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This work employs ground- and space-based observations, together with model data, to study columnar abundances of atmospheric trace gases (XH2O, XCO2, XCH4 and XCO) in two high-latitude Russian cities, St. Petersburg and Yekaterinburg. Two portable COllaborative Column Carbon Observing Network (COCCON) spectrometers were used for continuous measurements at these locations during 2019 and 2020. Additionally, a subset of data of special interest (a strong gradient in XCH4 and XCO was detected) collected in the framework of a mobile city campaign performed in 2019 using both instruments is investigated. All studied satellite products (TROPOMI, OCO-2, GOSAT, MUSICA IASI) show generally good agreement with COCCON observations. Satellite and ground-based observations at high latitudes are much sparser than at low or mid latitudes, which makes direct coincident comparisons between remote-sensing observations more difficult. Therefore, a method of scaling continuous Copernicus Atmosphere Monitoring Service (CAMS) model data to the ground-based observations is developed and used for creating virtual COCCON observations. These adjusted CAMS data are then used for satellite validation, showing good agreement in both Peterhof and Yekaterinburg. The gradients between the two study sites (ΔXgas) are similar between CAMS and CAMS-COCCON datasets, indicating that the model gradients are in agreement with the gradients observed by COCCON. This is further supported by a few simultaneous COCCON and satellite ΔXgas measurements, which also agree with the model gradient. With respect to the city campaign observations recorded in St Petersburg, the downwind COCCON station measured obvious enhancements for both XCH4 (10.6 ppb) and XCO (9.5 ppb), which is nicely reflected by TROPOMI observations, which detect city-scale gradients of the order 9.4 ppb for XCH4 and 12.5 ppb for XCO.

In this paper, we compare column-averaged dry-air mole fractions of water vapor (XH2O) retrievals from the COllaborative Carbon Column Observing Network (COCCON) with retrievals from two co-located high-resolution Fourier transform infrared (FTIR) spectrometers as references at two boreal sites, Kiruna, Sweden, and Sodankylä, Finland, from 6 March 2017 to 20 September 2019. In the framework of the Network for the Detection of Atmospheric Composition Change (NDACC), an FTIR spectrometer is operated at Kiruna. The H2O product derived from these observations has been generated with the MUlti-platform remote Sensing of Isotopologues for investigating the Cycle of Atmospheric water (MUSICA) processor. In Sodankylä, a Total Carbon Column Observing Network (TCCON) spectrometer is operated, and the official XH2O data as provided by TCCON are used for this study. The datasets are in good overall agreement, with COCCON data showing a wet bias of (49.20±58.61) ppm ((3.33±3.37) %, R2=0.9992) compared with MUSICA NDACC and (56.32±45.63) ppm ((3.44±1.77) %, R2=0.9997) compared with TCCON. Furthermore, the a priori H2O volume mixing ratio (VMR) profiles (MAP) used as a priori information in the TCCON retrievals (also adopted for COCCON retrievals) are evaluated with respect to radiosonde (Vaisala RS41) profiles at Sodankylä. The MAP and radiosonde profiles show similar shapes and a good linear correlation of integrated XH2O, indicating that MAP is a reasonable approximation of the true atmospheric state and an appropriate choice for the scaling retrieval methods as applied by COCCON and TCCON. COCCON shows a reduced dry bias (−14.96 %) in comparison with TCCON (−19.08 %) with respect to radiosonde XH2O. Finally, we investigate the quality of satellite data at high latitudes. For this purpose, the COCCON XH2O is compared with retrievals from the Infrared Atmospheric Sounding Interferometer (IASI) generated with the MUSICA processor (MUSICA IASI) and with retrievals from the TROPOspheric Monitoring Instrument (TROPOMI). Both paired datasets generally show good agreement and similar correlations at the two sites. COCCON measures 4.64 % less XH2O at Kiruna and 3.36 % less at Sodankylä with respect to MUSICA IASI, whereas COCCON measures 9.71 % more XH2O at Kiruna and 7.75 % more at Sodankylä compared with TROPOMI. Our study supports the assumption that COCCON also delivers a well-characterized XH2O data product. This emphasizes that this approach might complement the TCCON network with respect to satellite validation efforts. This is the first published study where COCCON XH2O has been compared with MUSICA NDACC and TCCON retrievals and has been used for MUSICA IASI and TROPOMI validation.

El futuro del sistema Tierra-atmósfera dependerá, en gran medida, de nuestra capacidad para entender todos los procesos que están conduciendo al calentamiento global, y sus consecuencias climáticas, y, en este contexto, los gases de efecto invernadero (GEIs) juegan un papel clave como uno de los principales motores del cambio climático. Con esta idea nace el proyecto de investigación INMENSE (IASI for Surveying Methane and Nitrous Oxide in the Troposphere), el cual tiene como objetivo mejorar nuestra compresión de los balances atmosféricos de dos de los más importantes GEIs, el metano (CH4) y el óxido nitroso (N2O). Para ello, el proyecto INMENSE ha generado nuevas observaciones de concentraciones de CH4 y N2O en la troposfera media/alta a escala global a partir de las medidas satelitales del sensor IASI (Infrared Atmospheric Sounding Interferometer), que vuela a bordo de los satélites meteorológicos EUMETSAT/Metop. En este trabajo los productos INMENSE IASI de CH4 y N2O son presentados, caracterizados y extensamente validados usando una base de datos de referencia multiplataforma (perfiles verticales de avión, medidas in-situ y remotas desde superficie). Esta completa validación sugiere que los productos IASI de CH4 y N2O tienen una precisión entre el 1-3% y un error sistemático del 2%, así como que son consistentes temporal y espacialmente. Por último, las observaciones IASI de CH4 y N2O sobre la Península Ibérica han sido comparadas a las simulaciones del modelo de transporte químico MOCAGE, analizando el grado de acuerdo entre ambas bases de datos.

