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Campi Flegrei is a densely populated volcanic area in Italy. Its inner caldera periodically experiences uplift and subsidence, known as bradyseism, also accompanied by seismic activity. In the last decade, with uplift rates up to 2 cm/month, about nine-thousand earthquakes were recorded. Upon request of the local administration, the most updated data were collected and analyzed to evaluate the risk management strategy consisting of structural retrofitting according to the building code. Here it is shown that the reference moment magnitude is in the range 4.4, 5.1 , based on fault mapping, geomorphological inference, earthquake relocation, stress-drop analysis, and ground motion modelling. Earthquake forecasting enabled computing the exceedance probabilities of these magnitudes. Earthquake engineering showed that the minimum magnitudes expected to cause exceedance of design ground motion, are larger than the reference magnitudes. Finally, the risk reduction implied by the safety levels of new constructions was assessed for reinforced concrete buildings. The study investigates earthquake magnitude scenarios and seismic risk reduction policies for Campi Flegrei, a densely populated volcanic area in southern Italy, which is undergoing a bradyseism-related crisis in 2024. [ABSTRACT FROM AUTHOR]

Consumer trends towards nutrient-rich foods are contributing to global increasing demand for tropical fruit. However, commercial cultivars in the breeding pipeline that are tailored to meet market demand are at risk of possessing reduced fruit flavour qualities. This stems from recurrent prioritised selection for superior agronomic traits and not fruit flavour, which may in turn reduce consumer satisfaction. There is realisation that fruit quality traits, inclusive of flavour, must be equally selected for; but currently, there are limited tools and resources available to select for fruit flavour traits, particularly in tropical fruit species. Although sugars, acids, and volatile organic compounds are known to define fruit flavour, the specific combinations of these, that result in defined consumer preferences, remain unknown for many tropical fruit species. To define and include fruit flavour preferences in selective breeding, it is vital to determine the metabolites that underpin them. Then, objective quantitative analysis may be implemented instead of solely relying on human sensory panels. This may lead to the development of selective genetic markers through integrated omics approaches that target biosynthetic pathways of flavour active compounds. In this review, we explore progress in the development of tools to be able to strategically define and select for consumer-preferred flavour profiles in the breeding of new cultivars of tropical fruit species. [ABSTRACT FROM AUTHOR]

Human brain organoids (HBOs) are novel entities that may exhibit unique forms of cognitive potential. What moral status, if any, do they have? Several authors propose that consciousness may hold the answer to this question. Others identify various kinds of consciousness as crucially important for moral consideration, while leaving open the challenge of determining whether HBOs have them. This paper aims to make progress on these questions in two ways. First, it proposes a framework for thinking about the moral status of entities other than paradigmatic persons. This framework identifies four qualities that ground moral status: evaluative stance, self-directedness, agency, and other-directedness. Second, we speculate on ways in which these qualities are relevant to dimensions of conscious experience that have been, or could be, identified in nonhuman animals. We further explore how these approaches could be adapted for use in HBOs, and argue that such studies, or something similar to them, will have to be performed if we wish to have empirical indications that HBOs have consciousness of a morally significant kind. We end by proposing that in our current scientific and epistemic situation, it is too soon to attribute any moral status to HBOs, but that this might change in the future. [ABSTRACT FROM AUTHOR]

Modifying behaviors, such as alcohol consumption, is difficult. Creating psychological distance between unhealthy triggers and one's present experience can encourage change. Using two multisite, randomized experiments, we examine whether theory-driven strategies to create psychological distance—mindfulness and perspective-taking—can change drinking behaviors among young adults without alcohol dependence via a 28-day smartphone intervention (Study 1, N = 108 participants, 5492 observations; Study 2, N = 218 participants, 9994 observations). Study 2 presents a close replication with a fully remote delivery during the COVID-19 pandemic. During weeks when they received twice-a-day intervention reminders, individuals in the distancing interventions reported drinking less frequently than on control weeks—directionally in Study 1, and significantly in Study 2. Intervention reminders reduced drinking frequency but did not impact amount. We find that smartphone-based mindfulness and perspective-taking interventions, aimed to create psychological distance, can change behavior. This approach requires repeated reminders, which can be delivered via smartphones. [ABSTRACT FROM AUTHOR]

Background: Regional variations in healthcare outcomes in England have been historically reported. This study analyses the variations in long term colorectal cancer survival across different regions in England. Methods: Relative survival analysis of population data obtained from all cancer registries in England between 2010 and 2014. Results: Totally, 167,501 patients were studied. Regions in the southern England had better outcomes with Southwest and Oxford registries having 63.5 and 62.7% 5 year relative survival. In contrast, Trent and Northwest cancer registries had 58.1% relative survival (p < 0.01). The regions in the north fared below the national average. The survival outcomes reflected socio-economic deprivation status, the best performing regions in the south having low levels of deprivation (5.3 and 6.5% having maximum deprivation in Southwest and Oxford, respectively). The regions with worst long term cancer outcomes had high levels of deprivation with 25% and 17% having high levels of deprivation in Northwest and Trent regions. Conclusion: There are significant variations in long term colorectal cancer survival between different regions in England, southern England had better relative survival when compared with the northern regions. Disparities in socio-economic depravation status in different regions may be associated with worse colorectal cancer outcomes. [ABSTRACT FROM AUTHOR]

The gut-brain axis has received increasing attention recently due to evidence that colonic microbes can affect brain function and behavior. However, little is known about the innervation of the colon by a major component of the gut-brain axis, vagal afferent neurons. Furthermore, it is currently unknown whether individual NG neurons or DRG neurons innervate both the proximal and distal colon. We aimed to quantify the number of vagal and spinal afferent neurons that innervate the colon; and determine whether these individual neurons simultaneously innervate the mouse proximal and distal colon. C57Bl/6 mice received injections of a combination of retrograde tracers that were either injected into the muscularis externa of the proximal or the distal colon: fast blue, DiI and DiO. Five to seven percent of lumbosacral and thoracolumbar spinal afferent neurons, and 25% of vagal afferent neurons were labelled by injections of DiI and DiO into the colon. We also found that approximately 8% of NG neurons innervate the distal colon. Ten percent of labeled thoracolumbar and 15% of labeled lumbosacral DRG neurons innervate both the distal and proximal colon. Eighteen percent of labeled NG neurons innervated both the distal and proximal colon. In conclusion, vagal afferent innervation of the distal colon is less extensive than the proximal colon, whereas a similar gradient was not observed for the spinal afferent innervation. Furthermore, overlap appears to exist between the receptive fields of vagal and spinal afferent neurons that innervate the proximal and distal colon. [ABSTRACT FROM AUTHOR]

