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Thin strips of electrochemically deposited nanocrystalline nickel-iron with thicknesses of 320 or 330 µm are modified by defined grinding. Small changes in the cutting depth and the variation of the grinding process, up cut or down cut, result in different surface states. X-ray diffraction provides the analyses of the microstructures and residual stresses on the surfaces. In the initial state, the grain sizes have an average value of 9.3 nm, the micro strains 0.74% and the residual stresses predominantly values in the low-pressure range. Up grinding with the smallest depth of cut 1 µm causes the lowest compressive residual stresses at workpiece surface due to cold plastic deformation. Larger cutting depths and surface temperatures reduce the mechanical effects. Then prevailing thermal effects cause tensile residual stresses through thermoplastic deformation and through changes in the microstructure, which can be observed by grain enlargements and decreases in micro strains. However, the recovery and recrystallization processes are only partial. Down grinding with a cutting depth of 3 µm thus leads to a maximum grain size increase to 23.4 nm and a maximum decrease in micro strain to 0.41% as well as to maximum residual stresses of 880 MPa.

The endoplasmic reticulum (ER) undergoes continuous remodelling via a selective autophagy pathway, known as ER-phagy1. ER-phagy receptors have a central role in this process2, but the regulatory mechanism remains largely unknown. Here we report that ubiquitination of the ER-phagy receptor FAM134B within its reticulon homology domain (RHD) promotes receptor clustering and binding to lipidated LC3B, thereby stimulating ER-phagy. Molecular dynamics (MD) simulations showed how ubiquitination perturbs the RHD structure in model bilayers and enhances membrane curvature induction. Ubiquitin molecules on RHDs mediate interactions between neighbouring RHDs to form dense receptor clusters that facilitate the large-scale remodelling of lipid bilayers. Membrane remodelling was reconstituted in vitro with liposomes and ubiquitinated FAM134B. Using super-resolution microscopy, we discovered FAM134B nanoclusters and microclusters in cells. Quantitative image analysis revealed a ubiquitin-mediated increase in FAM134B oligomerization and cluster size. We found that the E3 ligase AMFR, within multimeric ER-phagy receptor clusters, catalyses FAM134B ubiquitination and regulates the dynamic flux of ER-phagy. Our results show that ubiquitination enhances RHD functions via receptor clustering, facilitates ER-phagy and controls ER remodelling in response to cellular demands.

Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)1. Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons2. Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss3, interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance.

Funding Acknowledgements Type of funding sources: None. Background/Introduction Catheter ablation of symptomatic atrial fibrillation (AF) is an established treatment option. Cryoballoon (CBA) and radiofrequency ablation (RFA) have demonstrated comparable high rates of freedom from atrial arrhythmia recurrence. Comparative data on quality of life (QoL) outcomes with respect to the used energy source are scarce. Purpose To compare QoL changes following CBA versus RFA in symptomatic AF. Methods This is a sub-analysis of the prospective multi-center FREEZE Cohort Study (ClinicalTrials.gov, NCT01360008). QoL changes were assessed by EQ-5D-3L self-report questionnaire and by EHRA symptom score at baseline and follow-up. Five dimensions of QoL were compared between the treatment groups: "mobility", "self-care", "usual activities", "pain/discomfort", and "anxiety/depression". Changes of Visual Analogue Scale (EQ-VAS) and general physical condition (GPC) were assessed. Results From 2011 to 2016, a total of N=4,189 patients were included, and N=2,110 (50.4%) - CBA N=1,590 (75%) and RFA N=529 (25%) - completed all QoL questionnaires. Differences between groups were observed. Mean age was 61.4±10.4 (CBA) and 63.2±10.4 (RFA) years (p/= II in 89.7% versus 92.9% of patients in CBA and RFA group at baseline (p At follow-up, atrial arrhythmia recurrence was documented in 45.0% and 56.9% of patients in the CBA and RFA group (p/= II was documented in 23.7% and 32.0% of patients (p Significant differences in QoL dimensions from baseline to follow-up were observed between the groups (see Figure): Patients in the CBA group showed a statistically significant greater improvement for the QoL dimension "pain/discomfort", „general physical condition", EQ-VAS, and EQ-5D-Score as compared to the RFA group (all p Conclusion Catheter ablation in symptomatic AF was associated with a significant improvement of AF symptoms, "pain/discomfort", "anxiety/depression", and GPC in both groups. However, there was only a small benefit of ablation on „mobility", „self-care", and „usual activities". Interestingly, in the CBA group patients reported significantly more frequently amelioration of "pain/discomfort" and „general physical condition". This finding was confirmed by a higher EQ-VAS and EQ-5D-Score as well as a higher level of satisfaction in the CBA group, and might be related to the lower recurrence rate.