We present the new isotope-enabled model ICON-ART-Iso. The physics package of the global ICOsahedral Nonhydrostatic (ICON) modeling framework has been extended to simulate passive moisture tracers and the stable isotopologues HDO and H218O. The extension builds on the infrastructure provided by ICON-ART, which allows for high flexibility with respect to the number of related water tracers that are simulated. The physics of isotopologue fractionation follow the model COSMOiso. We first present a detailed description of the physics of fractionation that have been implemented in the model. The model is then evaluated on a range of temporal scales by comparing with measurements of precipitation and vapor. A multi-annual simulation is compared to observations of the isotopologues in precipitation taken from the station network GNIP (Global Network for Isotopes in Precipitation). ICON-ART-Iso is able to simulate the main features of the seasonal cycles in δD and δ18O as observed at the GNIP stations. In a comparison with IASI satellite retrievals, the seasonal and daily cycles in the isotopologue content of vapor are examined for different regions in the free troposphere. On a small spatial and temporal scale, ICON-ART-Iso is used to simulate the period of two flights of the IAGOS-CARIBIC aircraft in September 2010, which sampled air in the tropopause region influenced by Hurricane Igor. The general features of this sample as well as those of all tropical data available from IAGOS-CARIBIC are captured by the model. The study demonstrates that ICON-ART-Iso is a flexible tool to analyze the water cycle of ICON. It is capable of simulating tagged water as well as the isotopologues HDO and H218O.

This work presents the methane (CH4) and nitrous oxide (N2O) products as generated by the IASI (Infrared Atmospheric Sounding Interferometer) processor developed during the project MUSICA (MUlti-platform remote Sensing of Isotopologues for investigating the Cycle of Atmospheric water). The processor retrieves CH4 and N2O with different water vapour and water vapour isotopologues (as well as HNO3) and uses a single a priori data set for all the retrievals (no variation in space and time). Firstly, the characteristics and errors of the products are analytically described. Secondly, the products are comprehensively evaluated by comparisons to the following reference data measured by different techniques and from different platforms as follows: (1) aircraft CH4 and N2O profiles from the five HIAPER Pole-to-Pole Observation (HIPPO) missions; (2) continuous in situ CH4 and N2O observations performed between 2007 and 2017 at subtropical and mid-latitude high-mountain observatories (Izaña Atmospheric Observatory and Jungfraujoch, respectively) in the framework of the WMO–GAW (World Meteorological Organization–Global Atmosphere Watch) programme; (3) ground-based FTIR (Fourier-transform infrared spectrometer) measurements made between 2007 and 2017 in the framework of the NDACC (Network for the Detection of Atmospheric Composition Change) at the subtropical Izaña Atmospheric Observatory, the mid-latitude station of Karlsruhe and the Kiruna polar site.The theoretical estimations and the comparison studies suggest a precision for the N2O and CH4 retrieval products of about 1.5–3 % and systematic errors due to spectroscopic parameters of about 2 %. The MUSICA IASI CH4 data offer a better sensitivity than N2O data. While for the latter the sensitivity is mainly limited to the UTLS (upper troposphere–lower stratosphere) region, for CH4 we are able to prove that at low latitudes the MUSICA IASI processor can detect variations that take place in the free troposphere independently from the variations in the UTLS region. We demonstrate that the MUSICA IASI data qualitatively capture the CH4 gradients between low and high latitudes and between the Southern Hemisphere and Northern Hemisphere; however, we also find an inconsistency between low- and high-latitude CH4 data of up to 5 %. The N2O latitudinal gradients are very weak and cannot be detected. We make comparisons over a 10-year time period and analyse the agreement with the reference data on different timescales. The MUSICA IASI data can detect day-to-day signals (only in the UTLS), seasonal cycles and long-term evolution (in the UTLS and for CH4 also in the free troposphere) similar to the reference data; however, there are also inconsistencies in the long-term evolution connected to inconsistencies in the used atmospheric temperature a priori data.Moreover, we present a method for analytically describing the a posteriori-calculated logarithmic-scale difference of the CH4 and N2O retrieval estimates. By correcting errors that are common in the CH4 and N2O retrieval products, the a posteriori-calculated difference can be used for generating an a posteriori-corrected CH4 product with a theoretically better precision than the original CH4 retrieval products. We discuss and evaluate two different approaches for such a posteriori corrections. It is shown that the correction removes the inconsistencies between low and high latitudes and enables the detection of day-to-day signals also in the free troposphere. Furthermore, they reduce the impact of short-term atmospheric dynamics, which is an advantage, because respective signals are presumably hardly comparable to model data. The approach that affects the correction solely on the scales on which the errors dominate is identified as the most efficient, because it reduces the inconsistencies and errors without removing measurable real atmospheric signals. We give a brief outlook on a possible usage of this a posteriori-corrected MUSICA IASI CH4 product in combination with inverse modelling.