The global COVID-19 pandemic brought considerable public and policy attention to the field of infectious disease modelling. A major hurdle that modellers must overcome, particularly when models are used to develop policy, is quantifying the uncertainty in a model's predictions. By including the most recent available data in a model, the quality of its predictions can be improved and uncertainties reduced. This paper adapts an existing, large-scale, individual-based COVID-19 model to explore the benefits of updating the model in pseudo-real time. We use Approximate Bayesian Computation (ABC) to dynamically recalibrate the model's parameter values as new data emerge. ABC offers advantages over alternative calibration methods by providing information about the uncertainty associated with particular parameter values and the resulting COVID-19 predictions through posterior distributions. Analysing such distributions is crucial in fully understanding a model and its outputs. We find that forecasts of future disease infection rates are improved substantially by incorporating up-to-date observations and that the uncertainty in forecasts drops considerably in later simulation windows (as the model is provided with additional data). This is an important outcome because the uncertainty in model predictions is often overlooked when models are used in policy. [ABSTRACT FROM AUTHOR]

Core body temperature (CBT) regulation is crucial for mammalian wellbeing and survival. Cattle pant to dissipate excess heat to regulate CBT when ambient conditions exceed thermoneutral zones. However, to date, neither the variability in cattle heat response, the lagged response of CBT to thermal indices, nor the diurnal patterns of thermal indices, CBT and panting have been reported in the literature. We decomposed thermal indices, CBT and panting time-series data for 99 feedlot heifers across three discrete heat events into diurnal, trend and residual components. Both raw and decomposed data were analysed to explore the lagged CBT and panting responses and the association between series. We show ambient thermal conditions impact CBT with a 1-h lag despite a lag of between 1.5 to 3 h from raw data. Average individual panting scores were used to identify heat-susceptible and heat-tolerant cattle. Heat-susceptible cattle showed greater CBT (P < 0.01) between 8:00 and 23:00 and greater panting duration (P < 0.05) between 10:00 and 18:00 than heat-tolerant cattle under the same thermal conditions and these variations followed a similar pattern despite differences in cattle breed. This new information enables targeted amelioration and selection of individuals against heat susceptibility. [ABSTRACT FROM AUTHOR]

The emergence of forests on Earth (~385 million years ago, Ma)1 has been linked to an order-of-magnitude decline in atmospheric CO2 levels and global climatic cooling by altering continental weathering processes, but observational constraints on atmospheric CO2 before the rise of forests carry large, often unbound, uncertainties. Here, we calibrate a mechanistic model for gas exchange in modern lycophytes and constrain atmospheric CO2 levels 410–380 Ma from related fossilized plants with bound uncertainties of approximately ±100 ppm (1 sd). We find that the atmosphere contained ~525–715 ppm CO2 before continents were afforested, and that Earth was partially glaciated according to a palaeoclimate model. A process-driven biogeochemical model (COPSE) shows the appearance of trees with deep roots did not dramatically enhance atmospheric CO2 removal. Rather, shallow-rooted vascular ecosystems could have simultaneously caused abrupt atmospheric oxygenation and climatic cooling long before the rise of forests, although earlier CO2 levels are still unknown. Dahl et al. present new evidence based on leaf gas-exchange in primitive vascular plants and fossil remains of some of their earliest ancestors. This alters our thinking on how plants impacted the Earth System and climate. [ABSTRACT FROM AUTHOR]

Polstar is a proposed NASA MIDEX mission that carries a high resolution UV spectropolarimeter capable of measure all four Stokes parameters onboard a 60 cm telescope. The mission has been designed to pioneer the field of time-domain UV spectropolarimetry. Time domain UV spectropolarimetry offers the best resource to determine the geometry and physical conditions of protoplanetary disks from the stellar surface to <5 AU. We detail two key objectives that a dedicated time domain UV spectropolarimetry survey, such as that enabled by Polstar or a similar mission concept, could achieve: 1) Test the hypothesis that magneto-accretion operating in young planet-forming disks around lower-mass stars transitions to boundary layer accretion in planet-forming disks around higher mass stars; and 2) Discriminate whether transient events in the innermost regions of planet-forming disks of intermediate mass stars are caused by inner disk mis-alignments or from stellar or disk emissions. [ABSTRACT FROM AUTHOR]

The current consensus is that at least half of the OB stars are formed in binary or multiple star systems. The evolution of OB stars is greatly influenced by whether the stars begin as close binaries, and the evolution of the binary systems depend on whether the mass transfer is conservative or nonconservative. FUV/NUV spectropolarimetry is poised to answer the latter question. This paper discusses how the Polstar spectropolarimetry mission can characterize the degree of nonconservative mass transfer that occurs at various stages of binary evolution, from the initial mass reversal to the late Algol phase, and quantify its amount. The proposed instrument combines spectroscopic and polarimetric capabilities, where the spectroscopy can resolve Doppler shifts in UV resonance lines with 10 km/s precision, and polarimetry can resolve linear polarization with 10 − 3 precision or better. The spectroscopy will identify absorption by mass streams and other plasmas seen in projection against the stellar disk as a function of orbital phase, as well as scattering from extended splash structures, including jets. The polarimetry tracks the light coming from material not seen against the stellar disk, allowing the geometry of the scattering to be tracked, resolving ambiguities left by the spectroscopy and light-curve information. For example, nonconservative mass streams ejected in the polar direction will produce polarization of the opposite sign from conservative transfer accreting in the orbital plane. Time domain coverage over a range of phases of the binary orbit are well supported by the Polstar observing strategy. Special attention will be given to the epochs of enhanced systemic mass loss that have been identified from IUE observations (pre-mass reversal and tangential gas stream impact). We show how the history of systemic mass and angular momentum loss/gain episodes can be inferred via ensemble evolution through the r–q diagram. Combining the above elements will significantly improve our understanding of the mass transfer process and the amount of mass that can escape from the system, an important channel for changing the final mass and ultimate supernova of a large number of massive stars found in binaries at close enough separation to undergo interaction. [ABSTRACT FROM AUTHOR]