Funding Acknowledgements Type of funding sources: None. Background Pulmonary vein isolation (PVI) is an effective treatment strategy in symptomatic atrial fibrillation (AF) patients. However, this approach shows worse long-term results in individuals suffering from persistent compared to the paroxysmal type. Purpose The objective was to investigate differences of left atrial (LA) as well as left atrial appendage (LAA) anatomy in persistent AF (persAF) and paroxysmal (PAF) and patients. Methods An observational single center study with a blinded retrospective analysis of cardiac computed tomography angiography (CCTA) images was conducted. Dimensions of LA, posterior wall box, pulmonary veins (PV) as well as LAA size and morphology were assessed and statistically analyzed. All important measures are depicted in the attached figure. Results From 2012 to 2016 a total of 1.103 patients underwent second generation cryoballoon PVI. Prior to PVI, CCTA was available for 725 (65.7%) patients with sufficient quality for measuring in 473 (65.2%). Mean age was 66.3±9.5 years; PAF was present in 277 (58.6%) participants. In persAF LA volume [mL] (111.8; 128.8; p Conclusion Compared to PAF, persAF patients had significantly larger LA volumes, posterior wall box areas, PV ostial dimensions as well as LAA volumes and LAA ostial perimeters. LAA morphological types were distributed equally in both groups.

Whereas European ground squirrels (Spermophilus citellus) do not utilize food caches during hibernation, it has occasionally been reported that they store food during the active season. Recent evidence for S. citellus maintaining food stores in summer arose during the long-term ecological supervision of a construction project in Vienna, Austria. From the onset of the project in 2012, ground squirrels were observed to forage on tubers of the tuberous vetchling (Lathyrus tuberosus). During the preparation of a building plot in July 2016, a cavity containing 380g of tubers of L. tuberosus was excavated by a digger when removing the upper 30 cm soil layer. When the construction area was expanded in July 2017, a ground squirrel repeatedly inspected a burrow on a future building plot, once carrying a tuber to the burrow. To examine if the burrow was vacant, it was stripped by layer, revealing a cache of 290g tubers in a blind-ending tunnel at a depth of about 90 cm. The structure consisted of one chamber without nesting material, and one tunnel containing the cache. We conclude that the burrow may have served as a hideout facilitating food intake while avoiding predation and other adverse external conditions.

This Viewpoint discusses recent legal directives by the DHHS and FDA that could increase health care entities’ liability for possible discriminatory biases of clinical algorithms and the need for additional legal clarity to avoid adverse effects on algorithm development and use.

Over twenty years have passed since JLME published “The Girl Who Cried Pain: A Bias Against Women in the Treatment of Pain.” This article revisits the conclusions drawn in that piece and explores what we have learned in the last two decades regarding the experience of men and women who have chronic pain and whether women continue to be treated less aggressively for their pain than men.

By regulating several hallmarks of cancer, BAG3 exerts oncogenic functions in a wide variety of malignant diseases including glioblastoma (GBM) and triple-negative breast cancer (TNBC). Here we performed global proteomic/phosphoproteomic analyses of CRISPR/Cas9-mediated isogenic BAG3 knockouts of the two GBM lines U343 and U251 in comparison to parental controls. Depletion of BAG3 evoked major effects on proteins involved in ciliogenesis/ciliary function and the activity of the related kinases aurora-kinase A and CDK1. Cilia formation was significantly enhanced in BAG3 KO cells, a finding that could be confirmed in BAG3-deficient versus -proficient BT-549 TNBC cells, thus identifying a completely novel function of BAG3 as a negative regulator of ciliogenesis. Furthermore, we demonstrate that enhanced ciliogenesis and reduced expression of SNAI1 and ZEB1, two key transcription factors regulating epithelial to mesenchymal transition (EMT) are correlated to decreased cell migration, both in the GBM and TNBC BAG3 knockout cells. Our data obtained in two different tumor entities identify suppression of EMT and ciliogenesis as putative synergizing mechanisms of BAG3-driven tumor aggressiveness in therapy-resistant cancers.