The rapid growth of product sectors for plant-based meat and dairy alternatives has raised significant scientific interest in their nutritional and ecological benefits. Here, it outlines the fractionation of plant-based raw materials and describes the technologies applied in the production of meat and dairy substitutes. Moreover, the study describes the effects of these new products on human nutrient supply and metabolic responses. Examples of meat-like products produced by extrusion technology and dairy alternatives are provided, addressing production challenges and the effects of processing on nutrient digestibility and bioavailability. In contrast to animal-based products, plant-based protein ingredients can contain many compounds produced by plants for defense or symbiotic interactions, such as lectins, phytates, and a wide range of secondary metabolites. The intake of these compounds as part of a plant-based diet can influence the digestion, bioaccessibility, and bioavailability of essential nutrients such as minerals and trace elements but also of amino acids. This is a critical factor, especially in regions with limited plant species for human consumption and inadequate technologies to eliminate these compounds. To fully understand these impacts and ensure that plant-based diets meet human nutritional needs, well-controlled human studies are needed., (© 2024 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we perform multi-region, single-cell DNA sequencing to characterize the SCNA landscape across tumor-rich and normal tissue in two male patients with localized prostate cancer. We identify two distinct karyotypes: 'pseudo-diploid' cells harboring few SCNAs and highly aneuploid cells. Pseudo-diploid cells form numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones. In contrast, aneuploid cells do not form subclones and are detected throughout the prostate, including normal tissue regions. Highly localized pseudo-diploid subclones are confined within tumor-rich regions and carry deletions in multiple tumor-suppressor genes. Our study reveals that SCNAs are widespread in normal and tumor regions across the prostate in localized prostate cancer patients and suggests that a subset of pseudo-diploid cells drive tumorigenesis in the aging prostate., (© 2024. The Author(s).)

Extrachromosomal circular DNAs (eccDNAs) have emerged as important intra-cellular mobile genetic elements that affect gene copy number and exert in trans regulatory roles within the cell nucleus. Here, we describe scCircle-seq, a method for profiling eccDNAs and unraveling their diversity and complexity in single cells. We implement and validate scCircle-seq in normal and cancer cell lines, demonstrating that most eccDNAs vary largely between cells and are stochastically inherited during cell division, although their genomic landscape is cell type-specific and can be used to accurately cluster cells of the same origin. eccDNAs are preferentially produced from chromatin regions enriched in H3K9me3 and H3K27me3 histone marks and are induced during replication stress conditions. Concomitant sequencing of eccDNAs and RNA from the same cell uncovers the absence of correlation between eccDNA copy number and gene expression levels, except for a few oncogenes, including MYC, contained within a large eccDNA in colorectal cancer cells. Lastly, we apply scCircle-seq to one prostate cancer and two breast cancer specimens, revealing cancer-specific eccDNA landscapes and a higher propensity of eccDNAs to form in amplified genomic regions. scCircle-seq is a scalable tool that can be used to dissect the complexity of eccDNAs across different cell and tissue types, and further expands the potential of eccDNAs for cancer diagnostics., (© 2024. The Author(s).)

Introduction: During deployment, soldiers are confronted with potentially morally injurious events. In many cases, these events violate their personal values and belief systems, resulting in feelings of anger, alienation, guilt, and shame. The psychological distress caused by such transgressions is defined as moral injury. It remains unclear to date, which therapeutic interventions are most appropriate for addressing this specific psychological condition. This study examines the effectiveness of value-based cognitive-behavioral group therapy combining elements of cognitive-behavioral therapy, acceptance and commitment therapy, spiritual care, and adaptive disclosure therapy., Materials and Methods: This controlled study uses the Compass of Shame Scale to assess symptom severity among participants both before and after a three-week inpatient group therapy regimen for moral injury. An intervention group ( n  = 45) was compared to a waiting-list control group ( n  = 40). A one-way between subjects ANOVA was conducted to determine the differences between the two measurement points in the intervention group compared to the control group. A positive ethics vote from the Humboldt University Berlin (Charité) was available (No.EA1/092/15)., Results: A significant difference was found on the shame-associated maladaptive strategies subscales of attack self ( F (1, 83) = 5.942, p  = 0.017, Cohen's f  = 0,27), withdrawal ( F (1, 83) = 8.263, p  = 0.005, Cohen's f  = 0,32), and attack others ( F (1, 83) = 10.552, p  = 0.002, Cohen's f = 0,36) of the Compass of Shame Scale between the intervention group and the control group at the p  < 0.05 level in the pre- and post-treatment (t1-t2) comparison., Conclusion: This study suggests that the special therapeutic focus in cognitive-behavioral group therapy can alter shame-based maladaptive coping behaviors in response to war-related moral injury. This study provides further evidence that therapeutic approaches - through fostering a reconciliatory, compassionate, and forgiving approach toward oneself and others - target the underlying mechanisms of moral injury. Therefore, value-based cognitive-behavioral interventions should be considered as a standard element of trauma care in a military setting. Future studies should further examine such interventions in randomized control trials. It would also be particularly valuable for future studies to include a follow-up time point., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Diekmann, Issels, Alliger-Horn, Rau, Fischer, Thiel, Willmund and Zimmermann.)

