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Sökning: AMNE:(NATURAL SCIENCES Biological Sciences Biophysics) > Karolinska Institutet

  • Resultat 1-10 av 93
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1.
  • Allison, Timothy M., et al. (författare)
  • Complementing machine learning‐based structure predictions with native mass spectrometry
  • 2022
  • Ingår i: Protein Science. - : John Wiley & Sons. - 0961-8368 .- 1469-896X. ; 31:6
  • Tidskriftsartikel (refereegranskat)abstract
    • The advent of machine learning-based structure prediction algorithms such as AlphaFold2 (AF2) and RoseTTa Fold have moved the generation of accurate structural models for the entire cellular protein machinery into the reach of the scientific community. However, structure predictions of protein complexes are based on user-provided input and may require experimental validation. Mass spectrometry (MS) is a versatile, time-effective tool that provides information on post-translational modifications, ligand interactions, conformational changes, and higher-order oligomerization. Using three protein systems, we show that native MS experiments can uncover structural features of ligand interactions, homology models, and point mutations that are undetectable by AF2 alone. We conclude that machine learning can be complemented with MS to yield more accurate structural models on a small and large scale.
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2.
  • Wedenberg, Mina, et al. (författare)
  • Analytical description of the LET dependence of cell survival using the repairable-conditionally repairable damage model
  • 2010
  • Ingår i: Radiation Research. - 0033-7587 .- 1938-5404. ; 96, s. S534-S534
  • Tidskriftsartikel (refereegranskat)abstract
    • In light-ion radiation therapy, both the dose and the local energy spectrum, which is often characterized with the linear energy transfer (LET), must be considered. In treatment optimization, it is advantageous to use a radiobiological model that analytically accounts for both dose and LET for the ion type of interest. With such a model the biological effect can also be estimated for dose and LET combinations for which there are no observations in the underlying experimental data. In this study, the repairable-conditionally repairable (RCR) damage model was extended by expressing its parameters as functions of LET to provide a radiobiological model that accounts for both the dose and the LET for a given ion type and cell line. This LET-parameterized RCR model was fitted to published cell survival data for HSG and V79 cells irradiated with carbon ions and for T1 cells irradiated with helium ions. To test the robustness of the model, fittings to only a subset of the data were performed. Good agreement with the cell survival data was obtained, including survival data for LET values not used for model fitting, opening up the possibility of using the model in treatment planning for light ions.
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3.
  • Mehmedovic, Majda, et al. (författare)
  • Disease causing mutation (P178L) in mitochondrial transcription factor A results in impaired mitochondrial transcription initiation
  • 2022
  • Ingår i: Biochimica Et Biophysica Acta-Molecular Basis of Disease. - : Elsevier BV. - 0925-4439 .- 1879-260X. ; 1868:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondrial transcription factor A (TFAM) is essential for the maintenance, expression, and packaging of mitochondrial DNA (mtDNA). Recently, a pathogenic homozygous variant in TFAM (P178L) has been associated with a severe mtDNA depletion syndrome leading to neonatal liver failure and early death. We have performed a biochemical characterization of the TFAM variant P178L in order to understand the molecular basis for the pathogenicity of this mutation. We observe no effects on DNA binding, and compaction of DNA is only mildly affected by the P178L amino acid change. Instead, the mutation severely impairs mtDNA transcription initiation at the mitochondrial heavy and light strand promoters. Molecular modeling suggests that the P178L mutation affects promoter sequence recognition and the interaction between TFAM and the tether helix of POLRMT, thus explaining transcription initiation deficiency.
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4.
  • Unnersjö-Jess, David, et al. (författare)
  • Super-resolution stimulated emission depletion imaging of slit diaphragm proteins in optically cleared kidney tissue.
  • 2016
  • Ingår i: Kidney International. - : Nature Publishing Group. - 0085-2538 .- 1523-1755. ; 89:1, s. 243-247
  • Tidskriftsartikel (refereegranskat)abstract
    • The glomerular filtration barrier, consisting of podocyte foot processes with bridging slit diaphragm, glomerular basement membrane, and endothelium, is a key component for renal function. Previously, the subtlest elements of the filtration barrier have only been visualized using electron microscopy. However, electron microscopy is mostly restricted to ultrathin two-dimensional samples, and the possibility to simultaneously visualize multiple different proteins is limited. Therefore, we sought to implement a super-resolution immunofluorescence microscopy protocol for the study of the filtration barrier in the kidney. Recently, several optical clearing methods have been developed making it possible to image through large volumes of tissue and even whole organs using light microscopy. Here we found that hydrogel-based optical clearing is a beneficial tool to study intact renal tissue at the nanometer scale. When imaging samples using super-resolution STED microscopy, the staining quality was critical in order to assess correct nanoscale information. The signal-to-noise ratio and immunosignal homogeneity were both improved in optically cleared tissue. Thus, STED of slit diaphragms in fluorescently labelled optically cleared intact kidney samples is a new tool for studying the glomerular filtration barrier in health and disease.
