المؤلفون: Borysiuk, Klaudia, Ostaszewska-Bugajska, Monika, Kryzheuskaya, Katsiaryna, Gardeström, Per, 1950, Szal, Bożena

المصدر: Plant Cell Reports. 41:2393-2413

مصطلحات موضوعية: Ammonium nutrition, d-Lactate dehydrogenase, Dicarbonyl stress, Glyoxalase, Methylglyoxal, Mitochondrial Complex I mutant

الوصف: Key message: Elevated methylglyoxal levels contribute to ammonium-induced growth disorders in Arabidopsis thaliana. Methylglyoxal detoxification pathway limitation, mainly the glyoxalase I activity, leads to enhanced sensitivity of plants to ammonium nutrition.Abstract: Ammonium applied to plants as the exclusive source of nitrogen often triggers multiple phenotypic effects, with severe growth inhibition being the most prominent symptom. Glycolytic flux increase, leading to overproduction of its toxic by-product methylglyoxal (MG), is one of the major metabolic consequences of long-term ammonium nutrition. This study aimed to evaluate the influence of MG metabolism on ammonium-dependent growth restriction in Arabidopsis thaliana plants. As the level of MG in plant cells is maintained by the glyoxalase (GLX) system, we analyzed MG-related metabolism in plants with a dysfunctional glyoxalase pathway. We report that MG detoxification, based on glutathione-dependent glyoxalases, is crucial for plants exposed to ammonium nutrition, and its essential role in ammonium sensitivity relays on glyoxalase I (GLXI) activity. Our results indicated that the accumulation of MG-derived advanced glycation end products significantly contributes to the incidence of ammonium toxicity symptoms. Using A. thaliana frostbite1 as a model plant that overcomes growth repression on ammonium, we have shown that its resistance to enhanced MG levels is based on increased GLXI activity and tolerance to elevated MG-derived advanced glycation end-product (MAGE) levels. Furthermore, our results show that glyoxalase pathway activity strongly affects cellular antioxidative systems. Under stress conditions, the disruption of the MG detoxification pathway limits the functioning of antioxidant defense. However, under optimal growth conditions, a defect in the MG detoxification route results in the activation of antioxidative systems.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-200516Test
https://doi.org/10.1007/s00299-022-02931-5Test
https://umu.diva-portal.org/smash/get/diva2:1726261/FULLTEXT01.pdfTest

المؤلفون: Marzano, Luca, 1995, Darwich, Adam S., Tendler, Salomon, Dan, Asaf, Lewensohn, Rolf, De Petris, Luigi, Raghothama, Jayanth, Meijer, Sebastiaan, Professor, 1979

المصدر: Clinical and Translational Science. 15(10):2437-2447

مصطلحات موضوعية: C reactive protein, carboplatin, cisplatin, etoposide, irinotecan, lactate dehydrogenase, platinum complex

الوصف: In recent studies, small cell lung cancer (SCLC) treatment guidelines based on Veterans’ Administration Lung Study Group limited/extensive disease staging and resulted in broad and inseparable prognostic subgroups. Evidence suggests that the eight versions of tumor, node, and metastasis (TNM) staging can play an important role to address this issue. The aim of the present study was to improve the detection of prognostic subgroups from a real-word data (RWD) cohort of patients and analyze their patterns using a development pipeline with thoracic oncologists and machine learning methods. The method detected subgroups of patients informing unsupervised learning (partition around medoids) including the impact of covariates on prognosis (Cox regression and random survival forest). An analysis was carried out using patients with SCLC (n = 636) with stage IIIA–IVB according to TNM classification. The analysis yielded k = 7 compacted and well-separated clusters of patients. Performance status (Eastern Cooperative Oncology Group-Performance Status), lactate dehydrogenase, spreading of metastasis, cancer stage, and CRP were the baselines that characterized the subgroups. The selected clustering method outperformed standard clustering techniques, which were not capable of detecting meaningful subgroups. From the analysis of cluster treatment decisions, we showed the potential of future RWD applications to understand disease, develop individualized therapies, and improve healthcare decision making.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-321440Test
https://doi.org/10.1111/cts.13371Test
https://kth.diva-portal.org/smash/get/diva2:1710821/FULLTEXT01.pdfTest

