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Sediments in oxygen-depleted marine environments can be an important sink or source of bio-essential trace metals in the ocean. However, the key mechanisms controlling the release from or burial of trace metals in sediments are not exactly understood. Here, we investigate the benthic biogeochemical cycling of iron (Fe) and cadmium (Cd) in the oxygen minimum zone off Peru. We combine bottom water and pore water concentrations, as well as benthic fluxes determined from pore water profiles and from in situ benthic chamber incubations, along a depth transect at 12∘ S. In agreement with previous studies, both concentration–depth profiles and in situ benthic fluxes indicate a release of Fe from sediments to the bottom water. Diffusive Fe fluxes and Fe fluxes from benthic chamber incubations (−0.3 to −17.5 mmol m−2 yr−1) are broadly consistent at stations within the oxygen minimum zone, where the flux magnitude is highest, indicating that diffusion is the main transport mechanism of dissolved Fe across the sediment–water interface. The occurrence of mats of sulfur-oxidizing bacteria on the seafloor represents an important control on the spatial distribution of Fe fluxes by regulating hydrogen sulfide (H2S) concentrations and, potentially, Fe sulfide precipitation within the surface sediment. Rapid removal of dissolved Fe after its release to anoxic bottom waters hints at oxidative removal by nitrite and interactions with particles in the near-bottom water column. Benthic flux estimates of Cd suggest a flux into the sediment within the oxygen minimum zone. Fluxes from benthic chamber incubations (up to 22.6 µmol m−2 yr−1) exceed diffusive fluxes ( µmol m−2 yr−1) by a factor of more than 25, indicating that downward diffusion of Cd across the sediment–water interface is of subordinate importance for Cd removal from benthic chambers. As Cd removal in benthic chambers covaries with H2S concentrations in the pore water of surface sediments, we argue that Cd removal is mediated by precipitation of cadmium sulfide (CdS) within the chamber water or directly at the sediment–water interface. A mass balance approach, taking the contributions of diffusive and chamber fluxes as well as Cd delivery with organic material into account, suggests that CdS precipitation in the near-bottom water could make an important contribution to the overall Cd mass accumulation in the sediment solid phase. According to our results, the solubility of trace metal sulfide minerals (Cd ≪ Fe) is a key factor controlling trace metal removal and, consequently, the magnitude and the temporal and spatial heterogeneity of sedimentary fluxes. We argue that, depending on their sulfide solubility, sedimentary source or sink fluxes of trace metals will change differentially as a result of declining oxygen concentrations and the associated expansion of sulfidic surface sediments. Such a trend could cause a change in the trace metal stoichiometry of upwelling water masses with potential consequences for marine ecosystems in the surface ocean.

The availability of the micronutrient iron (Fe) in surface waters determines primary production, N2 fixation, and microbial community structure in large parts of the world's ocean, and thus it plays an important role in ocean carbon and nitrogen cycles. Eastern boundary upwelling systems and the connected oxygen minimum zones (OMZs) are typically associated with elevated concentrations of redox-sensitive trace metals (e.g., Fe, manganese (Mn), and cobalt (Co)), with shelf sediments typically forming a key source. Over the last 5 decades, an expansion and intensification of OMZs has been observed and this trend is likely to proceed. However, it is unclear how trace-metal (TM) distributions and transport are influenced by decreasing oxygen (O2) concentrations. Here we present dissolved (d;  µm) and leachable particulate (Lp; >0.2 µm) TM data collected at seven stations along a 50 km transect in the Mauritanian shelf region. We observed enhanced concentrations of Fe, Co, and Mn corresponding with low O2 concentrations ( µmol kg−1), which were decoupled from major nutrients and nutrient-like and scavenged TMs (cadmium (Cd), lead (Pb), nickel (Ni), and copper (Cu)). Additionally, data from repeated station occupations indicated a direct link between dissolved and leachable particulate Fe, Co, Mn, and O2. An observed dFe (dissolved iron) decrease from 10 to 5 nmol L−1 coincided with an O2 increase from 30 to 50 µmol kg−1 and with a concomitant decrease in turbidity. The changes in Fe (Co and Mn) were likely driven by variations in their release from sediment pore water, facilitated by lower O2 concentrations and longer residence time of the water mass on the shelf. Variations in organic matter remineralization and lithogenic inputs (atmospheric deposition or sediment resuspension; assessed using Al as indicator for lithogenic inputs) only played a minor role in redox-sensitive TM variability. Vertical dFe fluxes from O2-depleted subsurface-to-surface waters (0.08–13.5 µmol m−2 d−1) driven by turbulent mixing and vertical advection were an order of magnitude larger than atmospheric deposition fluxes (0.63–1.43 µmol m−2 d−1; estimated using dAl inventories in the surface mixed layer) in the continental slope and shelf region. Benthic fluxes are therefore the dominant dFe supply to surface waters on the continental margins of the Mauritanian upwelling region. Overall, our results indicated that the projected future decrease in O2 concentrations in OMZs may result in increases in Fe, Mn, and Co concentrations.

Atmospheric deposition is an important source of micronutrients to the ocean, but atmospheric deposition fluxes remain poorly constrained in most ocean regions due to the limited number of field observations of wet and dry atmospheric inputs. Here we present the distribution of dissolved aluminium (dAl), as a tracer of atmospheric inputs, in surface waters of the Atlantic Ocean along GEOTRACES sections GA01, GA06, GA08, and GA10. We used the surface mixed-layer concentrations of dAl to calculate atmospheric deposition fluxes using a simple steady state model. We have optimized the Al fractional aerosol solubility, the dAl residence time within the surface mixed layer and the depth of the surface mixed layer for each separate cruise to calculate the atmospheric deposition fluxes. We calculated the lowest deposition fluxes of 0.15±0.1 and 0.27±0.13 g m−2 yr−1 for the South and North Atlantic Ocean (>40∘ S and >40∘ N) respectively, and the highest fluxes of 1.8 and 3.09 g m−2 yr−1 for the south-east Atlantic and tropical Atlantic Ocean, respectively. Overall, our estimations are comparable to atmospheric dust deposition model estimates and reported field-based atmospheric deposition estimates. We note that our estimates diverge from atmospheric dust deposition model flux estimates in regions influenced by riverine Al inputs and in upwelling regions. As dAl is a key trace element in the GEOTRACES programme, the approach presented in this study allows calculations of atmospheric deposition fluxes at high spatial resolution for remote ocean regions.

The island of South Georgia is situated in the iron (Fe)-depleted Antarctic Circumpolar Current of the Southern Ocean. Iron emanating from its shelf system fuels large phytoplankton blooms downstream of the island, but the actual supply mechanisms are unclear. To address this, we present an inventory of Fe, manganese (Mn), and aluminium (Al) in shelf sediments, pore waters, and the water column in the vicinity of South Georgia, alongside data on zooplankton-mediated Fe cycling processes, and provide estimates of the relative dissolved Fe (DFe) fluxes from these sources. Seafloor sediments, modified by authigenic Fe precipitation, were the main particulate Fe source to shelf bottom waters as indicated by the similar Fe ∕ Mn and Fe ∕ Al ratios for shelf sediments and suspended particles in the water column. Less than 1 % of the total particulate Fe pool was leachable surface-adsorbed (labile) Fe and therefore potentially available to organisms. Pore waters formed the primary DFe source to shelf bottom waters, supplying 0.1–44 µmol DFe m−2 d−1. However, we estimate that only 0.41±0.26 µmol DFe m−2 d−1 was transferred to the surface mixed layer by vertical diffusive and advective mixing. Other trace metal sources to surface waters included glacial flour released by melting glaciers and via zooplankton egestion and excretion processes. On average 6.5±8.2 µmol m−2 d−1 of labile particulate Fe was supplied to the surface mixed layer via faecal pellets formed by Antarctic krill (Euphausia superba), with a further 1.1±2.2 µmol DFe m−2 d−1 released directly by the krill. The faecal pellets released by krill included seafloor-derived lithogenic and authigenic material and settled algal debris, in addition to freshly ingested suspended phytoplankton cells.The Fe requirement of the phytoplankton blooms ∼ 1250 km downstream of South Georgia was estimated as 0.33±0.11 µmol m−2 d−1, with the DFe supply by horizontal/vertical mixing, deep winter mixing, and aeolian dust estimated as ∼ 0.12 µmol m−2 d−1. We hypothesize that a substantial contribution of DFe was provided through recycling of biogenically stored Fe following luxury Fe uptake by phytoplankton on the Fe-rich shelf. This process would allow Fe to be retained in the surface mixed layer of waters downstream of South Georgia through continuous recycling and biological uptake, supplying the large downstream phytoplankton blooms.