Das Spektrum medizinrechtlicher Probleme im notarztlichen Rettungsdienst ist umfangreich. Es mussen spezielle juristische Fragen geklart sein: einerseits beispielsweise die Wahrnehmung von Sonderrechten, die Zustandigkeit und Kompetenz fur bestimmte Masnahmen zwischen Rettungsdienstmitarbeitern/‑innen und Notarzten/‑innen, besondere Situationen wie die Therapieverweigerung, ein Suizidversuch, aggressive Patienten/‑innen, Verletzungen nach hauslicher Gewalt einschlieslich Kindesmisshandlung und Haftungsfragen, andererseits muss mit entscheidungsunfahigen Patienten/‑innen umgegangen werden, polizeiliche Masnahmen am Notfallort konnen zu einer Einbindung des Rettungsdiensts fuhren und es kann eine Todesfeststellung mit oder ohne grundliche Leichenschau und Ausfullen der entsprechenden Formulare erforderlich sein.

The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain-containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 co-precipitates with, and is directly phosphorylated by, mTOR. Using a phospho-specific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2-mediated phosphorylation in a growth factor-dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor- and amino acid-sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

Responding to a major pandemic and planning for allocation of scarce resources (ASR) under crisis standards of care requires coordination and cooperation across federal, state and local governments in tandem with the larger societal infrastructure. Maryland remains one of the few states with no state-endorsed ASR plan, despite having a plan published in 2017 that was informed by public forums across the state. In this article, we review strengths and weaknesses of Maryland’s response to COVID-19 and the role of the Maryland Healthcare Ethics Committee Network (MHECN) in bridging gaps in the state’s response to prepare health care facilities for potential implementation of ASR plans. Identified “lessons learned” include: Deliberative Democracy Provided a Strong Foundation for Maryland’s ASR Framework; Community Consensus is Informative, Not Normative; Hearing Community Voices Has Inherent Value; Lack of Transparency & Political Leadership Gaps Generate a Fragmented Response; Pandemic Politics Requires Diplomacy & Persistence; Strong Leadership is Needed to Avoid Implementing ASR … And to Plan for ASR; An Effective Pandemic Response Requires Coordination and Information-Sharing Beyond the Acute Care Hospital; and The Ability to Correct Course is Crucial: Reconsidering No-visitor Policies.

Objective The aim of this study was to describe a technique for performing miniature tibial tuberosity transposition and advancement (mTTTA). The secondary objective of this study was to compare the short-term outcome and complications in small breed dogs weighing less than 12 kg undergoing surgical correction of cranial cruciate ligament disease with concurrent medial patellar luxation via either extracapsular stabilization with tibial tuberosity transposition (ECS + TTT) or mTTTA. Study Design This is a retrospective case comparison study. Results There was no significant difference in overall outcome between the ECS + TTT group and the mTTTA group when comparing 8-week postoperative radiographic healing scores as well as 2- and 8-week postoperative lameness scores. Conclusion This study concluded that the mTTTA procedure was feasible and the overall outcome and complications for the dogs that underwent ECS + TTT and those that underwent mTTTA were comparable.

