Oxidative stress plays a vital role for the adaptive responses to physical training. However, excessive oxidative stress can precipitate cellular damage, necessitating protective mechanisms to ...mitigate this effect. Glucosinolates, found predominantly in cruciferous vegetables, can be converted into isothiocyanates, known for their antioxidative properties. These compounds activate crucial antioxidant defence pathways and support mitochondrial function and protein integrity under oxidative stress, in both Nrf2-dependent and independent manners. We here administered glucosinolate-rich broccoli sprouts (GRS), in a randomized double-blinded cross-over fashion to 9 healthy subjects in combination with daily intense exercise training for 7 days. We found that exercise in combination with GRS significantly decreased the levels of carbonylated proteins in skeletal muscle and the release of myeloperoxidase into blood. Moreover, it lowered lactate accumulation during submaximal exercise, and attenuated the severe nocturnal hypoglycaemic episodes seen during the placebo condition. Furthermore, GRS in combination with exercise improved physical performance, which was unchanged in the placebo condition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The mouse strains usually used to generate patient-derived xenografts (PDXs) are immunocompromised, rendering them unsuitable for immunotherapy studies. Here we assessed the value of immune-PDX mouse ...models for predicting responses to anti-PD-1 checkpoint inhibitor therapy in patients.
Melanoma biopsies contained in a retrospective biobank were transplanted into NOG mice or NOG mice expressing interleukin 2 (hIL2-NOG mice). Tumor growth was monitored, and comparisons were made with clinical data, sequencing data, and current in silico predictive tools.
Biopsies grew readily in NOG mice but growth was heterogeneous in hIL2-NOG mice. IL2 appears to activate T-cell immunity in the biopsies to block tumor growth. Biopsy growth in hIL2-NOG mice was negatively associated with survival in patients previously treated with PD-1 checkpoint blockade. In two cases, the prospective clinical decisions of anti-PD-1 therapy or targeted BRAF/MEK inhibitors were supported by the observed responses in mice.
Immune-PDX models represent a promising addition to future biomarker discovery studies and for clinical decision making in patients receiving immunotherapy.
•A patient-derived xenograft (PDX) model expressing human IL-2 can be used to assess the T cell quality in melanoma biopsies.•T cell activation in these immune-PDX models mirrors the heterogenic responses to immunotherapy in a population of patients.•Immune-PDX models can be useful to support clinical decision making or to predict relapse in patients with melanoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neurofilaments are structural components of neurons and are particularly abundant in highly myelinated axons. The levels of neurofilament light chain (NfL) in both cerebrospinal fluid (CSF) and ...plasma have been related to degeneration in several neurodegenerative conditions including frontotemporal dementia (FTD) and NfL is currently considered as the most promising diagnostic and prognostic fluid biomarker in FTD. Although the location and function of filaments in the healthy nervous system suggests a link between increased NfL and white matter degeneration, such a claim has not been fully elucidated in vivo, especially in the context of FTD. The present study provides evidence of an association between the plasma levels of NfL and white matter involvement in behavioral variant FTD (bvFTD) by relating plasma concentration of NfL to diffusion tensor imaging (DTI) metrics in a group of 20 bvFTD patients. The results of both voxel-wise and tract specific analysis showed that increased plasma NfL concentration is associated with a reduction in fractional anisotropy (FA) in a widespread set of white matter tracts including the superior longitudinal fasciculus, the fronto-occipital fasciculus the anterior thalamic radiation and the dorsal cingulum bundle. Plasma NfL concentration also correlated with cortical thinning in a portion of the right medial prefrontal cortex and of the right lateral orbitofrontal cortex. These results support the hypothesis that blood NfL levels reflect the global level of neurodegeneration in bvFTD and help to advance our understanding of the association between this blood biomarker for FTD and the disease process.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context. 