The distribution of dissolved aluminium (dAl) in the water column of the North Atlantic and Labrador Sea was studied along GEOTRACES section GA01 to unravel the sources and sinks of this element. Surface water dAl concentrations were low (median of 2.5 nM) due to low aerosol deposition and removal by biogenic particles (i.e. phytoplankton cells). However, surface water dAl concentrations were enhanced on the Iberian and Greenland shelves (up to 30.9 nM) due to continental inputs (rivers, glacial flour, and ice melt). Dissolved Al in surface waters scaled negatively with chlorophyll a and biogenic silica (opal) concentrations. The abundance of diatoms exerted a significant (p R2 > 0.76) west of the Iberian Basin, suggesting net release of dAl at depth during remineralization of sinking opal-containing particles. Enrichment of dAl at near-bottom depths was observed due to the resuspension of sediments. The highest dAl concentrations (up to 38.7 nM) were observed in Mediterranean Outflow Waters, which act as a major source of dAl to mid-depth waters of the eastern North Atlantic. This study clearly shows that the vertical and lateral distributions of dAl in the North Atlantic differ when compared to other regions of the Atlantic and global oceans. Responsible for these large inter- and intra-basin differences are the large spatial variabilities in the main Al source, atmospheric deposition, and the main Al sink, particle scavenging by biogenic particles.

Although atmospheric 222radon (222Rn) activity concentration measurements are currently performed worldwide, they are being made by many different laboratories and with fundamentally different measurement principles, so compatibility issues can limit their utility for regional-to-global applications. Consequently, we conducted a European-wide 222Rn ∕ 222Rn progeny comparison study in order to evaluate the different measurement systems in use, determine potential systematic biases between them, and estimate correction factors that could be applied to harmonize data for their use as a tracer in atmospheric applications. Two compact portable Heidelberg radon monitors (HRM) were moved around to run for at least 1 month at each of the nine European measurement stations included in this comparison. Linear regressions between parallel data sets were calculated, yielding correction factors relative to the HRM ranging from 0.68 to 1.45. A calibration bias between ANSTO (Australian Nuclear Science and Technology Organisation) two-filter radon monitors and the HRM of ANSTO ∕ HRM = 1.11 ± 0.05 was found. Moreover, for the continental stations using one-filter systems that derive atmospheric 222Rn activity concentrations from measured atmospheric progeny activity concentrations, preliminary 214Po ∕ 222Rn disequilibrium values were also estimated. Mean station-specific disequilibrium values between 0.8 at mountain sites (e.g. Schauinsland) and 0.9 at non-mountain sites for sampling heights around 20 to 30 m above ground level were determined. The respective corrections for calibration biases and disequilibrium derived in this study need to be applied to obtain a compatible European atmospheric 222Rn data set for use in quantitative applications, such as regional model intercomparison and validation or trace gas flux estimates with the radon tracer method.

Representation of atmospheric transport is a major source of error in the estimation of greenhouse gas sources and sinks by inverse modelling. Here we assess the impact on trace gas mole fractions of the new physical parameterizations recently implemented in the atmospheric global climate model LMDz to improve vertical diffusion, mesoscale mixing by thermal plumes in the planetary boundary layer (PBL), and deep convection in the troposphere. At the same time, the horizontal and vertical resolution of the model used in the inverse system has been increased. The aim of this paper is to evaluate the impact of these developments on the representation of trace gas transport and chemistry, and to anticipate the implications for inversions of greenhouse gas emissions using such an updated model. Comparison of a one-dimensional version of LMDz with large eddy simulations shows that the thermal scheme simulates shallow convective tracer transport in the PBL over land very efficiently, and much better than previous versions of the model. This result is confirmed in three-dimensional simulations, by a much improved reproduction of the radon-222 diurnal cycle. However, the enhanced dynamics of tracer concentrations induces a stronger sensitivity of the new LMDz configuration to external meteorological forcings. At larger scales, the inter-hemispheric exchange is slightly slower when using the new version of the model, bringing them closer to observations. The increase in the vertical resolution (from 19 to 39 layers) significantly improves the representation of stratosphere/troposphere exchange. Furthermore, changes in atmospheric thermodynamic variables, such as temperature, due to changes in the PBL mixing modify chemical reaction rates, which perturb chemical equilibriums of reactive trace gases. One implication of LMDz model developments for future inversions of greenhouse gas emissions is the ability of the updated system to assimilate a larger amount of high-frequency data sampled at high-variability stations. Others implications are discussed at the end of the paper.

Fast Repetition Rate fluorometry (FRRf) measurements of phytoplankton photophysiology from an across-basin South Atlantic cruise (as part of the GEOTRACES programme) characterised two dominant ecophysiological regimes which were interpreted on the basis of nutrient limitation. South of the South Subtropical Convergence (SSTC) in the northern sub-Antarctic sector of the Antarctic Circumpolar Current (ACC) in the Eastern Atlantic Basin, waters are characterised by elevated chlorophyll concentrations, a dominance by larger phytoplankton cells, and low apparent photochemical efficiency (Fv / Fm). Shipboard 24 h iron (Fe) addition incubation experiments confirmed that Fe stress was primarily responsible for the low Fv / Fm, with Fe addition to these waters, either within the artificial bottle additions or naturally occurring downstream enrichment from Gough Island, significantly increasing Fv / Fm values. To the north of the SSTC at the southern boundary of the South Atlantic Gyre, phytoplankton are characterised by high values of Fv / Fm which, coupled with the low macronutrient concentrations and increased presence of picocyanobacteria, are interpreted as conditions of Fe replete, balanced macronutrient-limited growth. Spatial correlation was found between Fv / Fm and Fe:nitrate ratios, supporting the suggestion that the relative supply ratios of these two nutrients can control patterns of limitation and consequently the ecophysiology of phytoplankton in subtropical gyre and ACC regimes.

Parallel monitoring of 222Rn and its short-lived progeny (218Po and 214Pb) were carried out from November 2007 to April 2008 close to the top of the Schauinsland mountain, partly covered with forest, in South-West Germany. Samples were aspired from the same location at 2.5 m above ground level. We measured 222Rn with a dual flow loop, two-filter detector and its short-lived progeny with a one-filter detector. A reference sector for events, facing a steep valley and dominated by pasture, was used to minimize differences between 222Rn and progeny-derived 222Rn activity concentrations. In the two major wind sectors covered by forest to a distance between 60 m and 80 m towards the station progeny-derived 222Rn activity concentration was on average equal to 87% (without precipitation) and 74% (with precipitation) of 222Rn activity concentration. The observations show that most of the time both detector types follow the same pattern. Still, there is no single disequilibrium factor that could be used to exactly transform short-lived progeny to 222Rn activity concentration under all meteorological conditions.