Eoarchean mantle and mantle-derived rocks can provide primary information on geodynamic processes operating on the early Earth. This study combines new petrological observations, comprehensive major and trace element data as well as Lu-Hf and Sm-Nd isotope compositions of > 3.81 Ga ultramafic rocks from the Itsaq Gneiss Complex (IGC) in southern West Greenland. The sample set includes mantle peridotites and associated amphibolites from the Narssaq ultramafic body (Faeringehavn terrane) and from the region south of the Isua supracrustal belt (Isukasia terrane). Lutetium-Hf whole rock age regression lines mainly yield Eoarchean ages of ca. 3.9 to 3.8 Ga, in good agreement with minimum ages inferred from field relationships (>3.8 Ga). Major and trace element signatures, the Lu-Hf isotope inventory as well as most major elements, MREE, HREE, and HFSE were only slightly disturbed during metamorphic overprint. Nearly flat primitive mantle-normalized REE patterns obtained for the mantle peridotites resemble those of refertilized modern abyssal peridotites and may reflect re-enrichment of initially depleted peridotite by melt-like subduction components, as also indicated by Th-HFSE-REE characteristics. Based on a simple evolution-model for the investigated mantle rocks, we suggest that the compositions are best explained by partial hydrous melt depletion in the spinel stability field, followed by refertilization by low quantities of adakite-like melt. Altogether, the geochemical data can be put in the framework of a geodynamic model, where Eoarchean mantle underwent significant melt extraction and subsequent re-fertilization by subduction-like components. Based on this finding, we propose that the Eoarchean mantle peridotites from SW Greenland represent remnants of a mantle wedge, confirming that subduction-like processes were in operation since at least the Eoarchean.

Cricetus cricetus (Linnaeus, 1758) is a medium-sized cricetid commonly called the common hamster. A sexually dimorphic rodent of unique coloration with robust body, blunt head, short legs, and rudimentary tail, it is the largest hamster and the only species in the genus Cricetus. It is easily recognizable by a color pattern of contrasting dark and light areas. Because its distribution extends from northwestern Europe to eastern China across 5,500 km of low altitude agricultural land, steppe, and forest steppe, the frequently used term European hamster is misleading. Both geographic range and relative abundance started declining in the 1960s on the western edge of its distribution, and now C. cricetus is protected by the Bern Convention and the Fauna-Flora-Habitats Directives.

Background Recently, a molecular signature describing the mesenchymal / proneural features of primary stem-cell-enriched glioblastoma cultures was identified correlating with invasiveness, radiation sensitivity and patient-outcome. However, generating and characterizing primary cultures is time-consuming and this might hamper translation into clinical concepts. The aim of this study was to evaluate the use of standard preoperative MR imaging (T1ce and T2FLAIR sequences) to predict the molecular signature and thus enable the development of clinical treatment concepts based on the molecular properties of the individual tumors. Material and Methods For 16 patients, for whom primary stem cell enriched cultures had been characterized for their mesenchymal / proneural signature and radiation sensitivity, tumor volume (hyperintense volume in T1ce), necrosis (hypointense volume inside the tumor volume) and edema (hyperintense volume in T2FLAIR) were contoured for volumetric analysis. Volume parameters were used to calculate ratios (edema/tumor and necrosis/tumor) and a MRI signature, which was then correlated with molecular parameters and patient outcome stratified by MGMT promoter methylation. Results As expected, the prognosis of patients with MGMT-promoter-methylated tumors was better (n.s.) compared to those with unmethylated MGMT promoters. Neither molecular nor imaging data were significantly different between these subgroups. In the subgroup of patients with unmethylated MGMT promoter, volumetric imaging parameters correlated with the molecular signature and cellular radiation sensitivity of the stem cell enriched cultures. This association was much weaker in the subgroup with methylated MGMT promoter. Conclusion In the subgroup of patients with unmethylated MGMT promoter, volumetric parameters on preoperative standard MR imaging might hint at the molecular properties of the respective tumor and its radiation sensitivity. This might be a clinically applicable method to stratify treatment according to molecular stem cell subtype without tissue culture and molecular analysis.