51 Eridani b is an exoplanet around a young (20 Myr) nearby (29.4 pc) F0-type star, which was recently discovered by direct imaging. It is one of the closest direct imaging planets in ...angular and physical separation (~0.5′′, ~13 au) and is well suited for spectroscopic analysis using integral field spectrographs. Aims. We aim to refine the atmospheric properties of the known giant planet and to constrain the architecture of the system further by searching for additional companions. Methods. We used the extreme adaptive optics instrument SPHERE at the Very Large Telescope (VLT) to obtain simultaneous dual-band imaging with IRDIS and integral field spectra with IFS, extending the spectral coverage of the planet to the complete Y- to H-band range and providing additional photometry in the K12-bands (2.11, 2.25 μm). The object is compared to other known cool and peculiar dwarfs. The posterior probability distributions for parameters of cloudy and clear atmospheric models are explored using MCMC. We verified our methods by determining atmospheric parameters for the two benchmark brown dwarfs Gl 570D and HD 3651B. We used archival VLT-NACO (L′) Sparse Aperture Masking data to probe the innermost region for additional companions. Results. We present the first spectrophotometric measurements in the Y and K bands for the planet and revise its J-band flux to values 40% fainter than previous measurements. Cloudy models with uniform cloud coverage provide a good match to the data. We derive the temperature, radius, surface gravity, metallicity, and cloud sedimentation parameter fsed. We find that the atmosphere is highly super-solar (Fe/H = 1.0 ± 0.1 dex), and the low \hbox{${f_{\rm sed} = 1.26^{+0.36}_{-0.29}}$}fsed=1.26-0.29+0.36 value is indicative of a vertically extended, optically thick cloud cover with small sized particles. The model radius and surface gravity estimates suggest higher planetary masses of \hbox{${M_\mathrm{gravity} = 9.1^{+4.9}_{-3.3} \, {M}_\mathrm{J}}$}Mgravity=9.1-3.3+4.9 MJ. The evolutionary model only provides a lower mass limit of > 2 MJ (for pure hot-start). The cold-start model cannot explain the luminosity of the planet. The SPHERE and NACO/SAM detection limits probe the 51 Eri system at solar system scales and exclude brown-dwarf companions more massive than 20 MJ beyond separations of ~2.5 au and giant planets more massive than 2 MJ beyond 9 au.
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FMFMET, NUK, UL, UM, UPUK
Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies and might also be associated with prognosis after CRC diagnosis. However, current evidence on ...smoking in association with CRC prognosis is limited.
For this individual patient data meta-analysis, sociodemographic and smoking behavior information of 12 414 incident CRC patients (median age at diagnosis: 64.3 years), recruited within 14 prospective cohort studies among previously cancer-free adults, was collected at baseline and harmonized across studies. Vital status and causes of death were collected for a mean follow-up time of 5.1 years following cancer diagnosis. Associations of smoking behavior with overall and CRC-specific survival were evaluated using Cox regression and standard meta-analysis methodology.
A total of 5229 participants died, 3194 from CRC. Cox regression revealed significant associations between former hazard ratio (HR) = 1.12; 95 % confidence interval (CI) = 1.04–1.20 and current smoking (HR = 1.29; 95% CI = 1.04–1.60) and poorer overall survival compared with never smoking. Compared with current smoking, smoking cessation was associated with improved overall (HR<10 years = 0.78; 95% CI = 0.69–0.88; HR≥10 years = 0.78; 95% CI = 0.63–0.97) and CRC-specific survival (HR≥10 years = 0.76; 95% CI = 0.67–0.85).
In this large meta-analysis including primary data of incident CRC patients from 14 prospective cohort studies on the association between smoking and CRC prognosis, former and current smoking were associated with poorer CRC prognosis compared with never smoking. Smoking cessation was associated with improved survival when compared with current smokers. Future studies should further quantify the benefits of nonsmoking, both for cancer prevention and for improving survival among CRC patients, in particular also in terms of treatment response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In vitro studies suggest that the G protein-coupled receptor (GPR) 30 is a functional estrogen receptor. However, the physiological role of GPR30 in vivo is unknown, and it remains to be determined ...whether GPR30 is an estrogen receptor also in vivo. To this end, we studied the effects of disrupting the GPR30 gene in female and male mice. Female GPR30(−/−) mice had hyperglycemia and impaired glucose tolerance, reduced body growth, increased blood pressure, and reduced serum IGF-I levels. The reduced growth correlated with a proportional decrease in skeletal development. The elevated blood pressure was associated with an increased vascular resistance manifested as an increased media to lumen ratio of the resistance arteries. The hyperglycemia and impaired glucose tolerance in vivo were associated with decreased insulin expression and release in vivo and in vitro in isolated pancreatic islets. GPR30 is expressed in islets, and GPR30 deletion abolished estradiol-stimulated insulin release both in vivo in ovariectomized adult mice and in vitro in isolated islets. Our findings show that GPR30 is important for several metabolic functions in female mice, including estradiol-stimulated insulin release.
