Isoforms of Retinol binding protein 4 (RBP4) are increased in chronic diseases of the kidney but not of the liver

<p>Abstract</p> <p>Background</p> <p>The levels of retinol-binding protein 4 (RBP4) – the carrier protein for Vitamin A in plasma – are tightly regulated under healthy circumstances. The kidney, the main site of RBP4 catabolism, contributes to an elevation of RBP4 levels during chronic kidney disease (CKD) whereas during chronic liver disease (CLD) RBP4 levels decrease. Little is known about RBP4 isoforms including apo-RBP4, holo-RBP4 as well as RBP4 truncated at the C-terminus (RBP4-L and RBP4-LL) except that RBP4 isoforms have been reported to be increased in hemodialysis patients. Since it is not known whether CLD influence RBP4 isoforms, we investigated RBP4 levels, apo- and holo-RBP4 as well as RBP4-L and RBP4-LL in plasma of 36 patients suffering from CKD, in 55 CLD patients and in 50 control subjects. RBP4 was determined by ELISA and apo- and holo-RBP4 by native polyacrylamide gel electrophoresis (PAGE). RBP4-L and RBP4-LL were analyzed after immunoprecipitation by mass spectrometry (MALDI-TOF-MS).</p> <p>Results</p> <p>RBP4 isoforms and levels were highly increased in CKD patients compared to controls (P < 0.05) whereas in CLD patients RBP4 isoforms were not different from controls. In addition, in hepatic dysfunction RBP4 levels were decreased whereas the amount of isoforms was not affected.</p> <p>Conclusion</p> <p>The occurrence of RBP4 isoforms is not influenced by liver function but seems to be strongly related to kidney function and may therefore be important in investigating kidney function and related disorders.</p

Spatio-temporal evolution of global surface temperature distributions

Climate is known for being characterised by strong non-linearity and chaotic behaviour. Nevertheless, few studies in climate science adopt statistical methods specifically designed for non-stationary or non-linear systems. Here we show how the use of statistical methods from Information Theory can describe the non-stationary behaviour of climate fields, unveiling spatial and temporal patterns that may otherwise be difficult to recognize. We study the maximum temperature at two meters above ground using the NCEP CDAS1 daily reanalysis data, with a spatial resolution of 2.5 by 2.5 degree and covering the time period from 1 January 1948 to 30 November 2018. The spatial and temporal evolution of the temperature time series are retrieved using the Fisher Information Measure, which quantifies the information in a signal, and the Shannon Entropy Power, which is a measure of its uncertainty -- or unpredictability. The results describe the temporal behaviour of the analysed variable. Our findings suggest that tropical and temperate zones are now characterized by higher levels of entropy. Finally, Fisher-Shannon Complexity is introduced and applied to study the evolution of the daily maximum surface temperature distributions.Comment: 7 pages, 4 figure

Improved protein structure prediction using potentials from deep learning

Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence1. This problem is of fundamental importance as the structure of a protein largely determines its function2; however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures3. Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force4 that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction5 (CASP13)—a blind assessment of the state of the field—AlphaFold created high-accuracy structures (with template modelling (TM) scores6 of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined7

Genetically Determined Folate Deficiency Is Associated With Abnormal Hepatic Folate Profiles in the Spontaneously Hypertensive Rat

Increased levels of plasma cysteine are associated with obesity and metabolic disturbances. Our recent genetic analyses in spontaneously hypertensive rats (SHR) revealed a mutated Folr1 (folate receptor 1) as the quantitative trait gene associated with diminished renal Folr1 expression, lower plasma folate levels, hypercysteinemia, hyperhomocysteinemia and metabolic disturbances. To further analyse the effects of the Folr1 gene expression on folate metabolism, we used mass spectrometry to quantify folate profiles in the plasma and liver of an SHR-1 congenic strain, with wild type Folr1 allele on the SHR genetic background, and compared them with the SHR strain. In the plasma, concentration of 5-methyltetrahydrofolate (5mTHF) was significantly higher in SHR-1 congenic rats compared to SHR (60±6 vs. 42±2 nmol/l, P<0.01) and 5mTHF monoglutamate was the predominant form in both strains (>99 % of total folate). In the liver, SHR-1 congenic rats showed a significantly increased level of 5mTHF and decreased concentrations of dihydrofolate (DHF), tetrahydrofolate (THF) and formyl-THF when compared to the SHR strain. We also analysed the extent of folate glutamylation in the liver. Compared with the SHR strain, congenic wild-type Folr1 rats had significantly higher levels of 5mTHF monoglutamate. On the other hand, 5mTHF penta- and hexaglutamates were significantly higher in SHR when compared to SHR-1 rats. This inverse relationship of rat hepatic folate polyglutamate chain length and folate sufficiency was also true for other folate species. These results strongly indicate that the whole body homeostasis of folates is substantially impaired in SHR rats compared to the SHR-1 congenic strain and might be contributing to the associated metabolic disturbances observed in our previous studies

Population changes in a whale breeding ground revealed by citizen science noninvasive genetics