Background Laryngeal paralysis is a disease process most commonly seen in older, large breed dogs. When both arytenoid cartilages are affected dogs can develop life-threatening respiratory compromise, therefore surgical intervention is recommended. While there are multiple surgical procedures that have been described to treat laryngeal paralysis, there remains a considerable risk for postoperative complications, most commonly aspiration pneumonia. The objective of this ex vivo experimental study was to evaluate the effects of a novel, 3D printed bilateral arytenoid abductor on laryngeal airway resistance in canine cadaver larynges. Laryngeal airway resistance was calculated for each specimen before (control) and after placement of a 3D printed, bilateral arytenoid abductor. The airway resistance was measured at an airflow of 10 L/min with the epiglottis closed and at airflows ranging from 15 L/min to 60 L/min with the epiglottis open. The effects of the bilateral arytenoid abductor on laryngeal airway resistance were evaluated statistically. Results With the epiglottis open, median laryngeal airway resistance in all larynges with a bilateral arytenoid abductor were significantly decreased at airflows of 15 L/min (0.0cmH2O/L/sec), 30 L/min (0.2cmH2O/L/sec), and 45 L/min (0.2cmH2O/L/sec) compared to the controls 15 L/min (0.4cmH2O/L/sec; P = 0.04), 30 L/min (0.9cmH2O/L/sec; P = 0.04), and 45 L/min (1.2cmH2O/L/sec; P = 0.04). When the epiglottis was closed, there was no significant difference in laryngeal resistance between the control (18.8cmH2O/L/sec) and the abducted larynges (18.1cmH2O/L/sec; P = 0.83). Conclusions Placement of a bilateral arytenoid abductor reduced laryngeal resistance in canine cadaver larynges compared to the controls when the epiglottis was open. With the epiglottis closed, there was no loss of laryngeal resistance while the device abducted the arytenoid cartilages. The results of this ex vivo study is encouraging for consideration of further evaluation of the bilateral arytenoid abductor to determine an appropriate material and tolerance of this device in vivo.

A state’s legal framework for response to a pandemic includes two domains, the enduring and the crisis-driven. In Maryland, the enduring law worked well and helped healthcare facilities cope with C...

Nanocrystalline nickel-iron layers are produced electrochemically on copper discs by varying the current density and then annealed in a vacuum furnace at a temperature range between 200 and 800 °C. Grain size, iron content, texture and microstrain of the microstructure are primarily characterized by X-ray diffraction (XRD). Instrumented indentation tests and microbending tests for mechanical characterization are carried out. The iron contents of the investigated layers are 5.7, 8.8, 13.5 and 17.7 wt.-%. By varying the annealing temperature, the reduction of the microstrains is initiated at 200 °C and ends at a temperature of about 280 °C. Primary recrystallization starts slightly higher at 220 °C and is completed at 300 °C. With higher iron content, the indicated temperatures shift to slightly higher values. Indentation modulus, Young's modulus, indentation hardness and strength change considerably after the annealing treatment. Fracture strain at the edge, as a measure of ductility, decreases immediately after annealing at 200 °C to 0 %. Low annealing temperatures occurring before the beginning of primary recrystallization lead to an increase in indentation hardness and 0.01-% offset bending yield strength Rp0.01∗ as compared to the electrochemically deposited initial state. After annealing at high temperatures, the mechanical parameters are mostly below the initial values for electrochemical deposition. Hall-Petch (HP) behavior is observed for Rp0.01∗, both for the electrochemically deposited specimens down to almost 6 nm and for the specimens annealed at high temperatures. Specimens annealed at low temperatures deviate from the HP straight line to higher values. In this case, an increase in strength is assumed to be due to the very small nanocrystalline (nc) grain sizes, segregation at the grain boundaries and a decrease in dislocation density. Indentation hardness measurements show almost no dependence on D−0.5 for the electrochemically deposited specimens and also for annealed specimens below 30nm grain size. Above 30nm, the indentation hardness values are considerably higher than for the HP straight line. Overall, the hardness and strength values of the nc specimens, electrochemically deposited or additionally annealed, are significantly higher than those of the microcrystalline (mc) specimens.

