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  • 1
    Electronic Resource
    Electronic Resource
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 95 (1991), S. 4397-4406 
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: An analysis of electronic polarizabilities, interionic potentials, and equilibrium geometries for 20 alkali–halide dimers such as Na2Cl2 is presented. The electronic polarizabilities of ions in dimers have been calculated by taking account of the electrostatic potential due to neighboring ions within the Seitz–Ruffa energy level analysis. The polarizabilities thus obtained for dimers are then used to evaluate the magnitudes of polarization energies and van der Waals dipole–dipole energies. For describing the overlap repulsive potential we have adopted two forms: (i) the revised version of the Born–Mayer potential and (ii) the Harrison form for the overlap repulsive energy. These potentials have been used to obtain the binding energies of monomers as well as dimers, spectroscopic constants of monomers, equilibrium geometries of dimers, and dimerization energies. The results have been discussed and compared with available experimental data.
    Type of Medium: Electronic Resource
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  • 2
    Keywords: IN-VITRO ; Germany ; MICROSCOPY ; DISEASE ; PROTEIN ; PROTEINS ; DYNAMICS ; BIOLOGY ; fibroblasts ; DAMAGE ; LENGTH ; vimentin ; ATOMIC-FORCE MICROSCOPY ; SMOOTH-MUSCLE ; electron microscopy ; molecular biology ; DEPENDENCE ; DESMIN ; desmin and vimentin intermediate filament ; ELASTIC LIGHT-SCATTERING ; F-ACTIN SOLUTIONS ; MICRORHEOLOGY ; persistence length ; rheology ; strain stiffening ; THERMAL FLUCTUATIONS
    Abstract: We have investigated the viscoelastic properties of the cytoplasmic intermediate filament (IF) proteins desmin and vimentin. Mechanical measurements were supported by time-dependent electron microscopy studies of the assembly process under similar conditions. Network formation starts within 2 min, but it takes more than 30 min until equilibrium mechanical network strength is reached. Filament bundling is more pronounced for desmin than for vimentin. Desmin filaments (persistence length l(p) approximate to 900 nm) are stiffer than vimentin filaments (l(p) approximate to 400 nm), but both IFs are much more flexible than microfilaments. e concentration dependence of the plateau modulus G(0) similar to c(alpha) is much weaker than predicted theoretically for networks of semiflexible filaments. This is more pronounced for vimentin (alpha = 0.47) than for desmin (alpha = 0.70). Both networks exhibit strain stiffening at large shear deformations. At the transition from linear to nonlinear viscoelastic response, only desmin shows characteristics of nonaffine network deformation. Strain stiffening and the maximum modulus occur at strain amplitudes about an order of magnitude larger than those for microfilaments. This is probably attributable to axial slippage within the tetramer building blocks of the IFs. Network deformation beyond a critical strain gamma(max) results in irreversible damage. Strain stiffening sets in at lower concentrations, is more pronounced, and is less sensitive to ionic strength for desmin than for vimentin. Hence, desmin exhibits strain stiffening even at low-salt concentrations, which is not observed for vimentin, and we conclude that the strength of electrostatic repulsion compared to the strength of attractive interactions forming the network junctions is significantly weaker for desmin than for vimentin filaments. These findings indicate that both IFs exhibit distinct mechanical properties that are adapted to their respective cellular surroundings [i.e., myocytes (desmin) and fibroblasts (vimentin)]. (C) 2009 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19281820
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  • 3
    Abstract: Inherited mutations in the gene coding for the intermediate filament protein desmin have been demonstrated to cause severe skeletal and cardiac myopathies. Unexpectedly, some of the mutated desmins, in particular those carrying single amino acid alterations in the non-alpha-helical carboxy-terminal domain ("tail"), have been demonstrated to form apparently normal filaments both in vitro and in transfected cells. Thus, it is not clear if filament properties are affected by these mutations at all. For this reason, we performed oscillatory shear experiments with six different desmin "tail" mutants in order to characterize the mesh size of filament networks and their strain stiffening properties. Moreover, we have carried out high-frequency oscillatory squeeze flow measurements to determine the bending stiffness of the respective filaments, characterized by the persistence length l(p). Interestingly, mesh size was not altered for the mutant filament networks, except for the mutant DesR454W, which apparently did not form proper filament networks. Also, the values for bending stiffness were in the same range for both the "tail" mutants (l(p)=1.0-2.0 microm) and the wild-type desmin (l(p)=1.1+/-0.5 microm). However, most investigated desmin mutants exhibited a distinct reduction in strain stiffening compared to wild-type desmin and promoted nonaffine network deformation. Therefore, we conclude that the mutated amino acids affect intrafilamentous architecture and colloidal interactions along the filament in such a way that the response to applied strain is significantly altered. In order to explore the importance of the "tail" domain as such for filament network properties, we employed a "tail"-truncated desmin. Under standard conditions, it formed extended regular filaments, but failed to generate strain stiffening. Hence, these data strongly indicate that the "tail" domain is responsible for attractive filament-filament interactions. Moreover, these types of interactions may also be relevant to the network properties of the desmin cytoskeleton in patient muscle.