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5.
  • Hassan, Sameer, et al. (författare)
  • Ligand Binding Site Comparison - LiBiSCo - a web-based tool for analyzing interactions between proteins and ligands to explore amino acid specificity within active sites
  • 2021
  • Ingår i: Proteins-Structure Function and Bioinformatics. - : Wiley. - 0887-3585 .- 1097-0134. ; 89:11, s. 1530-1540
  • Tidskriftsartikel (refereegranskat)abstract
    • Interaction between protein and ligands are ubiquitous in a biological cell, and understanding these interactions at the atom level in protein-ligand complexes is crucial for structural bioinformatics and drug discovery. Here, we present a web-based protein-ligand interaction application named Ligand Binding Site Comparison (LiBiSCo) for comparing the amino acid residues interacting with atoms of a ligand molecule between different protein-ligand complexes available in the Protein Data Bank (PDB) database. The comparison is performed at the ligand atom level irrespectively of having binding site similarity or not between the protein structures of interest. The input used in LiBiSCo is one or several PDB IDs of protein-ligand complex(es) and the tool returns a list of identified interactions at ligand atom level including both bonded and non-bonded interactions. A sequence profile for the interaction for each ligand atoms is provided as a WebLogo. The LiBiSco is useful in understanding ligand binding specificity and structural promiscuity among families that are structurally unrelated. The LiBiSCo tool can be accessed through .
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6.
  • Nilsson, Linnéa, et al. (författare)
  • Prompt apoptotic response to high glucose in SGLT expressing cells
  • 2019
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 316:5, s. F1078-F1089
  • Tidskriftsartikel (refereegranskat)abstract
    • It is generally believed that cells that are unable to downregulate glucose transport are particularly vulnerable to hyperglycemia. Yet little is known about the relation between expression of glucose transporters and acute toxic effects of high glucose exposure.Here we have, in an ex vivo study on rat renal cells, compared the apoptotic response to a moderate increase in glucose concentration. We have studied the cell types that commonly are targeted in diabetic kidney disease (DKD): proximal tubule cells (PTC) that express SGLT2, mesangial cells (MC) that express SGLT1, and podocytes that lack SGLT and take up glucose via the insulin dependent GLUT4.PTC and MC responded within 4-8 h exposure to 15 mM glucose with translocation of the apoptotic protein Bax to mitochondria and increased apoptotic index. SGLT down-regulation and exposure to SGLT inhibitors abolished the apoptotic response. Onset of overt DKD generally coincides with onset of albuminuria. Albumin had an additive effect on the apoptotic response. Ouabain, which interferes with apoptotic onset, rescued from the apoptotic response. Insulin supplemented podocytes remained resistant to 15 and 30 mM glucose for at least 24 h.Our study points to a previously unappreciated role of SGLT dependent glucose uptake as a risk-factor for diabetic complications and highlights the importance of therapeutic approaches that specifically target the different cell types in DKD.
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7.
  • Rönnlund, Daniel, et al. (författare)
  • Spatial organization of proteins in metastasizing cells
  • 2013
  • Ingår i: Cytometry Part A. - : John Wiley & Sons. - 1552-4922 .- 1552-4930. ; 83:9, s. 855-865
  • Tidskriftsartikel (refereegranskat)abstract
    • The ability of tumor cells to invade into the surrounding tissue is linked to defective adhesive and mechanical properties of the cells, which are regulated by cell surface adhesions and the intracellular filamentous cytoskeleton, respectively. With the aim to further reveal the underlying mechanisms and provide new strategies for early cancer diagnostics, we have used ultrahigh resolution stimulated emission depletion (STED) microscopy as a means to identify metastasizing cells, based on their subcellular protein distribution patterns reflecting their specific adhesive and mechanical properties. We have compared the spatial distribution of cell-matrix adhesion sites and the vimentin filamentous systems in a matched pair of primary, normal, and metastatic human fibroblast cells. We found that the metastatic cells showed significantly increased densities and more homogenous distributions of nanoscale adhesion-related particles. Moreover, they showed an increase in the number but reduced sizes of the areas of cell-matrix adhesion complexes. The organization of the vimentin intermediate filaments was also found to be significantly different in the metastasizing cells, showing an increased entanglement and loss of directionality. Image analysis procedures were established, allowing an objective detection and characterization of these features and distinction of metastatic cells from their normal counterparts. In conclusion, our results suggest that STED microscopy provides a novel tool to identify metastasizing cells from a very sparse number of cells, based on the altered spatial distribution of the cell-matrix adhesions and intermediate filaments.
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8.
