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ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans
(2020)
Background: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence.
Methods: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication.
Results: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low.
Conclusion: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.
The application of inhomogeneous AC electric fields for molecular immobilization is a very fast and simple method that does not require any adaptions to the molecule's functional groups or charges. Here, the method is applied to a completely new category of molecules: small organic fluorescence dyes, whose dimensions amount to only 1 nm or even less. The presented setup and the electric field parameters used allow immobilization of dye molecules on the whole electrode surface as opposed to pure dielectrophoretic applications, where molecules are attracted only to regions of high electric field gradients, i.e., to the electrode tips and edges. In addition to dielectrophoresis and AC electrokinetic flow, molecular scale interactions and electrophoresis at short time scales are discussed as further mechanisms leading to migration and immobilization of the molecules.
Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
Foraging is risky and involves balancing the benefits of resource acquisition with costs of predation. Optimal foraging theory predicts where, when and how long to forage in a given spatiotemporal distribution of risks and resources. However, significant variation in foraging behaviour and resource exploitation remain unexplained. Using single foragers in artificial landscapes of perceived risks and resources with diminishing returns, we aimed to test whether foraging behaviour and resource exploitation are adjusted to risk level, vary with risk during different components of foraging, and (co)vary among individuals. We quantified foraging behaviour and resource exploitation for 21 common voles (Microtus arvalis). By manipulating ground cover, we created simple landscapes of two food patches varying in perceived risk during feeding in a patch and/or while travelling between patches. Foraging of individuals was variable and adjusted to risk level and type. High risk during feeding reduced feeding duration and food consumption more strongly than risk while travelling. Risk during travelling modified the risk effects of feeding for changes between patches and resulting evenness of resource exploitation. Across risk conditions individuals differed consistently in when and how long they exploited resources and exposed themselves to risk. These among-individual differences in foraging behaviour were associated with consistent patterns of resource exploitation. Thus, different strategies in foraging-under-risk ultimately lead to unequal payoffs and might affect lower trophic levels in food webs. Inter-individual differences in foraging behaviour, i.e. foraging personalities, are an integral part of foraging behaviour and need to be fully integrated into optimal foraging theory.
Engineering biotechnological microorganisms to use methanol as a feedstock for bioproduction is a major goal for the synthetic metabolism community. Here, we aim to redesign the natural serine cycle for implementation in E. coli. We propose the homoserine cycle, relying on two promiscuous formaldehyde aldolase reactions, as a superior pathway design. The homoserine cycle is expected to outperform the serine cycle and its variants with respect to biomass yield, thermodynamic favorability, and integration with host endogenous metabolism. Even as compared to the RuMP cycle, the most efficient naturally occurring methanol assimilation route, the homoserine cycle is expected to support higher yields of a wide array of products. We test the in vivo feasibility of the homoserine cycle by constructing several E. coli gene deletion strains whose growth is coupled to the activity of different pathway segments. Using this approach, we demonstrate that all required promiscuous enzymes are active enough to enable growth of the auxotrophic strains. Our findings thus identify a novel metabolic solution that opens the way to an optimized methylotrophic platform.
Formate dehydrogenase (FDH) enzymes are versatile catalysts for CO2 conversion. The FDH from Rhodobacter capsulatus contains a molybdenum cofactor with the dithiolene functions of two pyranopterin guanine dinucleotide molecules, a conserved cysteine, and a sulfido group bound at Mo(VI). In this study, we focused on metal oxidation state and coordination changes in response to exposure to O-2, inhibitory anions, and redox agents using X-ray absorption spectroscopy (XAS) at the Mo K-edge. Differences in the oxidative modification of the bis-molybdopterin guanine dinucleotide (bis-MGD) cofactor relative to samples prepared aerobically without inhibitor, such as variations in the relative numbers of sulfido (Mo=S) and oxo (Mo=O) bonds, were observed in the presence of azide (N-3(-)) or cyanate (OCN-). Azide provided best protection against O-2, resulting in a quantitatively sulfurated cofactor with a displaced cysteine ligand and optimized formate oxidation activity. Replacement of the cysteine ligand by a formate (HCO2-) ligand at the molybdenum in active enzyme is compatible with our XAS data. Cyanide (CN-) inactivated the enzyme by replacing the sulfido ligand at Mo(VI) with an oxo ligand. Evidence that the sulfido group may become protonated upon molybdenum reduction was obtained. Our results emphasize the role of coordination flexibility at the molybdenum center during inhibitory and catalytic processes of FDH enzymes.
Objective
Plant carnivory is distributed across the tree of life and has evolved at least six times independently, but sequenced and annotated nuclear genomes of carnivorous plants are currently lacking. We have sequenced and structurally annotated the nuclear genome of the carnivorous Roridula gorgonias and that of a non-carnivorous relative, Madeira’s lily-of-the-valley-tree, Clethra arborea, both within the Ericales. This data adds an important resource to study the evolutionary genetics of plant carnivory across angiosperm lineages and also for functional and systematic aspects of plants within the Ericales.