BackgroundIrreversible Electroporation (IRE) is a novel image-guided tissue ablation technology that induces cell death via very short but strong pulsed electric fields. IRE has been shown to have preserving properties towards vessels and nerves and the extracellular matrix. This makes IRE an ideal candidate to treat prostate cancer (PCa) where other treatment modalities frequently unselectively destroy surrounding structures inducing severe side effects like incontinence or impotence. We report the retrospective assessment of 471 IRE treatments in 429 patients of all grades and stages of PCa with 6-year maximum follow-up time.Material and findingsThe patient cohort consisted of low (25), intermediate (88) and high-risk cancers (312). All had multi-parametric magnetic resonance imaging, and 199 men had additional 3D-mapping biopsy for diagnostic work-up prior to IRE. Patients were treated either focally (123), sub-whole-gland (154), whole-gland (134) or for recurrent disease (63) after previous radical prostatectomy, radiation therapy, etc. Adverse effects were mild (19.7%), moderate (3.7%) and severe (1.4%), never life-threatening. Urinary continence was preserved in all cases. IRE-induced erectile dysfunction persisted in 3% of the evaluated cases 12 months post treatment. Mean transient IIEF-5-Score reduction was 33% within 12-month post IRE follow-up and 15% after 12 months. Recurrences within the follow-up period occurred in 10% of the treated men, 23 in or adjacent to the treatment field and 18 outside the treatment field (residuals). Including residuals for worst case analysis, Kaplan Maier estimation on recurrence rate at 5 years resulted in 5.6% (CI95: 1.8-16.93) for Gleason 6, 14.6% (CI95: 8.8-23.7) for Gleason 7 and 39.5% (CI95: 23.5-61.4) for Gleason 8-10.ConclusionThe results indicate comparable efficacy of IRE to standard radical prostatectomy in terms of 5-year recurrence rates and better preservation of urogenital function, proving the safety and suitability of IRE for PCa treatment. The data also shows that IRE, besides focal therapy of early PCa, can also be used for whole-gland ablations, in patients with recurrent PCa, and as a problem-solver for local tumor control in T4-cancers not amenable to surgery and radiation therapy anymore.

Abstract Background Three‐dimensional (3D) ultrasonography is nonionizing and has been demonstrated to be a reliable tool for scoliosis assessment, including coronal and sagittal curvatures. It shows a great potential for axial vertebral rotation (AVR) evaluation, yet its validity and reliability need to be further demonstrated. Materials and Methods Twenty patients with adolescent idiopathic scoliosis (AIS) (coronal Cobb: 26.6 ± 9.1°) received 3D ultrasound scan for twice, 10 were scanned by the same operator, and the other 10 by different operators. EOS Bi‐planar x‐rays and 3D scan were conducted on another 29 patients on the same day. Two experienced 3D ultrasonographic researchers, with different experiences on AVR measurement, evaluated the 3D ultrasonographic AVR of the 29 patients (55 curves; coronal Cobb angle: 26.9 ± 11.3°). The gold standard AVR was determined from the 3D reconstruction of coronal and sagittal EOS radiographs. Intra‐class correlation coefficients (ICCs), mean absolute difference (MAD), standard error measurements (SEM), and Bland–Altman's bias were reported to evaluate the intra‐operator and inter‐operator/rater reliabilities of 3D ultrasonography. The reliability of 3D ultrasonographic AVR measurements was further validated using inter‐method with that of EOS. Results ICCs for intra‐operator and inter‐operator/rater reliability assessment were all greater than 0.95. MAD, SEM, and bias for the 3D ultrasonographic AVRs were no more than 2.2°, 2.0°, and 0.5°, respectively. AVRs between both modalities were strongly correlated (R2 = 0.901) and not significantly different (p = 0.205). Bland–Altman plot also shows that the bias was less than 1°, with no proportional bias between the difference and mean of expected and radiographic Cobb angles. Conclusion This study demonstrates that 3D ultrasonography is valid and reliable to evaluate AVR in AIS patients. 3D ultrasonography can be a potential tool for screening and following up subjects with AIS and evaluating the effectiveness of nonsurgical treatments.

Abstract In this work, a simple and fast method is proposed for the determination of ethanol in homeopathic medicines using thermal infrared enthalpimetry (TIE). Samples containing alcohol in a wide concentration range (from 5% to 95% v/v) were used. Purified water or absolute ethanol was added directly into homeopathic medicine and increase of temperature was monitored using an infrared camera. Total volume, stirring speed and dispensing rate of solutions were the most significant parameters studied for method optimization. A response surface methodology (RSM) was used for optimization of the experimental conditions. The method was validated in the following parameters: selectivity, linearity, linear range, precision (repeatability and intermediate precision), limit of detection and quantification, accuracy and robustness. Linear range was obtained from 4% to 55% (ethanol, v/v). The proposed method showed accuracy in agreement with the conventional one. The proposed method it was demonstrated a good alternative for determination of ethanol in homeopathic medicines, presenting low cost, fast analysis and agreement with the principles of green analytical chemistry.

Relic munitions from warfare and intentional dumping contaminate coastal waters worldwide, with an estimated 300,000 tons in the German Baltic Sea alone. These contain toxic conventional explosive chemicals, including 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitro-1,3,5-triazinane (RDX), and 1,3-dinitrobenzene (DNB). Corrosion of metal munition housings in seawater releases these munition chemicals (MCs) to the marine environment. The current study performed detailed environmental sampling throughout German waters of the southwest Baltic Sea in 2017 and 2018, and measured MCs in water, suspended particles, and sediments. At least one MC was detected in nearly every water sample, from sub-pmol/L up to several thousand pmol/L. Most MC were in the dissolved phase, not on suspended particles, and MC content in sediments was patchy and generally low. TNT levels were especially high in Kiel Bay, whereas RDX and DNB concentrations were highest in Lübeck Bay, likely reflecting regional differences in munitions types. A TNT module was developed and implemented in the General Estuarine Transport Model (GETM), incorporating TNT input to the water column by dissolution and removal by microbial degradation/transformation. Simulated TNT distributions matched observed environmental patterns well, indicating good parametrization of the primary controls. Dissolved concentrations of the target MCs were generally far below acute or chronic toxicity levels for aquatic organisms, but the highest observed concentrations approached toxic levels, especially for DNB. The inventory of dissolved MC in the study region was approximately 3000 kg, implying that current contamination levels can be sustained continuously for over 800 years by existing munitions on the seafloor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Ltd.)

Among fruits, the apple is unique for producing large amounts of the dihydrochalcone phloridzin, which, together with phloretin, its aglycone, is valuable to the pharmaceutical and food industries for its antidiabetic, antioxidant, and anticarcinogenic properties, as well as its use as a sweetener. We analysed the phloridzin concentration, total phenolic content, and antioxidant activity in the peel, flesh, seeds, juice, and pomace of 13 international and local apple varieties. In the unprocessed fruit, the seeds had the highest phloridzin content, while the highest total phenolic contents were mostly found in the peel. In processed samples, phloridzin and the total phenolic compounds especially were higher mostly in juice than in pomace. Moreover, the total phenolic content was much higher than the phloridzin content. Juice showed the highest antioxidant activity, followed by the peel and flesh. Across all samples, antioxidant activity did not directly correlate with phloridzin concentrations, suggesting that the antioxidant activity ascribed to phloridzin may need re-evaluation. In the Ferric Reducing Antioxidant Power (FRAP) assay, phloridzin only showed antioxidant activity at high concentrations when compared to its aglycone, phloretin. Considering the large amounts of apple juice produced by the juice industry, residual pomace is a promising source of phloridzin. For technical use, processing this phloridzin to phloretin would be advantageous.