  • Saini, Ravi Kanth Rao, et al. (författare)
  • Proteomics of dedifferentiation of SK-N-BE2 neuroblastoma cells
  • 2014
  • Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 454:1, s. 202-209
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuroblastoma develops through processes which include cellular dedifferentiation. Ability of tumors to form spheroids is one of the manifestations of dedifferentiation and carcinogenic transformation. To study mechanisms of dedifferentiation of neuroblastoma cells, we generated spheroids and performed a proteomics study to compare the spheroids with parental SK-N-BE2 cells. We observed that dedifferentiation induced extensive changes in the proteome profiles of the cells, which affected more than 30% of detected cellular proteins. Using mass spectrometry, we identified 239 proteins affected by dedifferentiation into spheroids as compared to the parental cells. These proteins represented such regulatory processes as transcription, cell cycle regulation, apoptosis, cell adhesion, metabolism, intracellular transport, stress response, and angiogenesis. A number of potent regulators of stemness, differentiation and cancer were detected as subnetworks formed by the identified proteins. Our validation tissue microarray study of 30 neuroblastoma cases confirmed that two of the identified proteins, DISC1 and DNA-PKcs, had their expression increased in advanced malignancies. Thus, our report unveiled extensive changes of the cellular proteome upon dedifferentiation of neuroblastoma cells, indicated top subnetworks and clusters of molecular mechanisms involved in dedifferentiation, and provided candidate biomarkers for clinical studies. (C) 2014 Elsevier Inc. All rights reserved.
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9.
  • Strömqvist, Johan, et al. (författare)
  • A modified FCCS procedure applied to Ly49A-MHC class Icis-interaction studies in cell membranes
  • 2011
  • Ingår i: Biophysical Journal. - : Elsevier. - 0006-3495 .- 1542-0086. ; 101:5, s. 1257-1269
  • Tidskriftsartikel (refereegranskat)abstract
    • The activity of natural killer (NK) cells is regulated by a fine-tuned balance between activating and inhibitory receptors. Dual-color fluorescence cross-correlation spectroscopy (FCCS) was used to directly demonstrate a so-called cis-interaction between a member of the inhibitory NK cell receptor family Ly49 (Ly49A), and its ligand, the major histocompatibility complex (MHC) class I, within the plasma membrane of the same cell. By a refined FCCS model, calibrated by positive and negative control experiments on cells from the same lymphoid cell line, concentrations and diffusion coefficients of free and interacting proteins could be determined on a collection of cells. Using the intrinsic intercellular variation of their expression levels for titration, it was found that the fraction of Ly49A receptors bound in cis increase with increasing amounts of MHC class I ligand. This increase shows a tendency to be more abrupt than for a diffusion limited three dimensional bimolecular reaction, which most likely reflects the two-dimensional confinement of the reaction. For the Ly49A- MHC class I interaction it indicates that within a critical concentration range the local concentration level of MHC class I can provide a distinct regulation mechanism of the NK cell activity.
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10.
  • Zhang, Bo, et al. (författare)
  • Covariation of Peptide Abundances Accurately Reflects Protein Concentration Differences
  • 2017
  • Ingår i: Molecular & Cellular Proteomics. - : American Society for Biochemistry and Molecular Biology. - 1535-9476 .- 1535-9484. ; 16:5, s. 936-948
  • Tidskriftsartikel (refereegranskat)abstract
    • Most implementations of mass spectrometry-based proteomics involve enzymatic digestion of proteins, expanding the analysis to multiple proteolytic peptides for each protein. Currently, there is no consensus of how to summarize peptides' abundances to protein concentrations, and such efforts are complicated by the fact that error control normally is applied to the identification process, and do not directly control errors linking peptide abundance measures to protein concentration. Peptides resulting from suboptimal digestion or being partially modified are not representative of the protein concentration. Without a mechanism to remove such unrepresentative peptides, their abundance adversely impacts the estimation of their protein's concentration. Here, we present a relative quantification approach, Diffacto, that applies factor analysis to extract the covariation of peptides' abundances. The method enables a weighted geometrical average summarization and automatic elimination of incoherent peptides. We demonstrate, based on a set of controlled label-free experiments using standard mixtures of proteins, that the covariation structure extracted by the factor analysis accurately reflects protein concentrations. In the 1% peptide-spectrum match-level FDR data set, as many as 11% of the peptides have abundance differences incoherent with the other peptides attributed to the same protein. If not controlled, such contradicting peptide abundance have a severe impact on protein quantifications. When adding the quantities of each protein's three most abundant peptides, we note as many as 14% of the proteins being estimated as having a negative correlation with their actual concentration differences between samples. Diffacto reduced the amount of such obviously incorrectly quantified proteins to 1.6%. Furthermore, by analyzing clinical data sets from two breast cancer studies, our method revealed the persistent proteomic signatures linked to three subtypes of breast cancer. We conclude that Diffacto can facilitate the interpretation and enhance the utility of most types of proteomics data.
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