Placer gold particles derived from epithermal deposits display distinct morphological and compositional features compared with particles from mesothermal systems. Here, it is hypothesized that the chemical composition of primary gold derived from different deposit types is a principle factor affecting the composition of resident biofilm communities as well as the transformation of placer particles. Gold particles were collected from placers originating from the epithermal system at the Eisenberg, Germany's largest primary gold deposit. For comparison, placer gold from mesothermal sources was studied. Morphological differences due to mechanical transport and physical reshaping were not observed. Biogeochemical gold/silver dissolution and gold re-precipitation were evident on epithermal particles and they accentuate the silver-fabrics and gold-rich clusters. In contrast, on mesothermally derived gold particles these processes led to the development of gold-rich rims via the formation of nano-porous secondary gold. Microprobe- and laser ablation mass spectrometric analyses of polished whole particle mounts confirmed differences in gold/silver content/distribution and trace metal content between particles from epi- and mesothermal sources, respectively. On particles from all sites nano- and micro-particulate gold is associated with polymorphic layers. These are composed of microbial cells, extracellular polymeric substances (EPS) and clay-sized minerals. Multivariate statistical analyses shows a significant difference between biofilm communities from epi- vs. mesothermally derived particles, which is linked to the chemical composition of the primary gold. While a number of key-species capable of gold transformation, e.g., Cupriavidus sp., Geobacter sp. and Rhodoferax sp., were detected on particles from both sources, higher numbers of organisms with the potential for gold solubilization, precipitation and detoxification were associated with particles from the epithermal sources. A range of species involved in gold transformation, i.e., Arthrobacter spp., Delftia sp., Shewanella sp., and Stenotrophomonas spp., were detected only on epithermally derived placer gold. This indicates the communities are sensitive to differences in gold/silver and possibly trace metal-cycling, resulting from differences in their content, distribution and mobilization behaviour in epi- vs. mesothermally derived particles. Ultimately, this study shows that the chemical composition of the primary deposit strongly influences the biogeochemical transformation of placer gold and the composition of associated biofilms, whereas physical transformations appear to be largely unaffected.

BACKGROUND Dipyrone (metamizole) is widely used for perioperative pain management in countries where it is marketed; however, uncertainty exists concerning the safe use of this drug, specifically considering the rare adverse event of an agranulocytosis. METHODS As evidence from published studies was lacking, an expert panel developed recommendations for the perioperative use of dipyrone. After a formal, structured consensus process, the recommendations were approved by the involved medical societies. RESULTS The panel agreed that blood cell counts shall not be standard for short-term perioperative use in patients unless they are at risk for neutropenia. The medical staff shall be aware of the symptoms and course of action when agranulocytosis is suspected. Patients shall be informed about the risks and benefits of dipyrone and about potential alternatives. The expert group concluded that dipyrone has a relatively positive risk-benefit ratio compared to other nonopioid analgesics. The group strongly recommended educating patients about the symptoms of agranulocytosis if they have received dipyrone over several days and/or treatment is to be continued after discharge, because agranulocytosis can occur several days after discontinuation of metamizole. Further recommendations refer to the information of the physician taking over the patient's care after discharge and the avoidance of re-exposure in patients having previously suffered from dipyrone-induced agranulocytosis. CONCLUSION The group's recommendations shall be communicated in order to raise medical staff's and patients' awareness of the appropriate use of dipyrone in the perioperative period.