Endogenous DNA double-strand breaks (DSBs) occurring in neural cells have been implicated in the pathogenesis of neurodevelopmental disorders (NDDs). Currently, a genomic map of endogenous DSBs arising during human neurogenesis is missing. Here, we applied in-suspension Breaks Labeling In Situ and Sequencing (sBLISS), RNA-Seq, and Hi-C to chart the genomic landscape of DSBs and relate it to gene expression and genome architecture in 2D cultures of human neuroepithelial stem cells (NES), neural progenitor cells (NPC), and post-mitotic neural cells (NEU). Endogenous DSBs were enriched at the promoter and along the gene body of transcriptionally active genes, at the borders of topologically associating domains (TADs), and around chromatin loop anchors. NDD risk genes harbored significantly more DSBs in comparison to other protein-coding genes, especially in NEU cells. We provide sBLISS, RNA-Seq, and Hi-C datasets for each differentiation stage, and all the scripts needed to reproduce our analyses. Our datasets and tools represent a unique resource that can be harnessed to investigate the role of genome fragility in the pathogenesis of NDDs., (© 2022. The Author(s).)

Background: O-(2-[ 18 F]-fluoroethyl)-L-tyrosine ( 18 F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). However, 30% of low- and 5% of high-grade gliomas do not present enhanced 18 F-FET uptake at primary diagnosis (" 18 F-FET-negative gliomas") and the pathophysiologic basis for this phenomenon remains unclear. The aim of this study was to determine the expression of LAT1 in a homogeneous group of newly diagnosed 18 F-FET-negative gliomas and to compare them to a matched group of 18 F-FET-positive gliomas. Forty newly diagnosed IDH-mutant astrocytomas without 1p/19q codeletion were evaluated (n = 20 18 F-FET-negative (tumour-to-background ratio (TBR) < 1.6), n = 20 18 F-FET-positive gliomas (TBR > 1.6)). LAT1 immunohistochemistry (IHC) was performed using SLC7A5/LAT1 antibody. The percentage of LAT1-positive tumour cells (%) and the staining intensity (range 0-2) were multiplied to an overall score (H-score; range 0-200) and correlated to PET findings as well as progression-free survival (PFS)., Results: IHC staining of LAT1 expression was positive in both, 18 F-FET-positive as well as 18 F-FET-negative gliomas. No differences were found between the 18 F-FET-negative and 18 F-FET-positive group with regard to percentage of LAT1-positive tumour cells, staining intensity or H-score. Interestingly, the LAT1 expression showed a significant negative correlation with the PFS (p = 0.031), whereas no significant correlation was found for TBR max , neither in the overall group nor in the 18 F-FET-positive group only (p = 0.651 and p = 0.140)., Conclusion: Although LAT1 is reported to mediate the uptake of 18 F-FET into tumour cells, the levels of LAT1 expression do not correlate with the levels of 18 F-FET uptake in IDH-mutant astrocytomas. In particular, the lack of tracer uptake in 18 F-FET-negative gliomas cannot be explained by a reduced LAT1 expression. A higher LAT1 expression in IDH-mutant astrocytomas seems to be associated with a short PFS. Further studies regarding mechanisms influencing the uptake of 18 F-FET are necessary., (© 2021. The Author(s).)

Background: Research suggests that postprandial events, as risk factors for cardiovascular diseases (CVDs), are influenced by meal composition and exercise., Objectives: We investigated the effect of walking versus rest on postprandial metabolic, inflammatory, and oxidative events following the consumption of test meals reflecting 2 different dietary patterns in older adults with an increased CVD risk., Methods: A randomized crossover trial was conducted in 26 men and women (aged 70 ± 5 y; BMI 30.3 ± 2.3 kg/m2). Each adult participated in 4 treatments combining 1 of 2 iso-energetic (4300 kJ) meals [Western diet high-fat meal (WD): total fat, 59.4 g; saturated fatty acids, 32.0 g, dietary fiber, 4.2 g; or Mediterranean-type diet meal (MD): total fat, 40.1 g; saturated fatty acids, 5.1 g; dietary fiber, 14.5 g] with 30 min walking (4.6 ± 0.1 km/h) or rest. Primary (serum triglycerides) and secondary [serum nonesterified fatty acids (NEFAs); parameters of glucose metabolism, inflammation, endothelial activation, oxidation; blood pressure/heart rate] outcomes were measured at fasting and 1.5, 3.0, and 4.5 h postprandially. Data were analyzed by linear mixed models., Results: Triglycerides were higher after the WD than after the MD [AUC in mmol/L × min: Western diet high-fat meal plus postprandial walking (WD-W), 218 ± 15.2; Western diet high-fat meal plus postprandial resting (WD-R), 207 ± 12.6; Mediterranean-type diet meal plus postprandial walking (MD-W), 139 ± 9.83; Mediterranean-type diet meal plus postprandial resting (MD-R), 149 ± 8.15; P  < 0.001]. No meal or activity effect was observed for NEFAs based on AUC data (WD-W, -43.5 ± 7.08; WD-R, -49.2 ± 6.94; MD-W, -48.0 ± 11.6; MD-R, -67.6 ± 7.58). Plasma glucose was higher after the MD than after the WD (WD-W, 222 ± 34.9; WD-R, 177 ± 32.8; MD-W, 314 ± 44.4; MD-R, 275 ± 57.8; P  < 0.001), as was serum insulin (AUC in nmol/L × min: WD-W, 82.0 ± 10.3; WD-R, 88.6 ± 12.8; MD-W, 129 ± 14.7; MD-R, 138 ± 20.5; P < 0.001). Plasma IL-6 was higher after walking than after resting (AUC in pg/mL × min: WD-W, 72.0 ± 34.0; WD-R, 14.3 ± 38.8; MD-W, 70.8 ± 39.4; MD-R, 5.60 ± 26.0; P < 0.05). Plasma vitamin C was higher after the MD than after the WD (P < 0.001) and after walking than after resting (P < 0.05; AUC in mg/L × min: WD-W, -305 ± 59.6; WD-R, -396 ± 84.0; MD-W, 113 ± 56.4; MD-R, -44.5 ± 48.1). We observed no meal or activity effects on parameters of oxidation and endothelial adhesion molecules. Our data revealed no significant meal × activity effects on all outcomes., Conclusions: In older adults with an increased CVD risk, the MD was associated with superior effects on several postprandial parameters (e.g., triglycerides), in comparison to the WD. Data revealed no relevant differences regarding the effects of postmeal walking and resting. None of the 4 treatments can be rated as superior regarding their acute effects on the shown postprandial metabolic, oxidative, and inflammatory parameters. The trial was registered at German Clinical Trials Register (DRKS; http://www.germanctr.de and http://www.drks.de) under identifier DRKS00012409., (Copyright © American Society for Nutrition 2019.)

