Grain Size seperation and sediment mixing in Artic Ocean sediments: evidence from the strontium isotope systematic

The (87)Rb/(86)Sr and (87)Sr/(86)Sr ratios of Laptev Sea sediments, of Arctic Ocean sediments and of suspended particulate matter (SPM) from Siberian rivers (Lena and Khatanga) form 'pseudo-isochrons' due to grain-size separation processes which are referred to as 'Lena Mixing Envelope' (LME) and as 'Flood Basalt Envelope' (FBE). At the land-ocean transition the reduction of the particle velocity causes a deposition of coarser grained material and the contact with saline water enhances a precipitation of finer-grained material. The coarse-grained material is enriched in Sr showing less radiogenic (87)Sr/(86)Sr ratios whereas fine grained material is depleted in Sr relative to Rb showing more radiogenic (87)Sr/(86)Sr ratios, The experimentally determined spread of the (87)Rb/(86)Sr and (87)Sr/(86)Sr ratios as a function of grain size in one sediment sample is on the same order as the natural spread of the (87)Sr/(86)Sr ratios observed in all samples from the Arctic Ocean. Chemical Index of Alteration (CIA) for the Lena river SPM tend to confirm previous observations that chemical alteration is negligible in the Arctic environment. Thus, these 'pseudo-isochrons' reflect an average age and the average isotope composition in the river drainage area. Calculated apparent ages from the FBE reflect the age of the Siberian flood basalt of about 220 Ma and the initial ratio of 0.707(1) reflects their mantle origin. The age calculated from the LME of about 125 Ma reflects accidentally the Jurassic and Cretaceous age of the sediments drained by the Lena river and the initial ratio of 0.714(1) reflects the crustal origin of their source rocks. Comparison of geographical locations reveals that all samples from the eastern Laptev Sea (east of 120 degrees E) fall along the LME whereas all samples from the western Laptev Sea (west of 120 degrees E) fall between LME and FBE. Mixing calculations based on (143)Nd/(144)Nd measurements, not influenced by grain size, show that about 75% of the western Laptev Sea sediments originate from the Lena drainage area whereas about 25% of the sediments are delivered from the Siberian flood basalt province. Sediments from the central Arctic Ocean are isotopically related to the Lena drainage area and the Siberian flood basalt province. However, sediments from the Arctic Ocean margins close to Novaya Semlya, Greenland, the Fram Strait and Svalbard originate from sources not yet identified. (C) 1999 Elsevier Science B.V. All rights reserved

Neuronal Plasticity and the Cholinergic System Are Affected in Atopic Dermatitis and in Response to Acute Experimental Mental Stress in a Randomized Controlled Pilot Study

Rationale In mouse models for atopic dermatitis (AD) hypothalamus pituitary adrenal axis (HPA) dysfunction and neuropeptide-dependent neurogenic inflammation explain stress-aggravated flares to some extent. Lately, cholinergic signaling has emerged as a link between innate and adaptive immunity as well as stress responses in chronic inflammatory diseases. Here we aim to determine in humans the impact of acute stress on neuro-immune interaction as well as on the non-neuronal cholinergic system (NNCS). Methods Skin biopsies were obtained from 22 individuals (AD patients and matched healthy control subjects) before and after the Trier social stress test (TSST). To assess neuro-immune interaction, nerve fiber (NF)-density, NF-mast cell contacts and mast cell activation were determined by immunohistomorphometry. To evaluate NNCS effects, expression of secreted mammal Ly-6/urokinase-type plasminogen activator receptor-related protein (SLURP) 1 and 2 (endogenous nicotinic acetylcholine receptor ligands) and their main corresponding receptors were assessed by quantitative RT-PCR. Results With respect to neuro-immune interaction we found higher numbers of NGF+ dermal NF in lesional compared to non-lesional AD but lower numbers of Gap43+ growing NF at baseline. Mast cell-NF contacts correlated with SCORAD and itch in lesional skin. With respect to the NNCS, nicotinic acetylcholine receptor α7 (α7nAChR) mRNA was significantly lower in lesional AD skin at baseline. After TSST, PGP 9.5+ NF numbers dropped in lesional AD as did their contacts with mast cells. NGF+ NF now correlated with SCORAD and mast cell-NF contacts with itch in non-lesional skin. At the same time, SLURP-2 levels increased in lesional AD skin. Conclusions In humans chronic inflammatory and highly acute psycho-emotional stress interact to modulate cutaneous neuro- immune communication and NNCS marker expression. These findings may have consequences for understanding and treatment of chronic inflammatory diseases in the future