المؤلفون: Koenekoop, Lucien, Åqvist, Johan

المصدر: Molecular biology and evolution. 40(5)

مصطلحات موضوعية: enzyme cold adaptation, lactate dehydrogenase, computer simulation

الوصف: Cold-adapted enzymes from psychrophilic and psychrotolerant species are characterized by a higher catalytic activity at low temperature than their mesophilic orthologs and are also usually found to be more thermolabile. Computer simulations of the catalytic reactions have been shown to be a very powerful tool for analyzing the structural and energetic origins of these effects. Here, we examine the cold adaptation of lactate dehydrogenases from two Antarctic and sub-Antarctic fish species using this approach and compare our results with those obtained for the orthologous dogfish enzyme. Direct calculations of thermodynamic activation parameters show that the cold-adapted fish enzymes are characterized by a lower activation enthalpy and a more negative entropy term. This appears to be a universal feature of psychrophilic enzymes, and it is found to originate from a higher flexibility of certain parts of the protein surface. We also carry out free energy simulations that address the differences in thermal stability and substrate binding affinity between the two cold-adapted enzymes, which only differ by a single mutation. These calculations capture the effects previously seen in in vitro studies and provide straightforward explanations of these experimental results.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-503099Test
https://doi.org/10.1093/molbev/msad099Test
https://uu.diva-portal.org/smash/get/diva2:1764950/FULLTEXT01.pdfTest

المؤلفون: Strandberg, Kristin, Ayoglu, Burcu, Roos, A., Reza, M., Niks, E., Signorelli, M., Fasterius, Erik, 1987, Pontén, F., Lochmüller, H., Domingos, J., Ala, P., Muntoni, F., Aartsma-Rus, A., Spitali, P., Nilsson, Peter, Al-Khalili Szigyarto, Cristina

المصدر: Journal of Neuromuscular Diseases. 7(3):231-246

مصطلحات موضوعية: Affinity-based proteomics, disease progression, Duchenne muscular dystrophy, protein biomarkers, serum and plasma, carbonate dehydratase III, collagen type 1, dystrophin, electron transferring flavoprotein, electron transferring flavoprotein A, lactate dehydrogenase, lactate dehydrogenase B, malate dehydrogenase, malate dehydrogenase 2, microtubule associated protein 4, myosin light chain, myosin light chain 3, nestin, troponin T, unclassified drug, adolescent, adult, aged, Article, blood sampling, breathing, child, controlled study, correlation analysis, disease course, female, gene mutation, human, immunohistochemistry, longitudinal study, major clinical study, male, middle aged, mobilization, preschool child, priority journal, protein analysis, protein expression, protein microarray, school child, six minute walk test, Western blotting, young adult

الوصف: Background: Duchenne Muscular Dystrophy is a severe, incurable disorder caused by mutations in the dystrophin gene. The disease is characterized by decreased muscle function, impaired muscle regeneration and increased inflammation. In a clinical context, muscle deterioration, is evaluated using physical tests and analysis of muscle biopsies, which fail to accurately monitor the disease progression. Objectives: This study aims to confirm and asses the value of blood protein biomarkers as disease progression markers using one of the largest longitudinal collection of samples. Methods: A total of 560 samples, both serum and plasma, collected at three clinical sites are analyzed using a suspension bead array platform to assess 118 proteins targeted by 250 antibodies in microliter amount of samples. Results: Nine proteins are confirmed as disease progression biomarkers in both plasma and serum. Abundance of these biomarkers decreases as the disease progresses but follows different trajectories. While carbonic anhydrase 3, microtubule associated protein 4 and collagen type I alpha 1 chain decline rather constantly over time, myosin light chain 3, electron transfer flavoprotein A, troponin T, malate dehydrogenase 2, lactate dehydrogenase B and nestin plateaus in early teens. Electron transfer flavoprotein A, correlates with the outcome of 6-minutes-walking-test whereas malate dehydrogenase 2 together with myosin light chain 3, carbonic anhydrase 3 and nestin correlate with respiratory capacity. Conclusions: Nine biomarkers have been identified that correlate with disease milestones, functional tests and respiratory capacity. Together these biomarkers recapitulate different stages of the disorder that, if validated can improve disease progression monitoring.