Research suggests that attention, mood, and satiety can be influenced by meal composition and postprandial activity. The present study examined whether this hypothesis applies to persons with a risk phenotype for the development of cardiovascular/neurodegenerative diseases. A randomized crossover trial was conducted in subjects with metabolic syndrome traits ( n = 26, 8 female, age 70 ± 5, BMI 30.3 ± 2.3 kg/m 2 ). Each subject participated in four interventions: iso-energetic (4300 kJ) meals (Western diet high-fat, WD, and Mediterranean-type diet, MD) followed by either 30 min of moderate walking (4.6 ± 0.1 km/h) or rest. Attention, mood, satiety and plasma cortisol concentrations were measured at fasting and 1.5, 3.0, 4.5 h postprandially. Data were analyzed by linear mixed models. In all interventions, attention increased continuously in the postprandial period (time effect, P < 0.001). After WD, attention was lower after walking compared to resting (meal × activity effect, P < 0.05). Postprandial mood was generally "good" with no intervention effects. Postprandial satiety increased reaching maximum at 1.5 h after meal (time effect, P < 0.001) and was higher after MD compared to WD (meal effect, P < 0.001). In all interventions, plasma cortisol decreased similar to its diurnal variation (time effect, P < 0.001). In our subjects, meal composition had no relevant impact on attention and mood. After typical WD, resting instead of walking seems to have a more beneficial effect on postprandial attention. MD leads to a strong and long-lasting feeling of satiety, possibly resulting in reduced energy intake in the further course of the day and, thus, long-term effect on weight control.

Background: PET represents a valuable tool for glioma imaging. In addition to amino acid tracers such as 18 F-FET, PET targeting the 18-kDa mitochondrial translocator-protein (TSPO) is of high interest for high-grade glioma (HGG) imaging due to its upregulation in HGG cells. 18 F-GE-180, a novel TSPO ligand, has shown a high target-to-background contrast in HGG. Therefore, we intra-individually compared its uptake characteristics to dynamic 18 F-FET PET and contrast-enhanced MRI in patients with HGG., Methods: Twenty HGG patients (nine IDH-wildtype, 11 IDH-mutant) at initial diagnosis (n = 8) or recurrence (n = 12) were consecutively included and underwent 18 F-GE-180 PET, dynamic 18 F-FET PET, and MRI. The maximal tumour-to-background ratios (TBR max ) and biological tumour volumes (BTV) were evaluated in 18 F-GE-180 and 18 F-FET PET. Dynamic 18 F-FET PET analysis included the evaluation of minimal time-to-peak (TTP min ). In MRI, the volume of contrast-enhancement was delineated (VOL CE ). Volumes were spatially correlated using the Sørensen-Dice coefficient., Results: The median TBR max tended to be higher in 18 F-GE-180 PET compared to 18 F-FET PET [4.58 (2.33-8.95) vs 3.89 (1.56-7.15); p = 0.062] in the overall group. In subgroup analyses, IDH-wildtype gliomas showed a significantly higher median TBR max in 18 F-GE-180 PET compared to 18 F-FET PET [5.45 (2.56-8.95) vs 4.06 (1.56-4.48); p = 0.008]; by contrast, no significant difference was observed in IDH-mutant gliomas [3.97 (2.33-6.81) vs 3.79 (2.01-7.15) p = 1.000]. Only 5/20 cases showed higher TBR max in 18 F-FET PET compared to 18 F-GE-180 PET, all of them being IDH-mutant gliomas. No parameter in 18 F-GE-180 PET correlated with TTP min (p > 0.05 each). There was a tendency towards higher median BTV GE-180 [32.1 (0.4-236.0) ml] compared to BTV FET [19.3 (0.7-150.2) ml; p = 0.062] with a moderate spatial overlap [median Sørensen-Dice coefficient 0.55 (0.07-0.85)]. In MRI, median VOL CE [9.7 (0.1-72.5) ml] was significantly smaller than both BTV FET and BTV GE180 (p < 0.001 each), leading to a poor spatial correlation with BTV GE-180 [0.29 (0.01-0.48)] and BTV FET [0.38 (0.01-0.68)]., Conclusion: PET with 18 F-GE-180 and 18 F-FET provides differing imaging information in HGG dependent on the IDH-mutational status, with diverging spatial overlap and vast exceedance of contrast-enhancement in MRI. Combined PET imaging might reveal new insights regarding non-invasive characterization of tumour heterogeneity and might influence patients' management.