The G protein-coupled receptor GPR30 maintains normal bone growth, glucose homeostasis, and blood pressure, and mediates estradiol-stimulated insulin release in female mice.
Rationale
The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia,
http://www.newmeds-europe.com
) is a large industrial-academic collaborative project aimed ...at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia.
Objectives
This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere.
Methods
The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory.
Results
The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks.
Conclusion
This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
The objective of this study is to document and evaluate recent changes and updates to the module for aerosols and aerosol-cloud-radiation interactions in the atmospheric module CAM4-Oslo of the core ...version of the Norwegian Earth System Model (NorESM), NorESM1-M. Particular attention is paid to the role of natural organics, sea salt, and mineral dust in determining the gross aerosol properties as well as the anthropogenic contribution to these properties and the associated direct and indirect radiative forcing. The aerosol module is extended from earlier versions that have been published, and includes life-cycling of sea salt, mineral dust, particulate sulphate, black carbon, and primary and secondary organics. The impacts of most of the numerous changes since previous versions are thoroughly explored by sensitivity experiments. The most important changes are: modified prognostic sea salt emissions; updated treatment of precipitation scavenging and gravitational settling; inclusion of biogenic primary organics and methane sulphonic acid (MSA) from oceans; almost doubled production of land-based biogenic secondary organic aerosols (SOA); and increased ratio of organic matter to organic carbon (OM/OC) for biomass burning aerosols from 1.4 to 2.6. Compared with in situ measurements and remotely sensed data, the new treatments of sea salt and dust aerosols give smaller biases in near-surface mass concentrations and aerosol optical depth than in the earlier model version. The model biases for mass concentrations are approximately unchanged for sulphate and BC. The enhanced levels of modeled OM yield improved overall statistics, even though OM is still underestimated in Europe and overestimated in North America. The global anthropogenic aerosol direct radiative forcing (DRF) at the top of the atmosphere has changed from a small positive value to -0.08 W m super(-2) in CAM4-Oslo. The sensitivity tests suggest that this change can be attributed to the new treatment of biomass burning aerosols and gravitational settling. Although it has not been a goal in this study, the new DRF estimate is closer both to the median model estimate from the AeroCom intercomparison and the best estimate in IPCC AR4. Estimated DRF at the ground surface has increased by ca. 60%, to -1.89 W m super(-2). We show that this can be explained by new emission data and omitted mixing of constituents between updrafts and downdrafts in convective clouds. The increased abundance of natural OM and the introduction of a cloud droplet spectral dispersion formulation are the most important contributions to a considerably decreased estimate of the indirect radiative forcing (IndRF). The IndRF is also found to be sensitive to assumptions about the coating of insoluble aerosols by sulphate and OM. The IndRF of -1.2 W m super(-2), which is closer to the IPCC AR4 estimates than the previous estimate of -1.9 W m super(-2), has thus been obtained without imposing unrealistic artificial lower bounds on cloud droplet number concentrations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Small-angle X-ray scattering (SAXS) is used to demonstrate the presence of density fluctuations in ambient water on a physical length-scale of almost equal to1 nm; this is retained with decreasing ...temperature while the magnitude is enhanced. In contrast, the magnitude of fluctuations in a normal liquid, such as CCl₄, exhibits no enhancement with decreasing temperature, as is also the case for water from molecular dynamics simulations under ambient conditions. Based on X-ray emission spectroscopy and X-ray Raman scattering data we propose that the density difference contrast in SAXS is due to fluctuations between tetrahedral-like and hydrogen-bond distorted structures related to, respectively, low and high density water. We combine our experimental observations to propose a model of water as a temperature-dependent, fluctuating equilibrium between the two types of local structures driven by incommensurate requirements for minimizing enthalpy (strong near-tetrahedral hydrogen-bonds) and maximizing entropy (nondirectional H-bonds and disorder). The present results provide experimental evidence that the extreme differences anticipated in the hydrogen-bonding environment in the deeply supercooled regime surprisingly remain in bulk water even at conditions ranging from ambient up to close to the boiling point.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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