وصف الملف: print

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-284778Test
https://doi.org/10.3233/JND-190454Test

المؤلفون: Banerjee, Indradumna, Salih, Tagrid, Ramachandraiah, Harisha, Erlandsson, Johan, Pettersson, Torbjörn, Araújo, A. C., Karlsson, M., Russom, Aman, Assoc.Prof.

المصدر: RSC Advances. 7(56):35048-35054

مصطلحات موضوعية: Chemical analysis, Chemical detection, Clocks, Colorimetric analysis, Colorimetry, Coefficient of determination, Colorimetric detection, Lactate dehydrogenase, Micro-chambers, Point of care, Point of care diagnostic, Red channels, Sample preparation, Microfluidics

الوصف: We report a microfluidic sample preparation platform called "Slipdisc" based on slipchip technology. Slipdisc is a rotational slipchip that uses a unique hand-wound clockwork mechanism for precise movement of specially fabricated polycarbonate discs. In operation, the microchannels and microchambers carved on the closely aligned microfluidic discs convert from continuous filled paths to defined compartments using the slip movement. The clockwork mechanism introduced here is characterised by a food dye experiment and a conventional HRP TMB reaction before measuring lactate dehydrogenase (LDH) enzyme levels, which is a crucial biomarker for neonatal diagnostics. The colorimetry based detection of LDH was performed with an unmodified camera and an image analysis procedure based on normalising images and observing changes in red channel intensity. The analysis showed a close to unity coefficient of determination (R2 = 0.96) in detecting the LDH concentration when compared with a standard Chemical Analyser, demonstrating the excellent performance of the slipdisc platform with colorimetric detection. The versatile point of care sample preparation platform should ideally be suited for a multitude of applications at resource-limited settings.

وصف الملف: print

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-219077Test
https://doi.org/10.1039/c7ra05209jTest

المؤلفون: Villamil Giraldo, A. -M, Eriksson, I., Wennmalm, Stefan, 1970, Fyrner, T., Ederth, T., Öllinger, K.

المصدر: International Journal of Molecular Sciences. 21(9)

مصطلحات موضوعية: Liposome, Lysosomal membrane permeabilization, Lysosome, Lysosomotropic detergent, MSDH, caspase 3, detergent, lactate dehydrogenase, methyl serine dodecylamide hydrochloride, n acetyl beta glucosaminidase, unclassified drug, AG1518 cell line, apoptosis, Article, cell damage, cell permeabilization, cell viability, confocal laser scanning microscopy, controlled study, cytotoxicity, cytotoxicity assay, endocytosis, enzyme activity, fibroblast cell line, fluorescence correlation spectroscopy, human, human cell, immunocytochemistry, incubation time, lipid bilayer, live cell imaging, molecular interaction, molecular stability, MTT assay, pH, photon correlation spectroscopy, spectrofluorometry, transmission electron microscopy, Western blotting

الوصف: O-methyl-serine dodecylamine hydrochloride (MSDH) is a detergent that accumulates selectively in lysosomes, a so-called lysosomotropic detergent, with unexpected chemical properties. At physiological pH, it spontaneously forms vesicles, which disassemble into small aggregates (probably micelles) below pH 6.4. In this study, we characterize the interaction between MSDH and liposomes at different pH and correlate the findings to toxicity in human fibroblasts. We find that the effect of MSDH on lipid membranes is highly pH-dependent. At neutral pH, the partitioning of MSDH into the liposome membrane is immediate and causes the leakage of small fluorophores, unless the ratio between MSDH and lipids is kept low. At pH 5, the partitioning of MSDH into the membrane is kinetically impeded since MSDH is charged and a high ratio between MSDH and the lipids is required to permeabilize the membrane. When transferred to cell culture conditions, the ratio between MSDH and plasma membrane lipids must therefore be low, at physiological pH, to maintain plasma membrane integrity. Transmission electron microscopy suggests that MSDH vesicles are taken up by endocytosis. As the pH of the endosomal compartment progressively drops, MSDH vesicles disassemble, leading to a high concentration of increasingly charged MSDH in small aggregates inside the lysosomes. At sufficiently high MSDH concentrations, the lysosome is permeabilized, the proteolytic content released to the cytosol and apoptotic cell death is induced.