Historical exploitation, and a combination of current anthropogenic impacts, such as climate change and habitat degradation, impact the population dynamics of marine mammalian megafauna. Right whales (Eubalaena spp.) are large cetaceans recovering from hunting, whose reproductive and population growth rate appear to be impacted by climate change. We apply noninvasive genetic methods to monitor southern right whale (E. australis, SRW) and test the application of noninvasive genetics to minimise the observer effects on the population. Our aim is to describe population structure, and interdecadal and interannual changes to assess species status in the Great Acceleration period of Anthropocene. As a basis for population genetic analyses, we collected samples from sloughed skin during post-migration epidermal moult. Considering the exploration-exploitation dilemma, we collaborated with whale watching companies, as part of a citizen science approach and to reduce ad hoc logistic operations and biopsy equipment. We used mitochondrial and microsatellite data and population genetic tools. We report for the first time the genetic composition and differentiation of the Namibian portion of the range. Population genetic parameters suggest that South Africa hosts the largest population. This corresponds with higher estimates of current gene flow from Africa compared to older samples. We have observed considerable interannual variation in population density at the breeding ground and an interdecadal shift in genetic variability, evidenced by an increase in the point estimate inbreeding. Clustering analyses confirmed differentiation between the Atlantic and Indo-Pacific, presumably originating during the ice ages. We show that population monitoring of large whales, essential for their conservation management, is feasible using noninvasive sampling within non-scientific platforms. Observed patterns are concurrent to changes of movement ecology and decline in reproductive success of the South African population, probably reflecting a large-scale restructuring of pelagic marine food webs.Charles University Grant Agency, Czech Republic.https://www.elsevier.com/locate/geccoam2023Mammal Research InstituteZoology and Entomolog

Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk

lung cancer ris

Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial

<p>Abstract</p> <p>Background</p> <p>Metabolic syndrome (METS) is an increasingly prevalent but poorly understood clinical condition characterized by insulin resistance, glucose intolerance, dyslipidemia, hypertension, and obesity. Increased oxidative stress catalyzed by accumulation of iron in excess of physiologic requirements has been implicated in the pathogenesis of METS, but the relationships between cause and effect remain uncertain. We tested the hypothesis that phlebotomy-induced reduction of body iron stores would alter the clinical presentation of METS, using a randomized trial.</p> <p>Methods</p> <p>In a randomized, controlled, single-blind clinical trial, 64 patients with METS were randomly assigned to iron reduction by phlebotomy (n = 33) or to a control group (n = 31), which was offered phlebotomy at the end of the study (waiting-list design). The iron-reduction patients had 300 ml of blood removed at entry and between 250 and 500 ml removed after 4 weeks, depending on ferritin levels at study entry. Primary outcomes were change in systolic blood pressure (SBP) and insulin sensitivity as measured by Homeostatic Model Assessment (HOMA) index after 6 weeks. Secondary outcomes included HbA1c, plasma glucose, blood lipids, and heart rate (HR).</p> <p>Results</p> <p>SBP decreased from 148.5 ± 12.3 mmHg to 130.5 ± 11.8 mmHg in the phlebotomy group, and from 144.7 ± 14.4 mmHg to 143.8 ± 11.9 mmHg in the control group (difference -16.6 mmHg; 95% CI -20.7 to -12.5; <it>P </it>< 0.001). No significant effect on HOMA index was seen. With regard to secondary outcomes, blood glucose, HbA1c, low-density lipoprotein/high-density lipoprotein ratio, and HR were significantly decreased by phlebotomy. Changes in BP and HOMA index correlated with ferritin reduction.</p> <p>Conclusions</p> <p>In patients with METS, phlebotomy, with consecutive reduction of body iron stores, lowered BP and resulted in improvements in markers of cardiovascular risk and glycemic control. Blood donation may have beneficial effects for blood donors with METS.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01328210">NCT01328210</a></p> <p>Please see related article: <url>http://www.biomedcentral.com/1741-7015/10/53</url></p

Maggot secretions suppress pro-inflammatory responses of human monocytes through elevation of cyclic AMP

AIMS/HYPOTHESIS: Maggots of the blowfly Lucilia sericata are used for the treatment of chronic wounds. As monocytes may contribute to the excessive inflammatory responses in such wounds, this study focussed on the effects of maggot secretions on the pro-inflammatory activities of these cells. METHODS: Freshly isolated monocytes were incubated with a range of secretions for 1 h and then stimulated with lipopolysaccharides (range 0-100 ng/ml) or lipoteichoic acid (range 0-5 microg/ml) for 18 h. The expression of cell surface molecules, cytokine and chemokine levels in culture supernatants, cell viability, chemotaxis, and phagocytosis and killing of Staphylococcus aureus were measured. RESULTS: Maggot secretions dose-dependently inhibited production of the pro-inflammatory cytokines TNF-alpha, IL-12p40 and macrophage migration inhibitory factor by lipopolysaccharides- and lipoteichoic acid-stimulated monocytes, while enhancing production of the anti-inflammatory cytokine IL-10. Expression of cell surface receptors involved in pathogen recognition remained unaffected by secretions. In addition, maggot secretions altered the chemokine profile of monocytes by downregulating macrophage inflammatory protein-1beta and upregulating monocyte chemoattractant protein-1 and IL-8. Nevertheless, chemotactic responses of monocytes were inhibited by secretions. Furthermore, maggot secretions did not affect phagocytosis and intracellular killing of S. aureus by human monocytes. Finally, secretions induced a transient rise in the intracellular cyclic AMP concentration in monocytes and Rp-cyclic AMPS inhibited the effects of secretions. CONCLUSIONS/INTERPRETATION: Maggot secretions inhibit the pro-inflammatory responses of human monocytes through a cyclic AMP-dependent mechanism. Regulation of the inflammatory processes by maggots contributes to their beneficial effects on chronic wound

A Coordinated Effort to Manage Soybean Rust in North America: A Success Story in Soybean Disease Monitoring

Existing crop monitoring programs determine the incidence and distribution of plant diseases and pathogens and assess the damage caused within a crop production region. These programs have traditionally used observed or predicted disease and pathogen data and environmental information to prescribe management practices that minimize crop loss (3,69). Monitoring programs are especially important for crops with broad geographic distribution or for diseases that can cause rapid and great economic losses. Successful monitoring programs have been developed for several plant diseases, including downy mildew of cucurbits, Fusarium head blight of wheat, potato late blight, and rusts of cereal crops (13,36,51,80)