Members of the Signal Peptide-Peptidase (SPP) and Signal Peptide-Peptidase-like (SPPL) family are intramembrane aspartyl-proteases like their well-studied homologs, the presenilins, which comprise the catalytically active subunit within the γ-secretase complex. The lack of in vitro cleavage assays for SPPL proteases limited their biochemical characterization as well as substrate identification and validation. So far, SPPL proteases have been analyzed exclusively in intact cells or membranes, restricting mechanistic analysis to co-expression of enzyme and substrate variants colocalizing in the same subcellular compartments. We describe the details of developing an in vitro cleavage assay for SPPL2b and its model substrate TNFα and analyzed the influence of phospholipids, detergent supplements, and cholesterol on the SPPL2b in vitro activity. SPPL2b in vitro activity resembles mechanistic principles that have been observed in a cellular context, such as cleavage sites and consecutive turnover of the TNFα transmembrane domain. The novel in vitro cleavage assay is functional with separately isolated protease and substrate and amenable to a high throughput plate-based readout overcoming previous limitations and providing the basis for studying enzyme kinetics, catalytic activity, substrate recognition, and the characteristics of small molecule inhibitors. As a proof of concept, we present the first biochemical in vitro characterization of the SPPL2a and SPPL2b specific small molecule inhibitor SPL-707., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We demonstrate a method for tissue microdissection using scanning laser ablation that is approximately two orders of magnitude faster than conventional laser capture microdissection. Our novel approach uses scanning laser optics and a slide coating under the tissue that can be excited by the laser to selectively eject regions of tissue for further processing. Tissue was dissected at 0.117 s/mm 2 without reduction in yield, sequencing insert size or base quality compared with undissected tissue. From eight cases, 58-416 mm 2 of tissue was obtained from one to four slides in 7-48 seconds total dissection time per case. These samples underwent exome sequencing and we found the variant allelic fraction increased in regions enriched for tumour as expected. This suggests that our ablation technique may be useful as a tool in both clinical and research labs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Signal-Peptide Peptidase Like-3 (SPPL3) is an intramembrane cleaving aspartyl protease that causes secretion of extracellular domains from type-II transmembrane proteins. Numerous Golgi-localized glycosidases and glucosyltransferases have been identified as physiological SPPL3 substrates. By SPPL3 dependent processing, glycan-transferring enzymes are deactivated inside the cell, as their active site-containing domain is cleaved and secreted. Thus, SPPL3 impacts on glycan patterns of many cellular and secreted proteins and can regulate protein glycosylation. However, the characteristics that make a substrate a favourable candidate for SPPL3-dependent cleavage remain unknown. To gain insights into substrate requirements, we investigated the function of a GxxxG motif located in the transmembrane domain of N-acetylglucosaminyltransferase V (GnTV), a well-known SPPL3 substrate. SPPL3-dependent secretion of the substrate's ectodomain was affected by mutations disrupting the GxxxG motif. Using deuterium/hydrogen exchange and NMR spectroscopy, we studied the effect of these mutations on the helix flexibility of the GnTV transmembrane domain and observed that increased flexibility facilitates SPPL3-dependent shedding and vice versa. This study provides first insights into the characteristics of SPPL3 substrates, combining molecular biology, biochemistry, and biophysical techniques and its results will provide the basis for better understanding the characteristics of SPPL3 substrates with implications for the substrates of other intramembrane proteases., (© 2022. The Author(s).)

The measurement of radioxenons ( 133 Xe, 131m Xe, 133m Xe, 135 Xe) in the atmosphere is a keystone for the verification of the Comprehensive Nuclear-Test-Ban Treaty (CTBT). At the German Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, BfS) activity concentrations of radioactive noble gases at several sites in Germany have been measured for more than 5 decades, initially to monitor nuclear facilities and since the mid-1990s also to support the development of measurement and monitoring systems and procedures for verification of the CTBT. Average 133 Xe activity concentration in air measured daily at station RN33 of the International Monitoring System (IMS) of the CTBTO on Mt Schauinsland has decreased since 2008. Due to the decreasing radioxenon background in the atmosphere, laboratory measurements with less sensitive proportional counters developed in-house are increasingly replaced by an isotope specific β-γ laboratory system for radioxenon analyses. Six years of radioxenon activity concentrations measured with the β-γ laboratory system in weekly samples from monitoring sites in Germany are presented. Activity concentrations of 133 Xe in southern Germany are now typically below 1 mBq m -3 and have decreased by an order of magnitude in the past 25 years. Magnitude and variability of 133 Xe activity concentrations are generally larger in northern and western Germany compared to the south, most likely due to the prevailing wind directions in the region. Selected, but typical, periods of elevated radioxenon levels at the stations are investigated and the value of stack emission data is demonstrated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Koopman and Perron-Frobenius operators for dynamical systems are becoming popular in a number of fields in science recently. Properties of the Koopman operator essentially depend on the choice of function spaces where it acts. Particularly, the case of reproducing kernel Hilbert spaces (RKHSs) is drawing increasing attention in data science. In this paper, we give a general framework for Koopman and Perron-Frobenius operators on reproducing kernel Banach spaces (RKBSs). More precisely, we extend basic known properties of these operators from RKHSs to RKBSs and state new results, including symmetry and sparsity concepts, on these operators on RKBS for discrete and continuous time systems.

The use of bioactive molecules is a promising approach to enhance the bone healing properties of biomaterials. The aim of this study was to define the role of bone sialoprotein (BSP) immobilized in collagen type I in various settings. In vitro studies with human primary osteoblasts in mono- or in co-culture with endothelial cells demonstrated a slightly increased gene expression of osteogenic markers as well as an increased proliferation rate in osteoblasts after application of BSP immobilized in collagen type I. Two critical size bone defect models were used to analyze bone regeneration. BSP incorporated in collagen type I increased bone regeneration only marginally at one concentration in a calvarial defect model. To induce the mechanical stability, three-dimensional printing was used to produce a stable porous cylinder of polylactide. The cylinder was filled with collagen type I and immobilized BSP and implanted into a femoral defect of critical size in rats. This hybrid material was able to significantly induce bone regeneration. Our study clearly shows the osteogenic effect of BSP when combined with collagen type I as carrier and thereby offers various approaches and options for its use as bioactive molecule in bone substitute materials., Competing Interests: Franz Paul Armbruster is the CEO of Immundiagnostik AG and Franziska Clauder is the employee of Immundiagnostik AG. All other authors state no conflicts of interest., (Copyright: © 2022 Kriegel, et al.)

Bidens ferulifolia is a yellow flowering plant, originating from Mexico, which is increasingly popular as an ornamental plant. In the past few years, new colour combinations ranging from pure yellow over yellow-red, white-red, pure white and purple have emerged on the market. We analysed 16 Bidens ferulifolia genotypes to provide insight into the (bio)chemical base underlying the colour formation, which involves flavonoids, anthochlors and carotenoids. In all but purple and white genotypes, anthochlors were the prevalent pigments, primarily derivatives of okanin, a 6'-deoxychalcone carrying an unusual 2'3'4'-hydroxylation pattern in ring A. The presence of a cytochrome-P450-dependent monooxygenase introducing the additional hydroxyl group in position 3' of both isoliquiritigenin and butein was demonstrated for the first time. All genotypes accumulate considerable amounts of the flavone luteolin. Red and purple genotypes additionally accumulate cyanidin-type anthocyanins. Acyanic genotypes lack flavanone 3-hydroxylase and/or dihydroflavonol 4-reductase activity, which creates a bottleneck in the anthocyanin pathway. The carotenoid spectrum was analysed in two Bidens genotypes and showed strong variation between the two cultivars. In comparison to anthochlors, carotenoids were present in much lower concentrations. Carotenoid monoesters, as well as diesters, were determined for the first time in B. ferulifolia flower extracts.