The winds of massive stars are important for their direct impact on the interstellar medium, and for their influence on the final state of a star prior to it exploding as a supernova. However, the dynamics of these winds is understood primarily via their illumination from a single central source. The Doppler shift seen in resonance lines is a useful tool for inferring these dynamics, but the mapping from that Doppler shift to the radial distance from the source is ambiguous. Binary systems can reduce this ambiguity by providing a second light source at a known radius in the wind, seen from orbitally modulated directions. From the nature of the collision between the winds, a massive companion also provides unique additional information about wind momentum fluxes. Since massive stars are strong ultraviolet (UV) sources, and UV resonance line opacity in the wind is strong, UV instruments with a high resolution spectroscopic capability are essential for extracting this dynamical information. Polarimetric capability also helps to further resolve ambiguities in aspects of the wind geometry that are not axisymmetric about the line of sight, because of its unique access to scattering direction information. We review how the proposed MIDEX-scale mission Polstar can use UV spectropolarimetric observations to critically constrain the physics of colliding winds, and hence radiatively-driven winds in general. We propose a sample of 20 binary targets, capitalizing on this unique combination of illumination by companion starlight, and collision with a companion wind, to probe wind attributes over a range in wind strengths. Of particular interest is the hypothesis that the radial distribution of the wind acceleration is altered significantly, when the radiative transfer within the winds becomes optically thick to resonance scattering in multiple overlapping UV lines. [ABSTRACT FROM AUTHOR]

We explored the role of negative performance beliefs and self-focused attention considered central to psychological models of social anxiety but not studied in autism. Firstly, we compared self- and observer ratings of performance on a social task for 71 young autistic people, 41 high and 30 low in social anxiety, finding a significant main effect of social anxiety but not rater. Subsequently, 76 autistic young people, 46 high and 30 low social anxiety completed measures of interoceptive sensibility and focus of attention following a social task. Only heightened interoceptive sensibility fully mediated the relationship between self-ratings of social performance and social anxiety. These findings suggest awareness of bodily sensations are critical to anxiety in social situations with implications for treatment. [ABSTRACT FROM AUTHOR]

Objectives: To describe the extrapolation approaches used to support intravenous (IV) golimumab for polyarticular juvenile idiopathic arthritis (pJIA) and juvenile psoriatic arthritis (jPsA) and subcutaneous (SC) ustekinumab for jPsA. Methods: Pharmacokinetic, clinical response, and safety data from trials of IV golimumab and SC ustekinumab in polyarticular-course JIA (pc-JIA) (GO-VIVA) or pediatric psoriasis (PsO) (CADMUS and CADMUS Jr) and data from pivotal, phase 3 trials of these agents in adults with similar diseases were used to support extrapolation in pJIA and jPsA. In the phase 3 GO-VIVA trial, patients with pc-JIA aged 2 to < 18 years received IV golimumab 80 mg/m2 at weeks 0, 4, then every 8 weeks (Q8W). In the phase 3, randomized, placebo-controlled CADMUS trial, patients with PsO aged ≥ 12 to < 18 years received ustekinumab at weeks 0, 4, then Q12W. In the phase 3 CADMUS Jr trial, patients with PsO aged ≥ 6 to < 12 years received ustekinumab at weeks 0, 4, then Q12W. The ustekinumab analyses used data only from patients who received the standard ustekinumab dosing regimen (≤ 60 kg: 0.75 mg/kg; > 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg). Results: In the 127 patients with pc-JIA treated with IV golimumab (GO-VIVA), pharmacokinetic and exposure-response results were similar to those in adults with rheumatoid arthritis treated with IV golimumab. Additionally, pharmacokinetic and clinical response data from five patients with jPsA in GO-VIVA were comparable to those in adults with PsA treated with IV golimumab. No new safety signals were observed in GO-VIVA. Pharmacokinetic and clinical response data observed in the four pediatric patients with PsO and jPsA treated with ustekinumab in CADMUS and CADMUS Jr were similar to those in the 91 pediatric patients with PsO without jPsA in these trials and to those in adults with PsA treated with ustekinumab. Safety was extrapolated from CADMUS or CADMUS Jr; no new signals were observed. Conclusions: These three sets of analyses corroborate similar exposure and efficacy of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in patients with jPsA to support extrapolation of established adult efficacy. The overall safety profiles of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in pediatric patients with PsO with or without jPsA were consistent with the safety profiles of these agents in the context of their clinical programs and cumulative use. Based on these analyses, the US Food and Drug Administration approved IV golimumab for polyarticular JIA and active PsA in patients 2 years and older and SC ustekinumab for pediatric PsA in patients 6 years and older, highlighting how use of an extrapolation approach can help streamline drug development for pediatric patient populations in whom larger clinical trials are not feasible. Clinical Trial Registration: GO-VIVA (NCT02277444) was registered at clinicaltrials.gov on 29 October 2014; CADMUS (NCT01090427) was registered on 22 March 2010; and CADMUS Jr (NCT02698475) was registered on 3 March 2016. [ABSTRACT FROM AUTHOR]

The Marine Isotope Stage (MIS) 2 is considered the coldest, driest and stormiest period during the last Glacial-Interglacial cycle in large parts of Eurasia. This resulted from strongly decreased northern hemisphere temperature and related maximum extension of northern ice sheets that strongly reinforced large-scale circulation modes such as westerlies and East Asian Winter Monsoon driven by the Siberian High. Normally, this intensified circulation is reflected by maximum loess deposition in numerous loess regions spanning Europe and Asia. However, here we present a new loess record from the Caucasus region in NE-Armenia providing evidence in support of heavily reduced or even lacking loess formation during the MIS-2. Owing to implementations of comprehensible luminescence dating work and a provenance survey using rock magnetic and geochemical data, we are able to define distinct loess formation phases and to retrace sediment transport pathways. By comparing our results to other Eurasian palaeo-records, we unveil general atmospheric circulation modes that are most likely responsible for loess formation in the Southern Caucasus. Moreover, we try to test different scenarios to explain lacking loess formation during MIS-2. In line with other archive information, we suggest that loess formation was hampered by higher regional moisture conditions caused by a southward-shift of westerlies and renewed moisture absorption over the Black Sea. Our results show that modifications of MIS-2 circulation modes induced a very heterogeneous moisture distribution, particularly in the lower mid-latitudes of Eurasia producing a juxtaposition of very dry (morphodynamically active) and moderately dry (morphodynamically stable) areas. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate associations between mode of presentation; categorized as emergency, suspected cancer outpatient referral pathway (2-week wait or 2WW pathway), non-cancer suspected outpatient referral (non-2-week wait pathway) or following screening, and stage of diagnosis and survival in patients with colorectal cancer in England. Methods: This was a retrospective cohort observational study of patients diagnosed with colorectal cancer between January 2010 and December 2014 in England using data from Public Health England collated from regional cancer registries. Results: The most common route to diagnosis among 167,501 patients diagnosed with colorectal cancer was via the non-cancer suspect (non-2WW) outpatient referral pathway (35.1%) followed by the suspected cancer (2WW) referral pathway (31.6%), emergency presentation (22.8%) and most infrequently following screening (10.6%) (p < 0.01). Screening confers the greatest likelihood of early-stage diagnosis (61.6%) compared to other modes of presentation. The 5-year overall survival was 81.8%, 53.3%, 53.0% and 27.6% in those diagnosed via screening, 2WW, non-2WW pathway and emergency presentation, respectively. Patients from most deprived regions were more likely to be diagnosed following emergency presentation (27.7 vs 19.7%, p < 0.01) and less likely via screening (8.1 vs 12%, p < 0.01). Conclusions: Asymptomatic individuals diagnosed following screening have earlier stage cancers and better survival, the opposite was observed in those diagnosed following emergency presentation. Patients referred via the 2WW pathway do not have better survival outcomes when compared to those referred via the non-2WW pathway. In addition, this study has identified socio-economic groups that need to be targeted with public health campaigns to improve screening uptake. [ABSTRACT FROM AUTHOR]