وصف الملف: print

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-277140Test
https://doi.org/10.3390/ijms21093136Test

المؤلفون: Sigurlásdóttir, Sara, Wassing, Gabriela M., Zuo, Fanglei, Arts, Melanie, Jonsson, Ann-Beth

المصدر: Frontiers in Microbiology. 10

مصطلحات موضوعية: Neisseria meningitidis, lactate dehydrogenase, eDNA, autolysis, biofilm, molekylär biovetenskap, Molecular Bioscience

الوصف: Neisseria meningitidis is a Gram-negative bacterium that asymptomatically colonizes the human nasopharyngeal mucosa. Pilus-mediated initial adherence of N. meningitidis to the epithelial mucosa is followed by the formation of three-dimensional aggregates, called microcolonies. Dispersal from microcolonies contributes to the transmission of N. meningitidis across the epithelial mucosa. We have recently discovered that environmental concentrations of host cell-derived lactate influences N. meningitidis microcolony dispersal. Here, we examined the ability of N. meningitidis mutants deficient in lactate metabolism to form biofilms. A lactate dehydrogenease A (idhA) mutant had an increased level of biofilm formation. Deletion of IdhA increased the N. meningitidis cell surface hydrophobicity and aggregation. In this study, we used FAM20, which belongs to clonal complex ST-11 that forms biofilms independently of extracellular DNA (eDNA). However, treatment with DNase I abolished the increased biofilm formation and aggregation of the ldhA-delicient mutant, suggesting a critical role for eDNA. Compared to wild-type, the IdhA-deficient mutant exhibited an increased autolytic rate, with significant increases in the eDNA concentrations in the culture supernatants and in biofilms. Within the IdhA mutant biofilm, the transcription levels of the capsule, pilus, and bacterial lysis genes were downregulated, while norB, which is associated with anaerobic respiration, was upregulated. These findings suggest that the absence of IdhA in N. meningitidis promotes biofilm formation and aggregation through autolysis-mediated DNA release.

وصف الملف: print

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-167499Test
https://doi.org/10.3389/fmicb.2019.00422Test

المؤلفون: Rydell-Törmänen, Kristina, Uller, Lena, Erjefält, Jonas

المصدر: European Respiratory Journal. 28(2):268-274

مصطلحات موضوعية: lactate dehydrogenase, apoptosis, neutrophils, endotoxin, inflammation, Medicin och hälsovetenskap, Klinisk medicin, Lungmedicin och allergi, Medical and Health Sciences, Clinical Medicine, Respiratory Medicine and Allergy

الوصف: Several pulmonary inflammatory conditions are characterised by infiltration of neutrophils. Normally, neutrophils are silently removed by apoptosis, followed by phagocytosis. However, if phagocytosis fails, apoptotic cells undergo secondary necrosis. Recent findings of increased levels of the pan-necrosis marker lactate dehydrogenase in bronchoalveolar lavage from lipopolysaccharide-exposed mice implies potential involvement of secondary necrosis. Using a similar model, this study aimed to identify the source of lactate dehydrogenase and to search for direct histological evidence of secondary necrosis. Lipopolysaccharide (LPS) was administered to the lungs of BALB/c mice, and bronchoalveolar lavage and tissue samples were collected 4, 12, 24, 36, 48, 60 and 72 h after administration. LPS induced a patchy neutrophil-rich lung inflammation, where the numbers of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-positive neutrophils were increased at 12 h and onwards. Lavage levels of neutrophils and lactate dehydrogenase increased significantly at 4 and 24 h, respectively. Detailed electron microscopic assessment of neutrophil activation and death modes revealed that up to 14% of the neutrophils were undergoing secondary necrosis, whereas apoptotic or primary necrotic structural cells were rarely found. In summary, this study provides direct evidence that secondary necrosis of neutrophils is a common process during intense lung inflammation. This implies that neutrophil apoptosis may cause rather than resolve airway inflammation.

الوصول الحر: https://lup.lub.lu.se/record/154873Test
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16510453&dopt=AbstractTest
http://dx.doi.org/10.1183/09031936.06.00126905Test

المؤلفون: Alam, M. T., Olin-Sandoval, V., Stincone, A., Keller, M. A., Zelezniak, Aleksej, 1984, Luisi, B. F., Ralser, M.