Sensing of pathogens by pattern recognition receptors (PRR) is critical to initiate protective host defence reactions. However, activation of the immune system has to be carefully titrated to avoid tissue damage necessitating mechanisms to control and terminate PRR signalling. Dectin-1 is a PRR for fungal β-glucans on immune cells that is rapidly internalised after ligand-binding. Here, we demonstrate that pathogen recognition by the Dectin-1a isoform results in the formation of a stable receptor fragment devoid of the ligand binding domain. This fragment persists in phagosomal membranes and contributes to signal transduction which is terminated by the intramembrane proteases Signal Peptide Peptidase-like (SPPL) 2a and 2b. Consequently, immune cells lacking SPPL2b demonstrate increased anti-fungal ROS production, killing capacity and cytokine responses. The identified mechanism allows to uncouple the PRR signalling response from delivery of the pathogen to degradative compartments and identifies intramembrane proteases as part of a regulatory circuit to control anti-fungal immune responses., (© 2022. The Author(s).)

A decrease in ocean pH of 0.3 units will likely double the proportion of dissolved copper (Cu) present as the free metal ion, Cu 2+ , the most bioavailable form of Cu, and one of the most common marine pollutants. We assess the impact of ocean acidification and Cu, separately and in combination, on calcification, photosynthesis and respiration of sub-colonies of a single tropical Stylophora pistillata colony. After 15 days of treatment, total calcification rates were significantly decreased in corals exposed to high seawater pCO 2 (∼1000-μatm, 2100 scenario) and at both ambient (1.6-1.9 nmols) and high (2.5-3.6 nmols) dissolved Cu concentrations compared to controls. The effect was increased when both stressors were combined. Coral respiration rates were significantly reduced by the combined stressors after 2 weeks of exposure, indicating the importance of experiment duration. It is therefore likely rising atmospheric CO 2 will exacerbate the negative effects of Cu pollution to S. pistillata., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Relic munitions are a hazardous legacy of the two world wars present in coastal waters worldwide. The southwest Baltic Sea has an especially high prevalence of unexploded ordnance and dumped munition material, which represent a large potential source of toxic explosive chemicals (munition compounds, MC). In the current study, diverse biota (plankton, macroalgae, tunicate, sponge, mollusc, echinoderm, polychaete, anemone, crustacea, fish) were collected from the Kiel Bight and a munitions dumpsite at Kolberger Heide, Germany, to evaluate the potential bioaccumulation of explosives and their derivatives (2,4,6-trinitrotoluene, TNT; 2-amino-4,6-dinitrotoluene and 4-amino-2,6-dinitrotoluene, ADNT; 2,4-diamino-6-nitrotoluene and 2,6-diamino-4-nitrotoluene, DANT; 1,3-dinitrobenzene, DNB; and 1,3,5-trinitro-1,3,5-triazinane, RDX). One or more MCs were detected in >98% of organisms collected throughout the study region (n = 178), at a median level of 6 pmol/g (approximately 1 ng/g) and up to 2 × 10 7  pmol/g (TNT in Asterias rubens collected from Kolberger Heide). In most cases, TNT and its transformation product compounds ADNT and DANT were significantly higher in biota from the munitions dumpsite compared with other locations. Generally, DNB and RDX were detected less frequently and at lower concentrations than TNT, ADNT, and DANT. In commercially important fish species (plaice, flounder) from Kolberger Heide, TNT and ADNT were detected in 17 and 33% of samples, respectively. In contrast DANT was detected in every fish sample, including those outside the dumpsite. Dinitrobenzene was the second most prevalent MC in fish tissue. Fish viscera (stomach, kidney, liver) showed higher levels of DANT than edible muscle flesh, with highest DANT in liver, suggesting reduced risk to seafood consumers. This study provides some of the first environmental evidence for widespread bioaccumulation of MC in a coastal marine food web. Although tissue MC content was generally low, corrosion of munition housings may lead to greater MC release in the future, and the ecological risk of this exposure is unknown., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Chronic infections of Candida albicans are characterised by the embedding of budding and entwined filamentous fungal cells into biofilms. The biofilms are refractory to many drugs and Candida biofilms are associated with ocular fungal infections. The objective was to test the activity of nanoparticulate amphotericin B (AmB) against Candida biofilms., Methods: AmB was encapsulated in the Molecular Envelope Technology (MET, N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan) nanoparticles and tested against Candida biofilms in vitro. Confocal laser scanning microscopy (CLSM) imaging of MET nanoparticles' penetration into experimental biofilms was carried out and a MET-AmB eye drop formulation was tested for its stability., Results: MET-AmB formulations demonstrated superior activity towards C. albicans biofilms in vitro with the EC50 being ~30 times lower than AmB alone (EC50 MET-AmB = 1.176 μg mL -1 , EC50 AmB alone = 29.09 μg mL -1 ). A similar superior activity was found for Candida glabrata biofilms, where the EC50 was ~10× lower than AmB alone (EC50 MET-AmB = 0.0253 μg mL -1 , EC50 AmB alone = 0.289 μg mL -1 ). CLSM imaging revealed that MET nanoparticles penetrated through the C. albicans biofilm matrix and bound to fungal cells. The activity of MET-AmB was no different from the activity of AmB alone against C. albicans cells in suspension (MET-AmB MIC90 = 0.125 μg mL -1 , AmB alone MIC90 = 0.250 μg mL -1 ). MET-AmB eye drops were stable at room temperature for at least 28 days., Conclusions: These biofilm activity findings raise the possibility that MET-loaded nanoparticles may be used to tackle Candida biofilm infections, such as refractory ocular fungal infections.

In recent decades, natural swimming pools (NSPs) have gained popularity in Europe, especially in Germany and Austria. NSPs differ from swimming pools in that they utilize biological treatment processes based on wetland processes with no disinfection residual. However, data are missing on the specific log-reduction performance of NSPs to address enteric virus, bacteria, and parasitic protozoa removal considered necessary to meet the North American risk-based benchmark (<35 illnesses per 1,000 swimming events) set by the USEPA for voluntary swimming. In this study, we examined Canada's first NSP at Borden Park, Edmonton, Canada, to address the following three questions: (1) Given normal faecal shedding rates by bathers, what is the total log reduction (TLR) theoretically needed to meet the EPA benchmark? (2) what is the in-situ performance of the NSP based on spiking suitable microbial surrogates (MS2 coliphage, Enterococcus faecalis, and Saccharomyces cerevisiae [Baker's yeast])? and (3) how much time is required to reach acceptable bather risk levels under different representative volume-turnover rates? A reverse-quantitative microbial risk assessment (QMRA) revealed that of the four reference pathogens selected (Norovirus, Campylobacter, Cryptosporidium, and Giardia), only Norovirus was estimated to exceed the risk benchmark at the 50th, 75th, and 95th percentiles, while Campylobacter was the only other reference pathogen to exceed at the 95th percentile. Log-reduction values (LRVs) were similar to previous reports for bacterial indicators, and novel LRVs were estimated for the other two surrogates. A key finding was that more than 24 h treatment time would be necessary to provide acceptable bather protection following heavy bather use (378 bathers/day for main pool and 26 bathers/day for children's pool), due to the mixing dynamics of the treated water diluting out possible residual pool faecal contamination. The theoretical maximum number of people in the pool per day to be below USEPA's 35 gastro cases in 1,000 swimming events was 113, 47, and 8, at the 50th, 75th, and 95th percentiles. Further, the use of ultra-violet disinfection to the pool return flow had little effect on reducing the treatment time required.