Establishing a permanent human presence on the Moon or Mars requires a secure supply of oxygen for life support and refueling. The electrolysis of water has attracted significant attention in this regard as water-ice may exist on both the Moon and Mars. However, to date there has been no study examining how the lower gravitational fields on the Moon and Mars might affect gas-evolving electrolysis when compared to terrestrial conditions. Herein we provide experimental data on the effects of gravitational fields on water electrolysis from 0.166 g (lunar gravity) to 8 g (eight times the Earth's gravity) and show that electrolytic oxygen production is reduced by around 11% under lunar gravity with our system compared to operation at 1 g. Moreover, our results indicate that electrolytic data collected using less resource-intensive ground-based experiments at elevated gravity (>1 g) may be extrapolated to gravitational levels below 1 g. Oxygen production using electrolysis will be critical for life support and refueling on the Moon and Mars. Herein, electrolysis under lunar and Martian gravity was found to be less efficient than electrolysis under Earth's gravity, and predictable from data obtained using ground-based systems. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to understand the reasons for canakinumab initiation among patients with Still's disease, including systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still's disease (AOSD), in US clinical practice. Methods: Physicians retrospectively reviewed the medical charts of patients with Still's disease (regardless of age at symptom onset) who were prescribed canakinumab from 2016 to 2018. Patients aged < 16 years at symptom onset were classified as having SJIA and those aged ≥ 16 years at symptom onset (calculated from case-record forms) were classified as having AOSD. Patient treatment history and physician reasons for canakinumab initiation were analyzed. Overall results were presented as SJIA/AOSD. Sensitivity analyses were performed for the robustness of the results. Results: Forty-three physicians in the USA (rheumatologists/dermatologists/immunologists/allergists: 51.2/27.9/11.6/9.3%; subspecialty in adults/pediatrics: 67.4/32.6%) abstracted information for 72 patients with SJIA/AOSD (SJIA/AOSD/age unknown at symptom onset: 75.0/18.1/6.9%; mean age 19.4 years; children 61.1%; females 56.9%). Most patients (90.3%) received treatment directly preceding canakinumab initiation (etanercept 27.7%; anakinra 18.5%; adalimumab 16.9%); the respective treatment was discontinued due to lack of efficacy/effectiveness (43.1%) and availability of a new treatment (27.8%). Most common reasons for canakinumab initiation were physician perceived/experienced efficacy/effectiveness of canakinumab (77.8%; children/adults: 81.8/71.4%), lack-of-response to previous treatment (45.8%; children/adults: 36.4/60.7%), convenient administration/dosing (26.4%; children/adults: 29.5/21.4%) and ability to discontinue/spare steroids (25.0%; children/adults: 20.5/32.1%). The sensitivity analysis provided similar results. Conclusions: In US clinical practice, physician perceived/experienced efficacy/effectiveness of canakinumab and lack-of-response to previous treatment were the primary reasons for canakinumab initiation among patients with SJIA/AOSD. Physician perceived/experienced efficacy/effectiveness and convenient administration/dosing of canakinumab were the most common reasons for canakinumab initiation among children, whereas lack-of-response to previous treatment and ability to discontinue/spare steroids being the most frequent reasons among adults. [ABSTRACT FROM AUTHOR]

In order to understand the health outcomes for distinct sub-groups of the population or across different geographies, it is advantageous to be able to build bespoke groupings from individual level data. Individuals possess distinct characteristics, exhibit distinct behaviours and accumulate their own unique history of exposure or experiences. However, in most disciplines, not least public health, there is a lack of individual level data available outside of secure settings, especially covering large portions of the population. This paper provides detail on the creation of a synthetic micro dataset for individuals in Great Britain who have detailed attributes which can be used to model a wide range of health and other outcomes. These attributes are constructed from a range of sources including the United Kingdom Census, survey and administrative datasets. It provides a rationale for the need for this synthetic population, discusses methods for creating this dataset and provides some example results of different attribute distributions for distinct sub-population groups and over different geographical areas. Measurement(s) Health Disparity Populations • socio-economic outcomes Technology Type(s) computational modeling technique • digital curation Factor Type(s) geographical area Sample Characteristic - Location Great Britain [ABSTRACT FROM AUTHOR]

Lake sediments are important archives of past climate variability and lake responses to climate. In order to accurately infer past climates, it is necessary to understand, and account for, the ecological processes that affect the record of indicators preserved in lake sediment. This is particularly the case with respect to the concentration of carbon and nitrogen (TOC, TN, and calculated C:N), and the stable isotope composition of organic matter preserved in lake sediments. These are common, yet ambiguous, tracers of environmental change. Ideally, palaeoenvironmental reconstructions using the concentration and isotope composition of organic matter should be grounded in a detailed understanding of the sources of the organic material. This study documents the history and evolution of Blue Lake, an environmentally and culturally important oligotrophic, groundwater window lake on North Stradbroke Island, Queensland, Australia. We utilise organic matter δ13C, TOC, TN, and C:N from a 2.4 m sediment core with a basal age of 7.5 cal kyr BP, to investigate changing organic matter sources as a measure of the climate sensitivity of Blue Lake. This interpretation is supported by data from contemporary algae, aquatic and terrestrial plants, and catchment soils. We show that lake nutrient dynamics drove an increase in algal biomass at 4.2 cal kyr BP. This change coincides with a widely documented intensification of the El Niño-Southern Oscillation, which we infer to have influenced lake nutrient concentrations by reducing groundwater throughflow. Climatic changes resulted in marked changes in lake primary productivity, despite relatively little turnover of the lake diatom flora and catchment vegetation. This suggests that south-east Queensland dune lakes are sensitive to climate changes and helps to refine past and future palaeoclimate research using sediments from these lakes. It also indicates that increased nutrient concentrations in Blue Lake may result from projected changes in 21st Century climate. [ABSTRACT FROM AUTHOR]