Estimating steatosis and fibrosis: comparison of acoustic structure quantification with established techniques

To compare ultrasound-based acoustic structure quantification (ASQ) with established non-invasive techniques for grading and staging fatty liver disease

Estimating steatosis and fibrosis: comparison of acoustic structure quantification with established techniques

To compare ultrasound-based acoustic structure quantification (ASQ) with established non-invasive techniques for grading and staging fatty liver disease

Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive® CV9201 immunotherapy

ABSTRACT We recently completed a phase I/IIa trial of RNActive® CV9201, a novel mRNA-based therapeutic vaccine targeting five tumor-associated antigens in non-small cell lung cancer (NSCLC) patients. The aim of the study presented here was to comprehensively analyze changes in peripheral blood during the vaccination period and to generate hypotheses facilitating the identification of potential biomarkers correlating with differential clinical outcomes post RNActive® immunotherapy. We performed whole-genome expression profiling in a subgroup of 22 stage IV NSCLC patients before and after initiation of treatment with CV9201. Utilizing an analytic approach based on blood transcriptional modules (BTMs), a previously described, sensitive tool for blood transcriptome data analysis, patients segregated into two major clusters based on transcriptional changes post RNActive® treatment. The first group of patients was characterized by the upregulation of an expression signature associated with myeloid cells and inflammation, whereas the other group exhibited an expression signature associated with T and NK cells. Patients with an enrichment of T and NK cell modules after treatment compared to baseline exhibited significantly longer progression-free and overall survival compared to patients with an upregulation of myeloid cell and inflammatory modules. Notably, these gene expression signatures were mutually exclusive and inversely correlated. Furthermore, our findings correlated with phenotypic data derived by flow cytometry as well as the neutrophil-to-lymphocyte ratio. Our study thus demonstrates non-overlapping, distinct transcriptional profiles correlating with survival warranting further validation for the development of biomarker candidates for mRNA-based immunotherapy

A Common Variant of PNPLA3 (p.I148M) Is Not Associated with Alcoholic Chronic Pancreatitis

Contains fulltext : 110441.pdf (publisher's version ) (Open Access)BACKGROUND: Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a common PNPLA3 variant (p.I148M) is associated with the development of alcoholic liver cirrhosis (ALC). Since, alcoholic CP and ALC share the same aetiology PNPLA3 variant (p.I148M) possibly influences the development of alcoholic CP. METHODS: Using melting curve analysis we genotyped the variant in 1510 patients with pancreatitis or liver disease (961 German and Dutch alcoholic CP patients, 414 German patients with idiopathic or hereditary CP, and 135 patients with ALC). In addition, we included in total 2781 healthy controls in the study. RESULTS: The previously published overrepresentation of GG-genotype was replicated in our cohort of ALC (p-value <0.0001, OR 2.3, 95% CI 1.6-3.3). Distributions of genotype and allele frequencies of the p.I148M variant were comparable in patients with alcoholic CP, idiopathic and hereditary CP and in healthy controls. CONCLUSIONS: The absence of an association of PNPLA3 p.I148M with alcoholic CP seems not to point to a common pathway in the development of alcoholic CP and alcoholic liver cirrhosis

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Cholesterin-Interaktion mit G-Protein-gekoppelten Rezeptoren und intrazelluläre Verteilung

