particularly on fluoride and other volcanic gas-derived chemical contamination in areas surrounding the volcanic centres. Little immediate contamination of the environment was evident for areas affected by volcanic ash and gas on Tanna, with water fluoride concentrations being elevated (to 0.42 mg x l(-1)) only within a lake adjacent to the active volcanic cone. Selected re-sampling in April 2001 following the long active phase of Yasur, revealed higher F levels in surface waters (to 1.05 mg x l(-1)). Analysis of cow rib bone and teeth indicated a possible long-term accumulation of F in grazing animals, which probably consume F-bearing volcanic ash and gas hydrates on the surface of plant leaves. No human impacts (including stress and respiratory problems) were noted, probably due to the constant and familiar low-level activity, plus the coarse nature of most ash ejecta. Ambrym appears to be a more F-concentrated system than Tanna, with volcanic ash containing 281 total and 36.7-43.6 soluble mg F x kg(-1) (cf. 178 total and 7.3-9.1 soluble mg F x kg(-1) on Tanna), and water levels reaching up to 2.8 mg F x l(-1) in rainwater tanks. The drinking water F levels on Ambrym are higher than WHO recommended levels, despite the being sampled during a substantial lull in eruptive activity, and signal potential for chronic dental and skeletal fluorosis.