We present a 45-year-old man with newly generalized tonic-clonic seizures due to a contrast-enhancing frontal lesion with perifocal edema suggestive for high-grade glioma (HGG). For further evaluation, a dynamic F-FET PET scan was performed, which showed high F-FET-uptake with early peak and constantly decreasing time-activity curves, a characteristic feature of HGG. Stereotactic biopsy and histological evaluation excluded a neoplastic lesion but confirmed a manifestation of neurosarcoidosis with strong expression of the L-amino-acid-transporter considered responsible for F-FET-uptake. Therefore, unknown manifestations of neurosarcoidosis represent a clinical pitfall in F-FET PET and can mimic HGG.

This article summarizes our efforts around the formally verified static analysis of iptables rulesets using Isabelle/HOL. We build our work around a formal semantics of the behavior of iptables firewalls. This semantics is tailored to the specifics of the filter table and supports arbitrary match expressions, even new ones that may be added in the future. Around that, we organize a set of simplification procedures and their correctness proofs: we include procedures that can unfold calls to user-defined chains, simplify match expressions, and construct approximations removing unknown or unwanted match expressions. For analysis purposes, we describe a simplified model of firewalls that only supports a single list of rules with limited expressiveness. We provide and verify procedures that translate from the complex iptables language into this simple model. Based on that, we implement the verified generation of IP space partitions and minimal service matrices. An evaluation of our work on a large set of real-world firewall rulesets shows that our framework provides interesting results in many situations, and can both help and out-compete other static analysis frameworks found in related work.

Objective: To evaluate two different protocols of cold compression therapy (CCT) for pain management and functional recovery in dogs undergoing tibial plateau leveling osteotomy (TPLO)., Material and Methods: A total of 27 adult dogs (n = 30 stifles; staged bilateral procedures: n = 3) undergoing routine TPLO were randomly allocated to three groups (n = 10/group). Dogs of group I received CCT once before and immediately after surgery. In dogs of group II CCT was performed postoperatively four times at 6-hour intervals. Dogs of the control group did not receive CCT. Circumference of the stifle joint and the following pain-related parameters were measured by a single blinded observer before surgery and 1, 10 and 42 days after surgery: stifle joint range of motion (ROM), subjective degree of lameness, and score of a modified Glasgow Pain Scale (GPS)., Results: Both CCT groups showed significantly greater ROM and lower GPS scores 24 hours after surgery compared to the control group. Ten days after surgery there was a significantly lower degree of lameness in both CCT groups compared to the control group. Fourty-two days after surgery a significantly greater ROM was observed in both CCT groups compared to the control group. Group II also showed a significant improvement in the degree of lameness and GPS. There were no significant differences in any of the parameters between the two CCT groups at any time point., Conclusion: CCT applied preoperatively and immediately postoperatively showed similar short- and long-term beneficial results compared to a previously established protocol of applying CCT four times postoperatively. This protocol may be more suitable for practical use., Clinical Significance: The reported data can be used to establish the new protocol of CCT in a clinical surrounding and to support postoperative rehabilitation of the canine patient.

Objective: To define the radiographic origin and insertion of the canine medial glenohumeral ligament (MGHL) at the scapula and the humerus of dogs as radiographic aim points for the surgical ligament reconstruction., Material and Methods: The forelimbs (n = 20) from 10 adult, orthopaedically unaffected dogs (> 20 kg body weight) were used. Radiopaque markers (1 mm steel bullet) were placed into the visual origin and insertion of the MGHL. Finally, virtual digital radiographs were produced in medio-lateral and cranio-caudal projection and the location of the origin and insertion points were expressed using four different methods (4x4 grid box method, percentage position in the grid box for the medio-lateral projection, the percentage position orientated at different landmarks and the clock-face scale method)., Results: The relative positions of the centre of origin and insertion points of the MGHL were located constantly in radiographs in relation to anatomical landmarks in the canine shoulder. Therefore the described methods are useful for determination., Conclusion: The radiographic location of the origin and insertion points of the MGHL can be consistently predicted in radiographs of dogs with a body weight above 20 kg., Clinical Significance: The reported data can be used to verify the correct placement of the insertion of bone anchors for stabilising a medial shoulder instability by ligament reconstruction in dogs.