A 70-year old male with stage I large cell neuroendocrine carcinoma (LCNEC) of the lung underwent resection of a metachronous 5 cm brain metastasis and received postoperative hypofractionated stereotactic radiotherapy (hfSRT). Five sequential nodular leptomeningeal metastases up to 5.3 cm in diameter were diagnosed on MRI within 10 months and were treated with SRT. Currently the patient has no evidence of intracranial disease 24 months after last irradiation without chemotherapy or whole brain radiotherapy. This is the first report of sustained complete remission of multiple large leptomeningeal metastases achieved with hfSRT, highlighting this brain-sparing approach in selected patients with LCNEC lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: The outcomes of five fraction stereotactic radiotherapy (hfSRT) following brain metastasectomy were evaluated and compared with published series. Methods: 30 Gy in 5 fractions HfSRT prescribed to the surgical cavity was reduced to 25 Gy if the volume of 'brain−GTV' receiving 20 Gy exceeded 20 cm3. Endpoints were local recurrence, nodular leptomeningeal recurrence, new brain metastases and radionecrosis. The literature was searched for reports of clinical and dosimetric outcomes following postoperative hfSRT in 3–5 fractions. Results: 39 patients with 40 surgical cavities were analyzed. Cavity local control rate at 1 year was 33/40 (82.5%). 3 local failures followed 30 Gy/5 fractions and 4 with 25 Gy/5 fractions. The incidence of leptomeningeal disease (LMD) was 7/40 (17.5%). No grade 3–4 toxicities, particularly no radionecrosis, were reported. The incidence of distant brain metastases was 15/40 (37.5%). The median overall survival was 15 months. Across 13 published series, the weighted mean local control was 83.1% (adjusted for sample size), the mean incidence of LMD was 14.9% (7–34%) and the mean rate of radionecrosis was 10.3% (0–20.6%). Conclusion: Postoperative hfSRT can be delivered with 25–30 Gy in 5 fractions with efficacy in excess of 82% and no significant toxicity when the dose to 'brain−GTV' does not exceed 20 cm3. [ABSTRACT FROM AUTHOR]

The future of the meat industry will require the management of important trade-offs between economic, environmental and health aspects of both humans and animals. Understanding the patterns and trends of meat expenditure and consumption is crucial for assessing the current resilience of the system and for economic, planning, health and environmental applications. Here, we show how the technique of geodemographic classification, combined with fine scale expenditure estimates can be used to explore temporal and spatial patterns of meat expenditure in Great Britain between 2008 and 2017. Whilst the expenditure patterns of some food categories such as sausages remained relatively consistent, others such as lamb show a trend towards a reduced proportion of expenditure and increased inequality of purchases. Short term changes in expenditure patterns also occurred, potentially due to product specific price variability, price elasticities or zoonotic disease scare. Environmental attitudes, financial constraints and the prominence of communities who do not eat meat for religious or cultural reasons are likely to be driving the differences between geodemographic groups. The methodology and results could be a valuable tool for policy makers in the meat industry and beyond. [ABSTRACT FROM AUTHOR]

Purpose: Methylation of ingested inorganic arsenic (InAs) to monomethyl- (MMAs) and dimethyl-arsenical species (DMAs) facilitates urinary arsenic elimination. Folate and creatine supplementation influenced arsenic methylation in a randomized controlled trial. Here, we examine if baseline status of one-carbon metabolism nutrients (folate, choline, betaine, and vitamin B12) modified the effects of FA and creatine supplementation on changes in homocysteine, guanidinoacetate (GAA), total blood arsenic, and urinary arsenic metabolite proportions and indices. Methods: Study participants (N = 622) received 400 or 800 μg FA, 3 g creatine, 400 μg FA + 3 g creatine, or placebo daily for 12 weeks. Results: Relative to placebo, FA supplementation was associated with greater mean increases in %DMAs among participants with betaine concentrations below the median than those with levels above the median (FDR < 0.05). 400 μg FA/day was associated with a greater decrease in homocysteine among participants with plasma folate concentrations below, compared with those above, the median (FDR < 0.03). Creatine treatment was associated with a significant decrease in %MMAs among participants with choline concentrations below the median (P = 0.04), but not among participants above the median (P = 0.94); this effect did not significantly differ between strata (P = 0.10). Conclusions: Effects of FA and creatine supplementation on arsenic methylation capacity were greater among individuals with low betaine and choline status, respectively. The efficacy of FA and creatine interventions to facilitate arsenic methylation may be modified by choline and betaine nutritional status. Clinical trial registration: Clinical Trial Registry Identifier: NCT01050556, U.S. National Library of Medicine, https://clinicaltrials.gov; registered January 15, 2010. [ABSTRACT FROM AUTHOR]

We report on a comparative dosimetrical study between deep inspiration breath hold (DIBH) and shallow breathing (SB) in prone crawl position for photon and proton radiotherapy of whole breast (WB) and locoregional lymph node regions, including the internal mammary chain (LN_MI). We investigate the dosimetrical effects of DIBH in prone crawl position on organs-at-risk for both photon and proton plans. For each modality, we further estimate the effects of lung and heart doses on the mortality risks of different risk profiles of patients. Thirty-one patients with invasive carcinoma of the left breast and pathologically confirmed positive lymph node status were included in this study. DIBH significantly decreased dose to heart for photon and proton radiotherapy. DIBH also decreased lung doses for photons, while increased lung doses were observed using protons because the retracting heart is displaced by low-density lung tissue. For other organs-at-risk, DIBH resulted in significant dose reductions using photons while minor differences in dose deposition between DIBH and SB were observed using protons. In patients with high risks for cardiac and lung cancer mortality, average thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 3.12% (photon DIBH), 4.03% (photon SB), 1.80% (proton DIBH) and 1.66% (proton SB). The radiation-related mortality risk could not outweigh the ~ 8% disease-specific survival benefit of WB + LN_MI radiotherapy in any of the assessed treatments. [ABSTRACT FROM AUTHOR]