The practical application of genome-scale technologies to precision oncology research requires flexible tissue processing strategies that can be used to differentially select both tumour and normal cell populations from formalin-fixed, paraffin-embedded tissues. As tumour sequencing scales towards clinical implementation, practical difficulties in scheduling and obtaining fresh tissue biopsies at scale, including blood samples as surrogates for matched 'normal' DNA, have focused attention on the use of formalin-preserved clinical samples collected routinely for diagnostic purposes. In practice, such samples often contain both tumour and normal cells which, if correctly partitioned, could be used to profile both tumour and normal genomes, thus identifying somatic alterations. Here we report a semi-automated method for laser microdissecting entire slide-mounted tissue sections to enrich for cells of interest with sufficient yield for whole genome and transcriptome sequencing. Using this method, we demonstrated enrichment of tumour material from mixed tumour-normal samples by up to 67%. Leveraging new methods that allow for the extraction of high-quality nucleic acids from small amounts of formalin-fixed tissues, we further showed that the method was successful in yielding sequence data of sufficient quality for use in BC Cancer's Personalized OncoGenomics (POG) program. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: Multiple studies have demonstrated the National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) to be a responsive and efficient measure for patients undergoing orthopaedic surgery. While these studies were rigorous in their protocol and methodology, no efforts in recent literature have been made to identify if these reference scores apply to elite athletes., Purpose/hypothesis: The purpose of this study was to determine whether there is a difference in the baseline scores of elite athletes versus the general population. We hypothesized that athletes' PROMIS upper extremity general function (PROMIS-UE) and general physical function (PROMIS-PF) scores would vary substantially from the mean health state of the general population. We further hypothesized that these scores would be affected by specific sport and level of competition., Study Design: Cross-sectional study; Level of evidence, 3., Methods: Three PROMIS computer adaptive test (CAT) domains were administered to elite athlete (≥18 years) volunteers (either in person or through email). An elite athlete was defined as one participating in sports at the collegiate level or higher. Test domains included PROMIS-PF, PROMIS-UE, and pain interference (PROMIS-PI). PROMIS domain t scores were defined and assessed against NIH reference values to identify significant differences. Distribution analysis was conducted using histograms and normality assessments. Domains were also subject to correlation analysis. Finally, subgroup analysis was conducted for all athlete characteristics to identify any factors associated with variance., Results: In total, 196 elite athletes (mean age, 21.1 years; range, 18.0-36.7 years) completed all 3 PROMIS-CAT forms. Overall, the mean scores were 56.0 ± 6.4, 58.1 ± 7.7, and 47.1 ± 7.3 for PROMIS-UE, PROMIS-PF, and PROMIS-PI, respectively. Distribution analysis showed nonnormal distribution for all 3 PROMIS domains (Kolmogorov-Smirnov test, P < .001). Similarly, in all 3 PROMIS domains the athletes displayed more disparate scores than the NIH-reported reference values (1-way sign test, P < .001). Only the presence of pain and sport played showed association with variance in PROMIS domain scores ( P < .001 and P = .003, respectively)., Conclusion: Elite athletes displayed more disparate reference scores than the NIH-reported average of 50 for PROMIS-UE, PROMIS-PF, and PROMIS-PI. Furthermore, these forms were sensitive to varying levels of sport among collegiate athletes., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: K.R.O. has received educational support from Medwest and Smith & Nephew and hospitality payments from Medical Device Business Services, Stryker, Wright Medical, and Zimmer Biomet. E.C.M. has received educational support from Arthrex and Pinnacle and consulting fees from Smith & Nephew. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

We report on in vitro wound-healing and cell-growth studies under the influence of radio-frequency (rf) cell stimuli. These stimuli are supplied either by piezoactive surface acoustic waves (SAWs) or by microelectrode-generated electric fields, both at frequencies around 100 MHz. Employing live-cell imaging, we studied the time- and power-dependent healing of artificial wounds on a piezoelectric chip for different cell lines. If the cell stimulation is mediated by piezomechanical SAWs, we observe a pronounced, significant maximum of the cell-growth rate at a specific SAW amplitude, resulting in an increase of the wound-healing speed of up to 135 ± 85% as compared to an internal reference. In contrast, cells being stimulated only by electrical fields of the same magnitude as the ones exposed to SAWs exhibit no significant effect. In this study, we investigate this effect for different wavelengths, amplitude modulation of the applied electrical rf signal, and different wave modes. Furthermore, to obtain insight into the biological response to the stimulus, we also determined both the cell-proliferation rate and the cellular stress levels. While the proliferation rate is significantly increased for a wide power range, cell stress remains low and within the normal range. Our findings demonstrate that SAW-based vibrational cell stimulation bears the potential for an alternative method to conventional ultrasound treatment, overcoming some of its limitations., Competing Interests: The authors declare no competing interest.

In July 2015, the currently only active monitoring station for atmospheric 85 Kr measurements in the southern hemisphere went operational at the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Adelaide, Australia. Here, this new data is presented and combined with measurements from historic monitoring stations, to generate a 85 Kr input function for the southern hemisphere which is crucial for the application of 85 Kr as a dating tracer for water and ice. After a linear increase in atmospheric 85 Kr concentrations between 1980 and 2005, concentrations stabilized yielding mean 85 Kr activity concentration during the Adelaide monitoring period of 1.3 ± 0.15 Bq/m³ air with slight variations indicating seasonal effects. Data from three northern hemispheric monitoring stations Schauinsland, Freiburg and Jungfraujoch of the German Federal Office for Radiation Protection (BfS), located in Central Europe are used to calculate an interhemispheric exchange time of 1.25 ± 0.24 years, using a simple box model approach. Furthermore, it is investigated whether a southern hemispheric 85 Kr input function can be calculated from the baseline of the northern hemispheric data set. A comparison between the calculated and the fitted input function shows that analytical techniques can just resolve the concentration differences, emphasising the need of southern hemispheric monitoring stations for 85 Kr. Analysing the decay-corrected input function and taking the current detection limit of low-level counting and Atom Trap Trace Analysis of 0.05 Bq/m³ air, a maximum apparent 85 Kr tracer age of 40 years can be determined in the southern hemisphere. Finally, the 85 Kr measurements are used to derive global 85 Kr emission rates which are found to be in good agreement with published emissions from nuclear reprocessing plants., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

With a half-life of 10.7 years, the noble gas radioisotope 85 Kr is perfectly suited as a tracer to date ice and water that formed during the past half century. Furthermore, due to its inhomogeneous input into the atmosphere, it is a useful tool to investigate atmospheric circulation and back-trajectory analysis. The data presented here represent a comprehensive time series of atmospheric 85 Kr activity concentrations in ground level air that can be used to model northern and southern hemispheric input functions, which is essential to apply 85 Kr as a dating tracer. The collection comprises 11 datasets from 4 monitoring stations in the northern and 7 monitoring stations in the southern hemisphere, respectively. In total, it contains about 8000 measurements performed over the past 60 years, making it the largest published 85 Kr record., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2020 The Authors. Published by Elsevier Inc.)