ZusammenfassungIn dieser Arbeit konnte gezeigt werden, dass neben dem Oxytocinrezeptor auch die anderen Rezeptoren der Familie der Neurohypophysenhormone, die Vasopressinrezeptoren, in der gleichen Weise in ihren Bindungseigenschaften von Cholesterin beeinflusst werden. Im Gegensatz dazu zeigt der Cholecystokininrezeptor Typ B keine direkte Wechselwirkung mit Cholesterin. Durch Austausch der Transmembranhelices 6 und 7 des Oxytocinrezeptors mit entsprechenden Bereichen des Cholecystokininrezeptors wurde ein Rezeptor erzeugt, der bezüglich Bindungsverhalten und Cholesterinabhängigkeit keine Unterschiede zu dem Wildtyp-Oxytocinrezeptor zeigte. Durch den Einsatz von computergestütztem 'Modeling' wurde für die Interaktion des Oxytocinrezeptors mit Cholesterin eine Stelle zwischen den Transmembranhelices 5 und 6 vorgeschlagen. Um die Verteilung des Cholesterins in der Zelle zu untersuchen, wurde ein selbst synthetisiertes, fluoreszierendes Cholesterinderivat (Fluochol) eingesetzt. Die Komplexierung in Cyclodextrinen ermöglichte die Einlagerung von Fluochol in die Plasmamembran von Zellen. Der Einstrom des Fluochol in das ER erfolgte innerhalb von Minuten und war energieunabhängig. Schließlich wurde Fluochol in Lipidtröpfchen transportiert, die in fast allen Zellen für die Speicherung überschüssiger intrazellulärer Lipide dienen. Die Tröpfchen werden aus dem endoplasmatischen Retikulum gebildet und enthalten neben Phospholipiden auch Cholesterin, das durch das Enzym ACAT mit langkettigen Fettsäuren verestert wird.AbstractLigand binding of the oxytocin receptor is affected by cholesterol in a direct and specific manner. In contrast, the cholecystokinin receptor exhibits no direct interaction with cholesterol. This study revealed that also the other members of the family of pituitary gland hormone receptors, the vasopressin receptors, are specifically regulated by cholesterol. The exchange of transmembrane helices 6 and 7 of the oxytocin receptor with corresponding regions of the cholecystokinin receptor generated a receptor that exhibited equal ligand binding and cholesterol dependence. Additionally conducted computer modelling studies suggested a site for the oxytocin receptor-cholesterol interaction between helices 5 and 6. A fluorescent cholesterol analogue (fluochol) was synthesized to examine the distribution of cholesterol within the cell. Fluochol could be complexed with cyclodextrines which enabled the labelling of the plasma membranes of cells. The itinerary of fluochol to the endoplasmic reticulum occurred within a few minutes and was energy-independent. Finally, fluochol was transported to lipid droplets. These droplets emerge from the endoplasmic reticulum and they contain phospholipids and cholesterol that is esterified with long chain fatty acids by the enzyme ACA

Chronic and Acute Effects of Imidacloprid on a Simulated BEEHAVE Honeybee Colony

Honeybees (Apis mellifera) are important pollinators for wild plants as well as for crops, but honeybee performance is threatened by several stressors including varroa mites, gaps in foraging supply, and pesticides. The consequences of bee colony longtime exposure to multiple stressors are not well understood. The vast number of possible stressor combinations and necessary study duration require research comprising field, laboratory, and simulation experiments. We simulated long‐term exposure of a honeybee colony to the insecticide imidacloprid and to varroa mites carrying the deformed wing virus in landscapes with different temporal gaps in resource availability as single stressors and in combinations. Furthermore, we put a strong emphasis on chronic lethal, acute sublethal, and acute lethal effects of imidacloprid on honeybees. We have chosen conservative published values to parameterize our model (e.g., highest reported imidacloprid contamination). As expected, combinations of stressors had a stronger negative effect on bee performance than each single stressor alone, and effect sizes were larger after 3 years of exposure than after the first year. Imidacloprid‐caused reduction in bee performance was almost exclusively due to chronic lethal effects because the thresholds for acute effects were rarely met in simulations. In addition, honeybee colony extinctions were observed by the last day of the first year but more pronounced on the last days of the second and third simulation year. In conclusion, our study highlights the need for more long‐term studies on chronic lethal effects of pesticides on honeybees. Environ Toxicol Chem 2022;41:2318–2327. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659https://doi.org/10.5281/zenodo.656731

Evaluation of a novel tomographic ultrasound device for abdominal examinations.

Conventional ultrasound (US) is the first-line imaging method for abdominal pathologies, but its diagnostic accuracy is operator-dependent, and data storage is usually limited to two-dimensional images. A novel tomographic US system (Curefab CS, Munich, Germany) processes imaging data combined with three-dimensional spatial information using a magnetic field tracking. This enables standardized image presentation in axial planes and a review of the entire examination. The applicability and diagnostic performance of this tomographic US approach was analyzed in an abdominal setting using conventional US as reference. Tomographic US data were successfully compiled in all subjects of a training cohort (20 healthy volunteers) and in 50 patients with abdominal lesions. Image quality (35% and 79% for training and patient cohort respectively) and completeness of organ visualization (45% and 44%) were frequently impaired in tomographic US compared to conventional US. Conventional and tomographic US showed good agreement for measurement of organ sizes in the training cohort (right liver lobe and both kidneys with a median deviation of 5%). In the patient cohort, tomographic US identified 57 of 74 hepatic or renal lesions detected by conventional ultrasound (sensitivity 77%). In conclusion, this study illustrates the diagnostic potential of abdominal tomographic US, but current significant limitations of the tomographic ultrasound device demand further technical improvements before this and comparable approaches can be implemented in clinical practice