Purpose: Although litter decomposition and nutrient release patterns have been studied in cocoa agroforestry systems in general, studies focusing on organic and conventional cocoa systems are lacking which is critical as organic farms are particularly dependent on nutrient returns from decomposing litter. Materials and methods: Dynamics in leaf litter decomposition and the mineralisation of macro- and micro-nutrients in organic and conventional cocoa agroforestry systems were studied using the litterbag technique for 12 months. Results: The average monthly mass loss was more than two times higher on organic farms (9.2–14.4 g month−1) compared to conventional farms (4.2–7.3 g month−1) in the first five months. The annual rate of decomposition (k) was higher on organic farms (1.9) compared to conventional systems (1.4). The time required for 50% (t50) and 99% (t99) decomposition of leaf litter was both lower on organic farms (t50 = 0.4 years, t99 = 2.6 years) than conventional farms (t50 = 0.5 years, t99 = 3.5 years). The estimated k values for macro- and micro-nutrients on organic cocoa systems ranged from 2.3 for calcium to 4.5 for potassium compared to 1.6 (Ca) to 2.8 (K) on conventional farms. The k values of all nutrients (except nitrogen and phosphorus) were significantly greater on organic farms than conventional systems. The estimated k values for both litter decomposition and nutrient mineralisation correlated with soil pH and moisture content, but not initial litter chemistry. Conclusions: Organic management of smallholder cocoa agroforestry systems enhanced leaf litter decomposition and nutrient mineralisation through improved soil conditions. Thus, organic management of cocoa agroforestry systems may contribute to sustainable cocoa production in smallholder systems through enhanced nutrient return from litter decomposition. [ABSTRACT FROM AUTHOR]

To constrain global warming, we must strongly curtail greenhouse gas emissions and capture excess atmospheric carbon dioxide1,2. Regrowing natural forests is a prominent strategy for capturing additional carbon3, but accurate assessments of its potential are limited by uncertainty and variability in carbon accumulation rates2,3. To assess why and where rates differ, here we compile 13,112 georeferenced measurements of carbon accumulation. Climatic factors explain variation in rates better than land-use history, so we combine the field measurements with 66 environmental covariate layers to create a global, one-kilometre-resolution map of potential aboveground carbon accumulation rates for the first 30 years of natural forest regrowth. This map shows over 100-fold variation in rates across the globe, and indicates that default rates from the Intergovernmental Panel on Climate Change (IPCC)4,5 may underestimate aboveground carbon accumulation rates by 32 per cent on average and do not capture eight-fold variation within ecozones. Conversely, we conclude that maximum climate mitigation potential from natural forest regrowth is 11 per cent lower than previously reported3 owing to the use of overly high rates for the location of potential new forest. Although our data compilation includes more studies and sites than previous efforts, our results depend on data availability, which is concentrated in ten countries, and data quality, which varies across studies. However, the plots cover most of the environmental conditions across the areas for which we predicted carbon accumulation rates (except for northern Africa and northeast Asia). We therefore provide a robust and globally consistent tool for assessing natural forest regrowth as a climate mitigation strategy. A one-kilometre-resolution map of aboveground carbon accumulation rates of forest regrowth shows 100-fold variation across the globe, with rates 32% higher on average than IPCC estimates. [ABSTRACT FROM AUTHOR]

Elevated atmospheric CO2 may create greater methane (CH4) emissions from subarctic wetlands. To date such ecosystem feedbacks remain poorly understood, particularly in relation to how different wetland plant species will control such feedbacks. In this study we exposed plant-peat mesocosms planted with four Cyperaceae species to 400 and 800 ppm atmospheric CO2 concentrations and measured plant and peat properties as well as CH4 fluxes. Above ground biomass for plants grown at 800 ppm CO2 increased for E. angustifolium, Eriophorum vaginatum and Carex brunnescens, but the total biomass of C. acuta decreased relative to the ambient CO2 treatment. The plant species and elevated CO2 treatment affected both peat redox potential and pore water chemistry. There was no overall effect of the elevated CO2 on CH4 emissions, however, CH4 emissions were related to above ground biomass and redox potential, both of which were significantly altered by elevated CO2. Our study shows that species composition poses an important control on how wetland communities will respond to elevated CO2 and that plant mediated changes of peat biogeochemical processes, in response to elevated CO2 levels, may affect CH4 emissions from sub-arctic wetlands, but any such responses will differ among species. [ABSTRACT FROM AUTHOR]

Willow (Salix spp.) is well known as a source of medicinal compounds, the most famous being salicin, the progenitor of aspirin. Here we describe the isolation, structure determination, and anti-cancer activity of a cyclodimeric salicinoid (miyabeacin) from S. miyabeana and S. dasyclados. We also show that the capability to produce such dimers is a heritable trait and how variation in structures of natural miyabeacin analogues is derived via cross-over Diels-Alder reactions from pools of ortho-quinol precursors. These transient ortho-quinols have a role in the, as yet uncharacterised, biosynthetic pathways around salicortin, the major salicinoid of many willow genotypes. [ABSTRACT FROM AUTHOR]

