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Sökning: L773:2399 3642

  • Resultat 1-10 av 22
  • [1]23Nästa
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1.
  • Adler, Jeremy, et al. (författare)
  • Conventional analysis of movement on non-flat surfaces like the plasma membrane makes Brownian motion appear anomalous
  • 2019
  • Ingår i: Communications Biology. - 2399-3642. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Cells are neither flat nor smooth, which has serious implications for prevailing plasma membrane models and cellular processes like cell signalling, adhesion and molecular clustering. Using probability distributions from diffusion simulations, we demonstrate that 2D and 3D Euclidean distance measurements substantially underestimate diffusion on non-flat surfaces. Intuitively, the shortest within surface distance (SWSD), the geodesic distance, should reduce this problem. The SWSD is accurate for foldable surfaces but, although it outperforms 2D and 3D Euclidean measurements, it still underestimates movement on deformed surfaces. We demonstrate that the reason behind the underestimation is that topographical features themselves can produce both super- and subdiffusion, i.e. the appearance of anomalous diffusion. Differentiating between topography-induced and genuine anomalous diffusion requires characterising the surface by simulating Brownian motion on high-resolution cell surface images and a comparison with the experimental data.
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3.
  • Blondelle, J., et al. (författare)
  • Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism
  • 2019
  • Ingår i: Communications Biology. - 2399-3642. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Biological roles of obscurin and its close homolog Obsl1 (obscurin-like 1) have been enigmatic. While obscurin is highly expressed in striated muscles, Obsl1 is found ubiquitously. Accordingly, obscurin mutations have been linked to myopathies, whereas mutations in Obsl1 result in 3M-growth syndrome. To further study unique and redundant functions of these closely related proteins, we generated and characterized Obsl1 knockouts. Global Obsl1 knockouts are embryonically lethal. In contrast, skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts. Only deletion of both proteins and removal of their functional redundancy revealed their roles for sarcolemmal stability and sarcoplasmic reticulum organization. To gain unbiased insights into changes to the muscle proteome, we analyzed tibialis anterior and soleus muscles by mass spectrometry, uncovering additional changes to the muscle metabolism. Our analyses suggest that all obscurin protein family members play functions for muscle membrane systems.
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4.
  • Camacho, Rafael, et al. (författare)
  • 2D polarization imaging as a low-cost fluorescence method to detect α-synuclein aggregation ex vivo in models of Parkinson’s disease
  • 2018
  • Ingår i: Communications Biology. - Nature Research. - 2399-3642. ; 1
  • Tidskriftsartikel (refereegranskat)abstract
    • A hallmark of Parkinson’s disease is the formation of large protein-rich aggregates in neurons, where α-synuclein is the most abundant protein. A standard approach to visualize aggregation is to fluorescently label the proteins of interest. Then, highly fluorescent regions are assumed to contain aggregated proteins. However, fluorescence brightness alone cannot discriminate micrometer-sized regions with high expression of non-aggregated proteins from regions where the proteins are aggregated on the molecular scale. Here, we demonstrate that 2-dimensional polarization imaging can discriminate between preformed non-aggregated and aggregated forms of α-synuclein, and detect increased aggregation in brain tissues of transgenic mice. This imaging method assesses homo-FRET between labels by measuring fluorescence polarization in excitation and emission simultaneously, which translates into higher contrast than fluorescence anisotropy imaging. Exploring earlier aggregation states of α-synuclein using such technically simple imaging method could lead to crucial improvements in our understanding of α-synuclein-mediated pathology in Parkinson’s Disease.
5.
  • Chattopadhyay, Subhayan, et al. (författare)
  • Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
  • 2019
  • Ingår i: Communications Biology. - Nature Research. - 2399-3642. ; 2:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, TH17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response.
6.
  • de Jong, Simone, et al. (författare)
  • Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
  • 2018
  • Ingår i: Communications Biology. - Nature Publishing Group. - 2399-3642. ; 1
  • Tidskriftsartikel (refereegranskat)abstract
    • Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
7.