Background: Overhydration is a common problem in peritoneal dialysis patients and has been shown to be associated with mortality. However, it still remains unclear whether overhydration per se is predictive of mortality or whether it is mainly a reflection of underlying comorbidities. The purpose of our study was to assess overhydration in peritoneal dialysis patients using bioimpedance spectroscopy and to investigate whether overhydration is an independent predictor of mortality., Methods: We analyzed and followed 54 peritoneal dialysis patients between June 2008 and December 2014. All patients underwent bioimpedance spectroscopy measurement once and were allocated to normohydrated and overhydrated groups. Overhydration was defined as an absolute overhydration/extracellular volume ratio > 15%. Simultaneously, clinical, echocardiographic and laboratory data were assessed. Heart failure was defined either on echocardiography, as a reduced left ventricular ejection fraction, or clinically according to the New York Heart Association functional classification. Patient survival was documented up until December 31st 2014. Factors associated with mortality were identified and a multivariable Cox regression model was used to identify independent predictors of mortality., Results: Apart from higher daily peritoneal ultrafiltration rate and cumulative diuretic dose in overhydrated patients, there were no significant differences between the 2 groups, in particular with respect to gender, body mass index, comorbidity and cardiac medication. Mortality was higher in overhydrated than in euvolemic patients. In the univariate analysis, increased age, overhydration, low diastolic blood pressure, raised troponin and NTproBNP, hypoalbuminemia, heart failure but not CRP were predictive of mortality. After adjustment, only overhydration, increased age and low diastolic blood pressure remained statistically significant in the multivariate analysis., Conclusions: Overhydration remains an independent predictor of mortality even after adjustment for heart failure in peritoneal dialysis patients and should therefore be actively sought and managed in order to improve survival in this population.

Precision phase readout of optical beat note signals is one of the core techniques required for intersatellite laser interferometry. Future space based gravitational wave detectors like eLISA require such a readout over a wide range of MHz frequencies, due to orbit induced Doppler shifts, with a precision in the order of μrad/√Hz at frequencies between 0.1 mHz and 1 Hz. In this paper, we present phase readout systems, so-called phasemeters, that are able to achieve such precisions and we discuss various means that have been employed to reduce noise in the analogue circuit domain and during digitisation. We also discuss the influence of some non-linear noise sources in the analogue domain of such phasemeters. And finally, we present the performance that was achieved during testing of the elegant breadboard model of the LISA phasemeter, which was developed in the scope of a European Space Agency technology development activity.

An individual's susceptibility to everyday cognitive failure constitutes a risk factor for physical and mental health. Different factors such as inefficiency of executive functioning and high trait impulsivity have been shown to affect this susceptibility. Furthermore, twin studies indicate a high heritability of failure susceptibility revealing genetic variables as an important biological influence. We tested for a molecular genetic association between variants on the dopamine D2 receptor gene (DRD2), which relate to executive control and impulsivity, and susceptibility to everyday cognitive failure as assessed by the cognitive failure questionnaire (CFQ) in a sample of N=500 (n=140 male, n=360 female, mean age M=24.62, SD=7.98) healthy participants of central European descent. Moreover, we assessed whether trait impulsivity as measured by the Barratt impulsiveness scale (BIS-11) qualifies as a mediator between DRD2 variants and CFQ scores. We found a positive association between DRD2 variants and the CFQ. This effect was in part yet not completely mediated by trait impulsivity. The DRD2 C/C variant constitutes a protective factor for the susceptibility to everyday cognitive failure. Results point towards at least two biopsychological pathways that may explain the observed effect., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Patients with chronic obstructive pulmonary disease (COPD) present with impairments of their cognitive performance. It is still unknown whether cognitive deficits influence driving abilities in patients with COPD. The present study investigates driving performance in patients with COPD and healthy controls. Driving simulation was performed in 17 patients with COPD and 10 healthy controls. Patients with COPD demonstrated significantly worse results in terms of accident frequency in the simulated driving situation. No correlations existed between the severity of disease, assessed from the polysomnographical findings (e.g., lung function, blood gas analysis, sleep disturbance, nocturnal ventilation, and oxygen saturation), and driving performance. We conclude that impairments of driving performance in patients with COPD cannot be predicted on the basis of the severity of the disease. The impairment of driving performance in the simulated driving situation in COPD patients may have crucial consequences for driving licensing in these patients.

Most potent antiretroviral drugs (e.g., HIV-1 protease inhibitors) poorly penetrate the blood-brain barrier. Brain distribution can be limited by the efflux transporter, P-glycoprotein (P-gp). The ability of a novel drug delivery system (block co-polymer P85) that inhibits P-gp, to increase the efficacy of antiretroviral drugs in brain was examined using a severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE). Severe combined immunodeficiency mice inoculated with HIV-1 infected human monocyte-derived macrophages (MDM) into the basal ganglia were treated with P85, antiretroviral therapy (ART) (zidovudine, lamivudine and nelfinavir (NEL)), or P85 and ART. Mice were killed on days 7 and 14, and brains were evaluated for levels of viral infection. Antiviral effects of NEL, P85, or their combination were evaluated in vitro using HIV-1 infected MDM and showed antiretroviral effects of P85 alone. In SCID mice injected with virus-infected MDM, the combination of ART-P85 and ART alone showed a significant decrease of HIV-1 p24 expressing MDM (25% and 33% of controls, respectively) at day 7 while P85 alone group was not different from control. At day 14, all treatment groups showed a significant decrease in percentage of HIV-1 infected MDM as compared with control. P85 alone and combined ART-P85 groups showed the most significant reduction in percentage of HIV-1 p24 expressing MDM (8% to 22% of control) that were superior to the ART alone group (38% of control). Our findings indicate major antiretroviral effects of P85 and enhanced in vivo efficacy of antiretroviral drugs when combined with P85 in a SCID mouse model of HIVE.