Results
Our assemblies have total lengths of 284 Mbp (R. gorgonias) and 511 Mbp (C. arborea) and show high BUSCO scores of 84.2% and 89.5%, respectively. We used their predicted genes together with publicly available data from other Ericales’ genomes and transcriptomes to assemble a phylogenomic data set for the inference of a species tree. However, groups of orthologs showed a marked absence of species represented by a transcriptome. We discuss possible reasons and caution against combining predicted genes from genome- and transriptome-based assemblies.
Apple replant disease (ARD) is a specific apple-related form of soil fertility loss due to unidentified causes and is also known as soil fatigue. The effect typically appears in monoculture production sites and leads to production decreases of up to 50%, even though the cultivation practice remains the same. However, an indication of replant disease is challenged by the lack of specification of the particular microbial group responsible for ARD. The objective of this study was to establish an algorithm for estimating growth suppression in orchards irrespective of the unknowns in the complex causal relationship by assessing plant-soil interaction in the orchard several years after planting. Based on a comparison between no-replant and replant soils, the Alternaria group (Ag) was identified as a soil-fungal population responding to replant with abundance. The trunk cross-sectional area (CSA) was found to be a practical and robust parameter representing below-ground and above-ground tree performance. Suppression of tree vigour was therefore calculated by dividing the two inversely related parameters, Q = ln(Ag)/CSA, as a function of soil-fungal proportions and plant responses at the single-tree level. On this basis, five clusters of tree vigour suppression (Q) were defined: (1) no tree vigour suppression/vital (0%), (2) escalating (- 38%), (3) strong (- 53%), (4) very strong (- 62%), and (5) critical (- 74%). By calculating Q at the level of the single tree, trees were clustered according to tree vigour suppression. The weighted frequency of clusters in the field allowed replant impact to be quantified at field level. Applied to a case study on sandy brown, dry diluvial soils in Brandenburg, Germany, the calculated tree vigour suppression was 46% compared to the potential tree vigour on no-replant soil in the same field. It is highly likely that the calculated growth suppression corresponds to ARD-impact This result is relevant for identifying functional changes in soil and for monitoring the economic effects of soil fatigue in apple orchards, particularly where long-period crop rotation or plot exchange are improbable.
In this work, a novel electrochemical molecularly imprinted polymer (MIP) sensor for the detection of the lipopeptide antibiotic Daptomycin (DAP) is presented which integrates gold decorated platinum nanoparticles (Au-Pt NPs) into the nanocomposite film. The sensor was prepared by electropolymerization of o-phenylenediamine (o-PD) in the presence of DAP using cyclic voltammetry. Cyclic voltammetry and differential pulse voltammetry were applied to follow the changes in the MIP-layer related to rebinding and removal of the target DAP by using the redox marker [Fe(CN)(6)](3-/4-). Under optimized operational conditions, the MIP/Au-Pt NPs/ GCE nanosensor exhibits a linear response in the range of 1-20 pM towards DAP. The limit of detection and limit of quantification were determined to be 0.161pM +/- 0.012 and 0.489pM +/- 0.012, respectively. The sensitivity towards the antibiotics Vancomycin and Erythromycin and the amino acids glycine and tryptophan was below 7 percent as compared with DAP. Moreover, the nanosensor was also successfully used for the detection of DAP in deproteinated human serum samples.
Background: The enzyme-linked immunosorbent assay (ELISA) is an indispensable tool for clinical diagnostics to identify or differentiate diseases such as autoimmune illnesses, but also to monitor their progression or control the efficacy of drugs. One use case of ELISA is to differentiate between different states (e.g. healthy vs. diseased). Another goal is to quantitatively assess the biomarker in question, like autoantibodies. Thus, the ELISA technology is used for the discovery and verification of new autoantibodies, too. Of key interest, however, is the development of immunoassays for the sensitive and specific detection of such biomarkers at early disease stages. Therefore, users have to deal with many parameters, such as buffer systems or antigen-autoantibody interactions, to successfully establish an ELISA. Often, fine-tuning like testing of several blocking substances is performed to yield high signal-to-noise ratios. <br /> Methods: We developed an ELISA to detect IgA and IgG autoantibodies against chitinase-3-like protein 1 (CHI3L1), a newly identified autoantigen in inflammatory bowel disease (IBD), in the serum of control and disease groups (n = 23, respectively). Microwell plates with different surface modifications (PolySorp and MaxiSorp coating) were tested to detect reproducibility problems. <br /> Results: We found a significant impact of the surface properties of the microwell plates. IgA antibody reactivity was significantly lower, since it was in the range of background noise, when measured on MaxiSorp coated plates (p < 0.0001). The IgG antibody reactivity did not differ on the diverse plates, but the plate surface had a significant influence on the test result (p = 0.0005). <br /> Conclusion: With this report, we want to draw readers' attention to the properties of solid phases and their effects on the detection of autoantibodies by ELISA. We want to sensitize the reader to the fact that the choice of the wrong plate can lead to a false negative test result, which in turn has serious consequences for the discovery of autoantibodies.