المصدر: Nature Communications. 8

مصطلحات موضوعية: Fructose 2, Pyruvate-Kinase, Substrate, Escherichia-Coli, Lactate-Dehydrogenase, Glycolysis, Triosephosphate Isomerase, Enzyme Function, Yeast, Genome, 6-Bisphosphate, Bacillus-Subtilis

الوصف: Metabolites can inhibit the enzymes that generate them. To explore the general nature of metabolic self-inhibition, we surveyed enzymological data accrued from a century of experimentation and generated a genome-scale enzyme-inhibition network. Enzyme inhibition is often driven by essential metabolites, affects the majority of biochemical processes, and is executed by a structured network whose topological organization is reflecting chemical similarities that exist between metabolites. Most inhibitory interactions are competitive, emerge in the close neighbourhood of the inhibited enzymes, and result from structural similarities between substrate and inhibitors. Structural constraints also explain one-third of allosteric inhibitors, a finding rationalized by crystallographic analysis of allosterically inhibited L-lactate dehydrogenase. Our findings suggest that the primary cause of metabolic enzyme inhibition is not the evolution of regulatory metabolite-enzyme interactions, but a finite structural diversity prevalent within the metabolome. In eukaryotes, compartmentalization minimizes inevitable enzyme inhibition and alleviates constraints that self-inhibition places on metabolism.

وصف الملف: electronic

الوصول الحر: https://research.chalmers.se/publication/251081Test
http://publications.lib.chalmers.se/records/fulltext/251081/local_251081.pdfTest

المؤلفون: Jerkeman, Mats, Aman, P, Cavallin-Ståhl, Eva, Torlakovic, E, Åkerman, Måns, Mitelman, Felix, Fioretos, Thoas

المصدر: International Journal of Oncology. 20(1):161-165

مصطلحات موضوعية: Gene Rearrangement B-Lymphocyte : genetics, Human, Immunophenotyping, Lymphoma B-Cell : drug therapy : genetics, Leucovorin : therapeutic use, Lactate Dehydrogenase : metabolism, Lymphoma Large-Cell Diffuse : drug therapy : genetics, Male, Methotrexate : therapeutic use, Middle Age, Neoplasm Staging, Prednisone : therapeutic use, Prognosis, Proto-Oncogene Proteins : genetics, Support Non-U.S. Gov't, Vincristine : therapeutic use, Transcription Factors : genetics, Doxorubicin : therapeutic use, DNA-Binding Proteins : genetics, DNA Neoplasm : analysis : metabolism, Cyclophosphamide : therapeutic use, Blotting Southern, Bleomycin : therapeutic use, Antineoplastic Combined Chemotherapy Protocols : therapeutic use, Aged, Adolescence, Adult, Medicin och hälsovetenskap, Klinisk medicin, Cancer och onkologi, Medical and Health Sciences, Clinical Medicine, Cancer and Oncology

الوصف: The purpose of this study was to investigate the prognostic implications of BCL6 rearrangement in a uniformly treated population of patients with diffuse large B-cell lymphoma (DLBCL) and to characterise the relationship between BCL6 rearrangement and prognostic factors. A total of 269 patients with DLBCL entered a randomised trial comparing the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) to the MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) regimen. In 44 cases, frozen tissue was available for assessment of BCL6 status by Southern blot analysis. BCL6 was rearranged in six of 43 evaluable cases (14%), and was associated with elevated lactate dehydrogenase (LDH), and a higher patient age. No association between BCL6 status and expression of BCL2, Ki-67 or TP53 was found. Patients presenting with BCL6 rearrangement displayed a weak trend towards better overall and failure-free survival (67 and 67% at 5 years), compared to patients with germline BCL6 (63 and 52%), but the difference was not statistically significant. In accordance with previously published series, the presence of BCL6 rearrangement does not define a prognostically distinct subgroup of DLBCL. Assessment of BCL6 status may, however, be of clinical interest when related to other prognostic variables.

الوصول الحر: https://lup.lub.lu.se/record/107004Test
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11743658Test
http://147.52.72.117/IJO/2002/volume20/number1/161-165.pdfTest