Ectodomain (EC) shedding defines the proteolytic removal of a membrane protein EC and acts as an important molecular switch in signaling and other cellular processes. Using tumor necrosis factor (TNF)α as a model substrate, we identify a non-canonical shedding activity of SPPL2a, an intramembrane cleaving aspartyl protease of the GxGD type. Proline insertions in the TNFα transmembrane (TM) helix strongly increased SPPL2a non-canonical shedding, while leucine mutations decreased this cleavage. Using biophysical and structural analysis, as well as molecular dynamic simulations, we identified a flexible region in the center of the TNFα wildtype TM domain, which plays an important role in the processing of TNFα by SPPL2a. This study combines molecular biology, biochemistry, and biophysics to provide insights into the dynamic architecture of a substrate's TM helix and its impact on non-canonical shedding. Thus, these data will provide the basis to identify further physiological substrates of non-canonical shedding in the future., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

Cherubism (OMIM#118400) is a craniofacial disorder characterized by destructive jaw expansion. Gain-of-function mutations in SH3-domain binding protein 2 (SH3BP2) are responsible for this rare disorder. We have previously shown that homozygous knock-in (KI) mice ( Sh3bp2 KI/KI ) recapitulate human cherubism by developing inflammatory lesions in the jaw. However, it remains unknown why heterozygous KI mice ( Sh3bp2 KI/+ ) do not recapitulate the excessive jawbone destruction in human cherubism, even though all mutations are heterozygous in humans. We hypothesized that Sh3bp2 KI/+ mice need to be challenged for developing exacerbated jawbone destruction and that bacterial stimulation in the oral cavity may be involved in the mechanism. In this study, we applied a ligature-induced periodontitis model to Sh3bp2 KI/+ mice to induce inflammatory alveolar bone destruction. Ligature placement induced alveolar bone resorption with gingival inflammation. Quantification of alveolar bone volume revealed that Sh3bp2 KI/+ mice developed more severe bone loss (male: 43.0% ± 10.6%, female: 42.6% ± 10.4%) compared with Sh3bp2 +/+ mice (male: 25.8% ± 4.0%, female: 30.9% ± 6.5%). Measurement of bone loss by the cement-enamel junction-alveolar bone crest distance showed no difference between Sh3bp2 KI/+ and Sh3bp2 +/+ mice. The number of osteoclasts on the alveolar bone surface was higher in male Sh3bp2 KI/+ mice, but not in females, compared with Sh3bp2 +/+ mice. In contrast, inflammatory cytokine levels in gingiva were comparable between Sh3bp2 KI/+ and Sh3bp2 +/+ mice with ligatures. Genetic deletion of the spleen tyrosine kinase in myeloid cells and antibiotic treatment suppressed alveolar bone loss in Sh3bp2 KI/+ mice, suggesting that increased osteoclast differentiation and function mediated by SYK and accumulation of oral bacteria are responsible for the increased alveolar bone loss in Sh3bp2 KI/+ mice with ligature-induced periodontitis. High amounts of oral bacterial load caused by insufficient oral hygiene could be a trigger for the initiation of jawbone destruction in human cherubism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research., (© 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.)

Periodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth-supporting tissues including alveolar bone are destructed. Previously, we have shown that the adaptor protein SH3-domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro-CT analysis of SH3BP2-deficient (Sh3bp2 -/- ) mice challenged with ligature-induced periodontitis revealed that Sh3bp2 -/- mice develop decreased alveolar bone loss (male 14.9% ± 10.2%; female 19.0% ± 6.0%) compared with wild-type control mice (male 25.3% ± 5.8%; female 30.8% ± 5.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with LysM-Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2-SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone-resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS-9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS-9973 treatment of bone marrow-derived M-CSF-dependent macrophages suppressed tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation with decreased mineral resorption capacity even when GS-9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2-SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Purpose: 4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. To overcome limitations of current 4-1BB-targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation., Experimental Design: PRS-343 was generated by the genetic fusion of 4-1BB-specific Anticalin proteins to a variant of trastuzumab with an engineered IgG4 isotype. Its activity was characterized using a panel of in vitro assays and humanized mouse models. The safety was assessed using ex vivo human cell assays and a toxicity study in cynomolgus monkeys., Results: PRS-343 targets 4-1BB and HER2 with high affinity and binds both targets simultaneously. 4-1BB-expressing T cells are efficiently costimulated when incubated with PRS-343 in the presence of cancer cells expressing HER2, as evidenced by increased production of proinflammatory cytokines (IL2, GM-CSF, TNFα, and IFNγ). In a humanized mouse model engrafted with HER2-positive SK-OV-3 tumor cells and human peripheral blood mononuclear cells, PRS-343 leads to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. In IND-enabling studies, PRS-343 was found to be well tolerated, with no overt toxicity and no relevant drug-related toxicologic findings., Conclusions: PRS-343 facilitates tumor-localized targeting of T cells by bispecific engagement of HER2 and 4-1BB. This approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity compared with current monospecific approaches. The reported data led to initiation of a phase I clinical trial with this first-in-class molecule. See related commentary by Su et al., p. 5732 ., (©2019 American Association for Cancer Research.)

For almost half a century weekly samples for the measurement of krypton-85 ( 85 Kr) activity concentrations in surface air have been collected by the Bundesamt für Strahlenschutz (BfS), Germany. Sampling started at Freiburg (230m asl) in 1973, Mt Schauinsland (1205m asl) in 1976 and Mt Jungfraujoch in Switzerland (3454 asl) in 1990. Distinct maxima in the time series of atmospheric 85 Kr activity concentration are caused by emissions from nuclear reprocessing plants in Europe, mainly the La Hague, France, and Sellafield, UK, reprocessing plants. Between 1970 and 1990 peak activity concentrations measured in winter along the Rhine Rift in Freiburg are often higher than at Mt Schauinsland, due to emissions from the operating pilot reprocessing plant in Karlsruhe - approximately 130 km to the north - and large-scale inversions that inhibit exchange of air masses within the Rhine Rift with those at higher altitudes. From the early 1990s onwards, after the shut-down of the pilot plant, differences between Freiburg and Schauinsland are much smaller. Activity concentrations measured at Jungfraujoch are generally lower and close to baseline levels, due to its location in the free troposphere. Weekly baseline and average 85 Kr activity concentration in the atmosphere in Central Europe were modelled from almost 12,000 individual measurements at 11 stations. The baseline and average have continuously increased, interrupted by a relatively stable period between 2009 and the end of 2014 with a baseline activity concentration of about 1.39 Bq/m 3 . Depending on the geographical location and hydrological conditions, the modelled baseline or average 85 Kr activity concentration time series can be used as input functions for the dating of young groundwater., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

As a consequence of World War II, large amounts of munition have been deposited in coastal waters. Deterioration of the mines and bombs is resulting in a release of munition compounds (MCs) like trinitrotoluene to the surrounding marine environment, with potential implications to ecosystems. Analytical methods have thus far been unable to detect these compounds reliably in seawater. We present a highly sensitive method for the analysis of MCs in the marine environment. We combine preconcentration and sample clean up by solid phase extraction with separation and detection by ultra-high performance liquid chromatography - electrospray ionisation - mass spectrometry (UHPLC-ESI-MS) for the detection of MCs dissolved in filtered (< 0.2 µm) seawater. For biota, dried and ground samples were extracted in acetonitrile and analysed after simple dilution. Eleven MCs were detected by UHPLC-ESI-MS with limits of detection between 0.01 and 25 pg. For the first time, we used heavy isotopes of trinitroluene and dinitrobenzene to improve quantification in environmental samples. We detected 7 MCs in waters sampled at a known munition disposal site in the Baltic Sea after a 1000-fold preconcentration and using an injection volume of 25 µL. Trinitrotoluene and dinitrobenzene were the most abundant MCs, occurring at concentrations between 0.1 and 11.8 ng L -1 . We observed 10 MCs at concentrations up to 24 µg g -1 dry weight in benthic organisms sampled from the site. The enhanced sensitivity of our method allowed us to detect MCs at concentrations relevant for assessment and management of munitions disposal sites in the marine environment., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Underwater munitions containing millions of tons of toxic explosives are present worldwide in coastal marine waters as a result of unexploded ordnance and intentional dumping. The dissolution flux of solid explosives following corrosion of metal munition housings controls the exposure of biological receptors to toxic munition compounds (MC), including TNT: 2,4,6-trinitrotoluene, RDX: 1,3,5-trinitro-1,3,5-triazinane, and DNB: 1,3-dinitrobenzene. Very little is known about the dissolution behavior of MC in the marine environment. In this work, we exploit a unique marine study site in the Baltic Sea with exposed solid explosives to quantify in situ MC dissolution fluxes using dissolved MC gradients near the exposed explosive surface, as well as benthic chamber incubations. The gradient method gave dissolution fluxes that ranged between 0.001 and 3.2, between 0.0001 and 0.04, and between 0.003 and 1.7 mg cm -2 day -1 for TNT, RDX, and DNB, respectively. Benthic chamber incubations indicated dissolution fluxes of 0.0047-0.277, 0-0.11, and 0.00047-1.45 mg cm -2 day -1 for TNT, RDX, and DNB, respectively. In situ dissolution fluxes estimated in the current study were lower than most dissolution rates reported for laboratory experiments, but they clearly demonstrated that MC are released from underwater munitions to the water column in the Baltic Sea.