Eoarchean rocks from the Isua region in southern West Greenland are known to exhibit isotope anomalies of 182W and 142Nd. The excess 182W in many rocks from the Isua region have been explained by two endmember models: (1) missing late veneer or (2) silicate differentiation shortly after Earth’s formation. Furthermore, it has been proposed that pristine W isotope systematics in rocks from the Isua region (herein the Isua supracrustal belt and adjacent area) have been obscured by metamorphic disturbance. To address these issues, we present a comprehensive dataset, combining high precision 182W isotope data with trace element data, including high precision elemental W-Th-U-Ta abundance data. We present an improved analytical protocol that allows processing gram-sized samples with W abundances in the lower ng/g range. This protocol also results in markedly improved ion exchange column yields and cleaner W fractions, thereby minimizing nuclear volume effects on 183W. To compare with previous studies, our dataset includes some samples from previously investigated units in the Isua region (Isua Supracrustal Belt (ISB) mafic–ultramafic assemblages and Ameralik dikes). In addition, several Eoarchean key units in the Isukasia terrane (Isua region) and the Faeringehavn terrane (Nuuk region) have been examined for their W isotope composition in this study for the first time. These newly investigated units include recently recognized mantle-like peridotites from both terranes that display PGE abundances and patterns similar to modern depleted mantle peridotites, felsic lithologies from the ISB, as well as key amphibolite and TTG localities from low-strain domains south of the ISB. Virtually all rocks from the Isua region show significant W enrichment with W/Th of up to 160 in mafic to ultramafic samples. None of the samples from SW Greenland that were object of 182W isotope analysis in this study and virtually all previous studies appear to have preserved near canonical W/Th ratios (i.e., between 0.09 and 0.24). Independent of W enrichment, however, it can now be shown that there is a uniform 182W isotope excess in the different rock types from the Itsaq Gneiss Complex (IGC) (average 12.8 ppm ± 1 ppm, 95% confidence interval). Importantly, none of the rock suites investigated exhibit modern mantle-like 182W isotope signatures of µ182W = 0. By combining 182W signatures in the different lithologies with elemental W systematics, we therefore can infer that the 182W excess in Eoarchean rocks from the Isua region is widespread, and independent of W enrichment. Hence, we regard the 182W excess as an intrinsic feature of the Eoarchean assemblages in the Isua region. Notably, mantle-like peridotites from both the Isukasia and Faeringehavn terranes display the same 182W excess, as all other units, although they have been shown to display the full inventory of Highly Siderophile Elements (HSE) found in Phanerozoic mantle peridotites. Evidently, the W isotope budget in these rocks is clearly decoupled from HSE systematics, which hampers a straightforward explanation for 182W isotope excesses in terms of the missing late veneer model. As Platinum Group Element (PGE) patterns in mantle-like Eoarchean peridotites from the Isua region are similar to those in Phanerozoic rocks, we rather propose that to a large extent the 182W excesses are a vestige of early silicate differentiation processes, in line with positive 142Nd anomalies found in rocks from the Isua region, suggesting initial silicate differentiation prior to 4.50 Ga.

Simple Summary Cancer cells with a stem-like phenotype that are thought to be highly tumorigenic are commonly described in glioblastoma, the most common primary adult brain cancer. This phenotype comprises high self-renewal capacity and resistance against chemotherapy and radiation therapy, thereby promoting tumor progression and disease relapse. Here, we show that calcitriol, the hormonally active form of the “sun hormone” vitamin D3, effectively suppresses stemness properties in glioblastoma stem-like cells (GSCs), supporting the hypothesis that calcitriol sensitizes them to additional chemotherapy. Indeed, a physiological organotypic brain slice model was used to monitor tumor growth of GSCs, and the effectiveness of combined treatment with temozolomide, the current standard-of-care, and calcitriol was proven. These findings indicate that further research on applying calcitriol, a well-known and safe drug, as a potential adjuvant therapy for glioblastoma is both justified and necessary. Abstract Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infiltrative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the expression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show, using in vitro limiting dilution assays, quantitative real-time PCR, quantitative proteomics and ex vivo adult organotypic brain slice transplantation cultures, that therapeutic doses of calcitriol, the hormonally active form of vitamin D3, reduce stemness to varying extents in a panel of investigated GSC lines, and that it effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to completely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in follow-up studies.

During the Covid‐19 pandemic, as resources dwindled, clinicians, health care institutions, and policymakers have expressed concern about potential legal liability for following crisis standards of care (CSC) plans. Although there is no robust empirical research to demonstrate that liability protections actually influence physician behavior, we argue that limited liability protections for health care professionals who follow established CSC plans may instead be justified by reliance on the principle of reciprocity. Expecting physicians to do something they know will harm their patients causes moral distress and suffering that may leave lasting scars. Limited liability shields are both appropriate and proportionate to the risk physicians are being asked to take in such circumstances. Under certain narrow circumstances, it remains unclear that the standard of care is sufficiently flexible to protect physicians from liability. Given this uncertainty, the likelihood that physicians would be sued for such an act, and their desire for such immunity, this limited protection is morally legitimate.