Background: Factors underlying physiological reactions from perceived discrimination and its relation to adverse health outcomes are not completely understood. The main purpose of this study was to test the hypothesis that experiences of discrimination (recent and lifetime) correlate with biomarkers of stress, oxidative stress, and obesity among adult females. Method: Data on 62 females who self-identify as African American (AA; n = 31) or European American (EA; n = 31) aged 21–45 years were included. Discrimination experiences (recent and lifetime) were evaluated based on a validated instrument. Stress was assessed based on hair cortisol (HC) and salivary cortisol (SC), hsC-reactive protein (hsCRP), cardiovascular markers, and LDL-cholesterol oxidation. Obesity was measured based on BMI, waist circumference, and body fat percent. Multiple linear regression analyses were performed to evaluate the influence of experiences of discrimination. Results: Significant differences in experiences of discrimination were observed by race (p < 0.05) and were higher in AA females. Results for the multiple regression models assessing the contribution of discrimination indicate that hsCRP and pulse were significantly associated with recent experiences of discrimination, and SC, HC, hsCRP, diastolic blood pressure (DBP), and pulse were significantly associated with lifetime experiences of discrimination when adjusted for BMI and race (p < 0.05). Finally, oxidation of LDL-cholesterol was significantly associated with salivary cortisol (p = 0.0420) when adjusted by lifetime experiences of discrimination (p = 0.0366) but not for BMI (p = 0.6252). Conclusion: In this cross-sectional study, AA females experienced more discrimination compared to EA females. Levels of recent and lifetime experiences of discrimination were associated with some stress biomarkers. Salivary cortisol was associated with oxidation of LDL-cholesterol with shorter lag times and increased risk for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Introduction: Voretigene neparvovec (VN) is a gene therapy and the first approved pharmacological treatment for biallelic RPE65-mediated inherited retinal dystrophies (IRD), a rare condition that starts in early life and causes vision to progressively deteriorate towards complete blindness. In a phase III trial, treatment with VN significantly improved functional vision and visual function, and in October 2019 the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) process recommended VN for patients in England and Wales. We assessed the cost-effectiveness of VN compared with best supportive care (BSC) in individuals with biallelic RPE65-mediated IRD in the UK.Methods: A Markov model was developed to estimate the incremental cost per quality-adjusted life-year (QALY) gained for VN compared with BSC, from the perspective of the UK National Health Service and Personal Social Services. Phase III trial data were used to inform transition probabilities up to year 1, after which the treatment effect was assumed to be maintained for 40 years, followed by a decline in vision. A bespoke elicitation exercise involving clinical experts, patients and carers was conducted to estimate utility values for each model health state.Results: At list price, VN is associated with incremental costs of £612,404 and incremental QALYs of 6.4, resulting in an incremental cost-effectiveness ratio (ICER) of £95,072 per QALY gained. Voretigene neparvovec is associated with a significant undiscounted QALY gain (20.5) and is therefore eligible for additional QALY weighting under the NICE HST process; an ICER of up to £205,000 per QALY gained could be considered cost-effective under this framework.Conclusion: The results of the model show VN to be a cost-effective use of healthcare resources in the UK at list price. The availability of a commercial discount in the UK (as considered in the NICE appraisal) means that in reality the ICER will be even lower. Plain language summary available for this article. [ABSTRACT FROM AUTHOR]

Cuticles have been a key part of palaeobotanical research since the mid-19th Century. Recently, cuticular research has moved beyond morphological traits to incorporate the chemical signature of modern and fossil cuticles, with the aim of using this as a taxonomic and classification tool. For this approach to work, cuticle chemistry would have to maintain a strong taxonomic signal, with a limited input from the ambient environment in which the plant grew. Here, we use attenuated total reflectance Fourier Transform infrared (ATR-FTIR) spectroscopy to analyse leaf cuticles from Ginkgo biloba plants grown in experimentally enhanced CO2 conditions, to test for the impact of changing CO2 regimes on cuticle chemistry. We find limited evidence for an impact of CO2 on the chemical signature of Ginkgo cuticles, with more pronounced differences demonstrated between the abaxial (lower leaf surface) and adaxial (upper leaf surface) cuticles. These findings support the use of chemotaxonomy for plant cuticular remains across geological timescales, and the concomitant large-scale variations in CO2 concentrations. [ABSTRACT FROM AUTHOR]

Objective: Little is known about the lived experiences of patients with metastatic melanoma undergoing checkpoint inhibitor treatment. We conducted a feasibility study of a supportive care intervention for melanoma patients being treated with pembrolizumab. Here, we report a secondary objective of the study, which was to explore the lived experience of being on pembrolizumab treatment for advanced melanoma.Methods: Twenty-eight participants with metastatic melanoma were recruited across two cohorts, all receiving 3-weekly immunotherapy treatment. Semi-structured interviews were conducted with 26 participants once at 9 weeks. Thematic analysis using interpretative phenomenological analysis (IPA) was performed with multiple iterations of data review to achieve consensus.Results: Three overarching themes were identified; here, we report the first and most dominant theme: how metastatic melanoma patients live within uncertain spaces. Although immunotherapy increases overall survival, metastatic melanoma patients live within an uncertain spectrum. They confront uncertainty related to immunotherapy treatment, their disease trajectory, family relationships, and decision-making. Melanoma patients attempt to normalize their lives, engaging in their usual activities. Uncertainty increases prior to active treatment and intensifies during investigation phases.Conclusions: Despite progress in melanoma patient treatment and outcomes, these patients face sustained uncertainty about their disease trajectory. [ABSTRACT FROM AUTHOR]

Introduction: Increasing numbers of metastatic melanoma (MM) patients are receiving immunotherapy treatment, including pembrolizumab, and the impact on their well-being is underexplored.Objectives: To assess the feasibility of a multimodal supportive care program to MM patients being treated with pembrolizumab.Methods: This pre-post-test feasibility cohort study recruited MM participants treated with pembrolizumab: (i) supportive care intervention with usual care and (ii) usual care. The intervention comprised comprehensive medical assessment by supportive care physician (SCP), exercise physiologist (EP), and dietitian then a tailored supportive care program. Programs included exercise, dietary advice, non-invasive complementary therapies, and psychology consultation. Outcome measures included adherence, patient-reported symptoms, anxiety and depression, and toxicity. Descriptive data are reported.Results: We recruited 28 participants: 13 intervention and 15 control; three did not complete the study. Most were male, with median age 66 (range 42-85) years. All intervention participants completed baseline assessments with SCP, EP, and dietitian. Two missed follow-up with EP or dietitian. Symptoms most troubling at baseline were as follows: fatigue (n = 6), sleep (n = 6), general aches and pains (n = 5), and memory (n = 4). All intervention participants were prescribed 16 exercise sessions; 8 (50%) completed all; overall exercise adherence was 85%. Integrative therapies were accessed by 85% (11) participants. Immunotherapy-related adverse event rates were low and SCP consultation identified symptoms not captured by CTCAE 4.0.Conclusions: A holistic supportive care intervention tailored to individual needs is feasible. The symptom burden in MM patients was low. Further investigation of the intervention is warranted, focused on populations with higher symptom burden to improve outcomes. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Effects of deep inspiration breath hold on prone photon or proton irradiation of breast and regional lymph nodes" published in Scientific Reports. The correction addresses an incomplete Acknowledgements section in the original version of the article. The corrected version now includes acknowledgements for the funding sources that supported the research. The authors of the article are listed as Bruno Speleers, Max Schoepen, Francesca Belosi, Vincent Vakaet, Wilfried De Neve, Pieter Deseyne, Leen Paelinck, Tom Vercauteren, Michael J. Parkes, Tony Lomax, Annick Van Greveling, Alessandra Bolsi, Damien C. Weber, Liv Veldeman, and Werner De Gersem. [Extracted from the article]

Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer. Methods Patients with advanced or metastatic solid tumours, who had progressed on standard therapy or for whom standard therapy was not known, were administered ASLAN-002 orally. The starting dose was 100 mg once daily (QD) with subsequent cohorts to receive doses of 200 mg QD, 300 mg QD, 450 mg QD, 600 mg QD, 300 mg twice daily (BID), 450 mg BID, and 600 mg BID. Results Forty patients were included across 7 dose cohorts. Cohort 8 (600 mg BID) was not opened due to the lack of appreciable pharmacokinetic (PK) differences between 300 mg BID and 450 mg BID and higher incidences of grade 3 or 4 adverse events (AE) in Cohort 7 (450 mg BID). Fifteen patients (37.5%) experienced a grade 3 or 4 AE. The most commonly reported AEs were nausea (55%), fatigue (47.5%) and constipation (30%). One dose limiting toxicity (DLT) of atrial fibrillation was observed with 450 mg BID. Conclusions ASLAN-002 is well tolerated at 300 mg BID and is the recommended dose for future phase II studies (RP2D). Clinical Trials Registry Number: NCT01721148. [ABSTRACT FROM AUTHOR]

Tracking changes in biodiversity through time requires an understanding of the relationship between modern diversity and how this diversity is preserved in the fossil record. Fossil pollen is one way in which past vegetation diversity can be reconstructed. However, there is limited understanding of modern pollen-vegetation diversity relationships from biodiverse tropical ecosystems. Here, pollen (palynological) richness and diversity (Hill N1) are compared with vegetation richness and diversity from forest and savannah ecosystems in the New World and Old World tropics (Neotropics and Palaeotropics). Modern pollen data were obtained from artificial pollen traps deployed in 1-ha vegetation study plots from which vegetation inventories had been completed in Bolivia and Ghana. Pollen counts were obtained from 15 to 22 traps per plot, and aggregated pollen sums for each plot were > 2,500. The palynological richness/diversity values from the Neotropics were moist evergreen forest = 86/6.8, semi-deciduous dry forest = 111/21.9, wooded savannah = 138/31.5, and from the Palaeotropics wet evergreen forest = 144/28.3, semi-deciduous moist forest = 104/4.4, forest-savannah transition = 121/14.1; the corresponding vegetation richness/diversity was 100/36.7, 80/38.7 and 71/39.4 (Neotropics), and 101/54.8, 87/45.5 and 71/34.5 (Palaeotropics). No consistent relationship was found between palynological richness/diversity, and plot vegetation richness/diversity, due to the differential influence of other factors such as landscape diversity, pollination strategy, and pollen source area. Palynological richness exceeded vegetation richness, while pollen diversity was lower than vegetation diversity. The relatively high global diversity of tropical vegetation was found to be reflected in the pollen rain. [ABSTRACT FROM AUTHOR]

The transition zone between Eastern Alps and Pannonian Basin is a key area for the investigation of the interplay between regional uplift, local tectonic subsidence and depositional environment. Our study area, the western margin of the Little Hungarian Plain, is characterized by gentle hills, plateaus and depressions, of which several are filled by lakes-including one of Austria's largest and shallowest lakes, Lake Neusiedl. Geological investigation is hampered by the scarcity of outcrops, and thus direct observation of sedimentological or structural features is difficult. Despite a long research history in the area, a consistent landscape evolution model considering all relevant constraints is lacking so far. In this study, we apply multidisciplinary methods to decipher the complex tectonic and fluvial depositional evolution of the region. Local data from shallow-lake drilling and seismic investigation are combined with regional data from industrial seismics and core data to gain new insights into the latest Pannonian (Late Miocene) and Quaternary evolution. Shallow-lake seismic data show the erosionally truncated Pannonian sediments dipping and thickening toward southeast, toward the modern depocenter of the Little Hungarian Plain. Overlying Quaternary fluvial sediments show a very similar thickening trend except for the area on the plateau north of the lake indicating ongoing subsidence in major parts of the basin. Drill cores from locations along the lake seismic lines were analyzed concerning their age, mineralogy and heavy minerals and compared with outcrop samples from the surrounding plains and the plateau to derive indications on sediment provenance. A key observation is the apparent lack of a significant gravel layer on top of the tilted Pannonian sediments beneath Lake Neusiedl. Small-scale faults can be observed in the lake seismic sections along with key sedimentary features. Significant differences of the current elevation of the top Pannonian between the surrounding plains and the plateau indicate post-Pannonian normal faulting, which is a key process in shaping the present-day morphology of the region. Luminescence ages of samples from the Quaternary fluvial gravels on top of the Pannonian sediments are a significantly higher (>300 ka) compared to the gravels in the plain (102 ± 11 and 76 ± 8 ka), suggesting ongoing tectonic subsidence. [ABSTRACT FROM AUTHOR]

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Diverse cellular and environmental stresses can activate the heat shock response, an evolutionarily conserved mechanism to protect proteins from denaturation. Stressors activate heat shock transcription factor 1 (HSF1), which binds to heat shock elements in the genes for heat shock proteins, leading to rapid induction of these important molecular chaperones. Both heat and noise stress are known to activate the heat shock response in the cochlea and protect it from subsequent noise trauma. However, the contribution of HSF1 to induction of heat shock proteins following noise trauma has not been investigated at the molecular level. We evaluated the role of HSF1 in the cochlea following noise stress by examining induction of heat shock proteins in Hsf1 ( +/- ) control and Hsf1 ( -/- ) mice. Heat stress rapidly induced expression of Hsp25, Hsp47, Hsp70.1, Hsp70.3, Hsp84, Hsp86, and Hsp110 in the cochleae of wild-type and Hsf1 ( +/- ) mice, but not in Hsf1 ( -/- ) mice, confirming the essential role of HSF1 in mediating the heat shock response. Exposure to broadband noise (2-20 kHz) at 106 dB SPL for 2 h produced partial hearing loss. Maximal induction of heat shock proteins occurred 4 h after the noise. In comparison to heat stress, noise stress resulted in lower induced levels of Hsp25, Hsp70.1, Hsp70.3, Hsp86, and Hsp110 in Hsf1 ( +/- ) mice. Induction of these heat shock proteins was attenuated, but not completely eliminated, in Hsf1 ( -/- ) mice. These same noise exposure conditions induced genes for several immediate early transcription factors and maximum induction occurred earlier than for heat shock proteins. Thus, additional signaling pathways and transcriptional regulators that are activated by noise probably contribute to induction of heat shock proteins in the cochlea. [ABSTRACT FROM AUTHOR]