Deep learning refers to a set of computer models that have recently been used to make unprecedented progress in the way computers extract information from images. These algorithms have been applied to tasks in numerous medical specialties, most extensively radiology and pathology, and in some cases have attained performance comparable to human experts. Furthermore, it is possible that deep learning could be used to extract data from medical images that would not be apparent by human analysis and could be used to inform on molecular status, prognosis, or treatment sensitivity. In this review, we outline the current developments and state-of-the-art in applying deep learning for cancer diagnosis, and discuss the challenges in adapting the technology for widespread clinical deployment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein β-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of β-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, β-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of β-synuclein in provoking T-cell-mediated pathology of the central nervous system.

Purpose: 3-D printing is an increasingly widespread technology that allows physical models to be constructed based on cross-sectional medical imaging data. We sought to develop a pipeline for production of 3-dimensional (3-D) models for presurgical planning and assess the value of these models for surgeons and patients., Methods: In this institutional review board-approved, single-center case series, participating surgeons identified cases for 3-D model printing, and after obtaining patient consent, a 3-D model was produced for each of the 7 participating patients based on preoperative cross-sectional imaging. Each model was given to the surgeon to use during the surgical consent discussion and preoperative planning. Patients and surgeons completed questionnaires evaluating the quality and usefulness of the models., Results: The 3-D models improved surgeon confidence in their operative approach, influencing the choice of operative approach in the majority of cases. Patients and surgeons reported that the model improved patient comprehension of the surgery during the consent discussion, including risks and benefits of the surgery. Model production time was as little as 4 days, and the average per-model cost was $350., Conclusions: 3-D printed models are useful presurgical tools from both surgeon and patient perspectives. Development of local hospital-based 3-D printing capabilities enables model production with rapid turnaround and modest cost, representing a value-added service for radiologists to offer their surgical colleagues., (Copyright © 2018 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.)

Dissolved iron (DFe) concentrations in oxygen minimum zones (OMZs) of Eastern Boundary Upwelling Systems are enhanced as a result of high supply rates from anoxic sediments. However, pronounced variations in DFe concentrations in anoxic coastal waters of the Peruvian OMZ indicate that there are factors in addition to dissolved oxygen concentrations (O 2 ) that control Fe cycling. Our study demonstrates that sediment-derived reduced Fe (Fe(II)) forms the main DFe fraction in the anoxic/euxinic water column off Peru, which is responsible for DFe accumulations of up to 200 nmol L -1 . Lowest DFe values were observed in anoxic shelf waters in the presence of nitrate and nitrite. This reflects oxidation of sediment-sourced Fe(II) associated with nitrate/nitrite reduction and subsequent removal as particulate Fe(III) oxyhydroxides. Unexpectedly, the highest DFe levels were observed in waters with elevated concentrations of hydrogen sulfide (up to 4 µmol L -1 ) and correspondingly depleted nitrate/nitrite concentrations (<0.18 µmol L -1 ). Under these conditions, Fe removal was reduced through stabilization of Fe(II) as aqueous iron sulfide (FeS aqu ) which comprises complexes (e.g., FeSH + ) and clusters (e.g., Fe 2 S 2 |4H 2 O). Sulfidic events on the Peruvian shelf consequently enhance Fe availability, and may increase in frequency in future due to projected expansion and intensification of OMZs.

Certification of trace metals in seawater certified reference materials (CRMs) NASS-7 and CASS-6 is described. At the National Research Council Canada (NRC), column separation was performed to remove the seawater matrix prior to the determination of Cd, Cr, Cu, Fe, Pb, Mn, Mo, Ni, U, V, and Zn, whereas As was directly measured in 10-fold diluted seawater samples, and B was directly measured in 200-fold diluted seawater samples. High-resolution inductively coupled plasma mass spectrometry (HR-ICPMS) was used for elemental analyses, with double isotope dilution for the accurate determination of B, Cd, Cr, Cu, Fe, Pb, Mo, Ni, U, and Zn in seawater NASS-7 and CASS-6, and standard addition calibration for As, Co, Mn, and V. In addition, all analytes were measured using standard addition calibration with triple quadrupole (QQQ)-ICPMS to provide a second set of data at NRC. Expert laboratories worldwide were invited to contribute data to the certification of trace metals in NASS-7 and CASS-6. Various analytical methods were employed by participants including column separation, co-precipitation, and simple dilution coupled to ICPMS detection or flow injection analysis coupled to chemiluminescence detection, with use of double isotope dilution calibration, matrix matching external calibration, and standard addition calibration. Results presented in this study show that majority of laboratories have demonstrated their measurement capabilities for the accurate determination of trace metals in seawater. As a result of this comparison, certified/reference values and associated uncertainties were assigned for 14 elements in seawater CRMs NASS-7 and CASS-6, suitable for the validation of methods used for seawater analysis.

Due to its half-life, chemical inertness and low solubility in water, radioactive 85 Kr is a valuable tracer for testing the performance of atmospheric dispersion models in simulating long-range transport of pollutants. This paper evaluates the capability of simulating the dispersion of radiokrypton emitted by a nuclear fuel reprocessing plant in north-west France. Three time periods during which elevated activity concentrations of 85 Kr in ground level air were detected in south-west Germany are chosen. Simulations have been performed using the HYSPLIT code and the European Centre for Median-Range Weather Forecasts (ECMWF) data base. Although their results show a slight trend of underestimating the measured 85 Kr concentrations, there is a significant correlation and moderate scatter between observations and simulations with about 50% of the results being within a factor of two of the measured concentrations. The simulated travel time distributions provided a valuable tool for providing additional insight into the dispersion of the tracer radionuclides and for identifying potential causes of deviations between measured and calculated concentrations., (Copyright © 2017. Published by Elsevier Ltd.)

To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimer's β-amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases.

Proportional counters and a β-γ coincidence system and their performance characteristics are described, with emphasis on internal and external quality controls. Typical limits of detection (LD) are 8mBqm -3 for 85 Kr and 4mBqm -3 for 133 Xe for the proportional counters, while for similar xenon volumes the LD for 133 Xe in the β-γ system is approximately 4 times lower. Results of comparative analyses agree above the limit of quantification. Xenon-133 levels in southern Germany are presently at or below the LD of the proportional counters, but above the LD of the β-γ system, which is now routinely used for analysis of environmental samples., (Copyright © 2017 Elsevier Ltd. All rights reserved.)