  • dongre, mitesh (författare)
  • Flagella-mediated secretion of a novel Vibrio cholerae cytotoxin affecting both vertebrate and invertebrate hosts
  • 2018
  • Ingår i: Communication Biology. - Nature Publishing Group. - 2399-3642.
  • Tidskriftsartikel (refereegranskat)abstract
    • Using Caenorhabditis elegans as an infection host model for Vibrio cholerae predator interactions, we discovered a bacterial cytotoxin, MakA, whose function as a virulence factor relies on secretion via the flagellum channel in a proton motive force-dependent manner. The MakA protein is expressed from the polycistronic makDCBA (motility-associated killing factor) operon. Bacteria expressing makDCBA induced dramatic changes in intestinal morphology leading to a defecation defect, starvation and death in C. elegans. The Mak proteins also promoted V. cholerae colonization of the zebrafish gut causing lethal infection. A structural model of purified MakA at 1.9 Å resolution indicated similarities to members of a superfamily of bacterial toxins with unknown biological roles. Our findings reveal an unrecognized role for V. cholerae flagella in cytotoxin export that may contribute both to environmental spread of the bacteria by promoting survival and proliferation in encounters with predators, and to pathophysiological effects during infections.
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8.
  • Dongre, Mitesh, et al. (författare)
  • Flagella-mediated secretion of a novel Vibrio cholerae cytotoxin affecting both vertebrate and invertebrate hosts
  • 2018
  • Ingår i: Communications Biology. - Springer Nature Publishing AG. - 2399-3642. ; 1
  • Tidskriftsartikel (refereegranskat)abstract
    • Using Caenorhabditis elegans as an infection host model for Vibrio cholerae predator interactions, we discovered a bacterial cytotoxin, MakA, whose function as a virulence factor relies on secretion via the flagellum channel in a proton motive force-dependent manner. The MakA protein is expressed from the polycistronic makDCBA (motility-associated killing factor) operon. Bacteria expressing makDCBA induced dramatic changes in intestinal morphology leading to a defecation defect, starvation and death in C. elegans. The Mak proteins also promoted V. cholerae colonization of the zebrafish gut causing lethal infection. A structural model of purified MakA at 1.9 Å resolution indicated similarities to members of a superfamily of bacterial toxins with unknown biological roles. Our findings reveal an unrecognized role for V. cholerae flagella in cytotoxin export that may contribute both to environmental spread of the bacteria by promoting survival and proliferation in encounters with predators, and to pathophysiological effects during infections.
9.
  • Enroth, Stefan, 1976-, et al. (författare)
  • High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer
  • 2019
  • Ingår i: Communications biology. - Nature Publishing Group. - 2399-3642. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations. The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85 and specificity = 0.93 for detection of ovarian cancer stages I-IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.
10.
  • Gräve, Kristine, et al. (författare)
  • Structure of Mycobacterium tuberculosis phosphatidylinositol phosphate synthase reveals mechanism of substrate binding and metal catalysis
  • 2019
  • Ingår i: Communications biology. - 2399-3642. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Tuberculosis causes over one million yearly deaths, and drug resistance is rapidly developing. Mycobacterium tuberculosis phosphatidylinositol phosphate synthase (PgsA1) is an integral membrane enzyme involved in biosynthesis of inositol-derived phospholipids required for formation of the mycobacterial cell wall, and a potential drug target. Here we present three crystal structures of M. tuberculosis PgsA1: in absence of substrates (2.9 angstrom), in complex with Mn2+ and citrate (1.9 angstrom), and with the CDP-DAG substrate (1.8 angstrom). The structures reveal atomic details of substrate binding as well as coordination and dynamics of the catalytic metal site. In addition, molecular docking supported by mutagenesis indicate a binding mode for the second substrate, D-myo-inositol-3-phosphate. Together, the data describe the structural basis for M. tuberculosis phosphatidylinositol phosphate synthesis and suggest a refined general catalytic mechanism-including a substrate-induced carboxylate shift-for Class I CDP-alcohol phosphotransferases, enzymes essential for phospholipid biosynthesis in all domains of life.
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  • Resultat 1-10 av 22
  • [1]23Nästa
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