Proteasomes (proteinase complexes, PR) and immunoproteasomes (IPR) degrade damaged proteins and affect protein processing required for antigen presentation by mononuclear phagocytes. These critical immune processes are attenuated during progressive HIV-1 infection and are affected by alcohol abuse. To investigate the mechanisms underlying these functional changes, we measured PR and CYP2E1 activities [an ethanol (EtOH) metabolizing enzyme] and reactive oxygen species (ROS) in human monocyte-derived macrophages (MDM) following HIV-1 infection and EtOH treatment. We observed progressive declines of PR activity and PR/IPR contents in HIV-1-infected MDM. PR activity and IPR expression increased after IFN-gamma stimulation but reduced after HIV-1 infection. EtOH inhibited both IFN-gamma-induced PR and IPR. Paradoxically, EtOH attenuated PR catalytic activity in infected MDM and suppressed viral replication. Elevated ROS followed EtOH exposure and paralleled decreased PR activity. The latter was restored by anti-oxidant. The data support the notion that HIV-1 infection and EtOH may work in concert to affect immune function including antigen presentation and thereby affect disease progression.

Background: Percutaneous ethanol injection (PEI) and cryosurgery are increasingly used for the treatment of liver malignancies. To create a safety margin and to destroy completely diffusely growing tumors, the precise destruction of healthy liver tissue is necessary. Little is known about the effects of operating on this type of tissue. This study evaluated the effects and side effects of PEI and cryosurgery when applied to normal parenchyma of the liver., Study Design: Two groups of six minipigs each were treated with either PEI or cryosurgery to create necrosis in the liver. During and after the procedures, vital signs were monitored and necrotic areas were observed by ultrasonography. Standard and immunohistochemistry stains were made from samples of the necrosis, the liver, and the lung., Results: In the PEI group, thromboembolic complications occurred in all animals (fatality rate 50%). Hematogenous spread of hepatocytes was demonstrated by immunohistochemistry and was a cause of pulmonary embolism. In the cryosurgery group, neither specific complications nor signs of cell spillage occurred. Because of an isolating effect of blood perfusion, hepatocytes close to the portal triads were less damaged, vital cells were present in the periphery, and the necroses were smaller than the induced lesions., Conclusions: The effect of PEI in healthy liver tissue is unpredictable. This makes the creation of a safety margin or the treatment of a diffusely infiltrating tumor impossible. PEI always introduces the risk of hematogenous cell spread. Effects of cryosurgery are less dependent on tissue qualities. In both techniques, the real extent of complete tissue destruction cannot be visualized by ultrasonography.

A potentiometric urea-sensitive biosensor using a NH4(+)-sensitive disposable electrode in double matrix membrane (DMM) technology as transducer is described. The ion-sensitive polymer matrix membrane was formed in the presence of an additional electrochemical inert filter paper matrix to improve the reproducibility in sensor production. The electrodes were prepared from one-side silver-coated filter paper, which is encapsulated for insulation by a heat-sealing film. A defined volume of the NH4(+)-sensitive polymer matrix membrane cocktail was deposited on this filter paper. To obtain the urea-biosensor a layer of urease was cast onto the ion-sensitive membrane. Poly (carbamoylsulfonate) hydrogel, produced from a hydrophilic polyurethane prepolymer blocked with bisulfite, served as immobilisation material. The disposable urea sensitive electrode was combined with a disposable Ag/AgCl reference electrode to obtain the disposable urea biosensor. The sensor responded rapidly and in a stable manner to changes in urea concentrations between 7.2 x 10(-5) and 2.1 x 10(-2)mol/l. The detection limit was 2 x 10(-5) mol/l urea and the slope in the linear range 52 mV/decade. By taking into consideration the influence of the interfering K(+)- and Na(+)-ions the sensor can be used for the determination of urea in human blood and serum samples (diluted or undiluted). A good correlation was found with the data obtained by the spectrophotometric routine method.

In this paper we describe a disposable sodium sensor in double matrix membrane technology. This sensor is prepared from filter paper with an evaporated silver conducting line on one side. For insulation the sensor is laminated with a pre-perforated heat-sealing film. A defined volume of an ion-sensitive polymer matrix membrane cocktail is filled into one hole. So an ion-sensitive coated film sensor in double matrix membrane technology is produced. The double matrix membrane is formed by the polymer matrix membrane and by the additional filter paper matrix. The response behaviour of the sodium electrode is comparable with conventional macro ion-selective electrodes. By this technology a mass production of low cost sensors is possible.

Nuclear mutations conferring resistance to oligomycin, a mitochondrial inhibitor, shorten the period of the circadian conidiation rhythm of Neurospora crassa from the normal 21.5 hours to 18 to 19 hours and slow the linear growth rate by 30 percent. These olir mutations map very close to frq, a locus at which mutations affecting periodicity have been previously obtained. The possibilities are discussed that mitochondria are involved in circadian rhythm generation and that certain period-length mutations affect mitochondrial functions.