    Type of Publication: Journal article published
    PubMed ID: 20171226
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  • 4
    Keywords: IN-VITRO ; PROTEIN ; INTERMEDIATE-FILAMENTS ; vimentin ; SKELETAL-MUSCLE ; ARCHITECTURE ; STRIATED-MUSCLE ; Z-DISC ; THIN-FILAMENTS ; MOTILE PROPERTIES
    Abstract: Desmin intermediate filaments (DIFs) form an intricate meshwork that organizes myofibers within striated muscle cells. The mechanisms that regulate the association of desmin to sarcomeres and their role in desminopathy are incompletely understood. Here we compare the effect nebulin binding has on the assembly kinetics of desmin and three desminopathy-causing mutant desmin variants carrying mutations in the head, rod, or tail domains of desmin (S46F, E245D, and T453I). These mutants were chosen because the mutated residues are located within the nebulin-binding regions of desmin. We discovered that, although nebulin M160-164 bound to both desmin tetrameric complexes and mature filaments, all three mutants exhibited significantly delayed filament assembly kinetics when bound to nebulin. Correspondingly, all three mutants displayed enhanced binding affinities and capacities for nebulin relative to wild-type desmin. Electron micrographs showed that nebulin associates with elongated normal and mutant DIFs assembled in vitro. Moreover, we measured significantly delayed dynamics for the mutant desmin E245D relative to wild-type desmin in fluorescence recovery after photobleaching in live-cell imaging experiments. We propose a mechanism by which mutant desmin slows desmin remodeling in myocytes by retaining nebulin near the Z-discs. On the basis of these data, we suggest that for some filament-forming desmin mutants, the molecular etiology of desminopathy results from subtle deficiencies in their association with nebulin, a major actin-binding filament protein of striated muscle.
    Type of Publication: Journal article published
    PubMed ID: 23615443
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; PLASMA ; DELIVERY ; MEMBRANE-VESICLES ; PROTEOMIC ANALYSIS ; exosomes ; MICROPARTICLES ; PROSTASOMES
    Abstract: MOTIVATION: Extracellular vesicles are spherical bilayered proteolipids, harboring various bioactive molecules. Due to the complexity of the vesicular nomenclatures and components, online searches for extracellular vesicle-related publications and vesicular components are currently challenging. RESULTS: We present an improved version of EVpedia, a public database for extracellular vesicles research. This community web portal contains a database of publications and vesicular components, identification of orthologous vesicular components, bioinformatic tools, and a personalized function. EVpedia includes 6,879 publications, 172,080 vesicular components from 263 high-throughput datasets, and has been accessed 〉65,000 times from 〉750 cities. In addition, about 350 members from 73 international research groups have participated in developing EVpedia. This free web-based database might serve as a useful resource to stimulate the emerging field of extracellular vesicle research. Availability and implementation: The web site was implemented in PHP, Java, MySQL and Apache, and is freely available at http://evpedia.info. CONTACT: ysgho@postech.ac.kr.
    Type of Publication: Journal article published
    PubMed ID: 25388151
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  • 6
  • 7
    Abstract: BACKGROUND: ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC. METHODS: ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516. FINDINGS: Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11.1 months (IQR 6.7-15.2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17.0 months (95% CI 11.3-non-estimable [NE]) in ALK inhibitor-naive patients and 8.3 months (6.8-9.7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18.4 months (95% CI 11.1-NE) in ALK inhibitor-naive patients and 6.9 months (5.6-8.7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3-4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis. INTERPRETATION: The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizot
    Type of Publication: Journal article published
    PubMed ID: 26973324
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  • 8
    Keywords: MISMATCH REPAIR ; DNA replication fidelity ; CTP biosynthesis ; DNA polymerases ; dNTP pool imbalance
    Abstract: Eukaryotic DNA replication fidelity relies on the concerted action of DNA polymerase nucleotide selectivity, proofreading activity, and DNA mismatch repair (MMR). Nucleotide selectivity and proofreading are affected by the balance and concentration of deoxyribonucleotide (dNTP) pools, which are strictly regulated by ribonucleotide reductase (RNR). Mutations preventing DNA polymerase proofreading activity or MMR function cause mutator phenotypes and consequently increased cancer susceptibility. To identify genes not previously linked to high-fidelity DNA replication, we conducted a genome-wide screen in Saccharomyces cerevisiae using DNA polymerase active-site mutants as a sensitized mutator background. Among the genes identified in our screen, three metabolism-related genes (GLN3, URA7, and SHM2) have not been previously associated to the suppression of mutations. Loss of either the transcription factor Gln3 or inactivation of the CTP synthetase Ura7 both resulted in the activation of the DNA damage response and imbalanced dNTP pools. Importantly, these dNTP imbalances are strongly mutagenic in genetic backgrounds where DNA polymerase function or MMR activity is partially compromised. Previous reports have shown that dNTP pool imbalances can be caused by mutations altering the allosteric regulation of enzymes involved in dNTP biosynthesis (e.g., RNR or dCMP deaminase). Here, we provide evidence that mutations affecting genes involved in RNR substrate production can cause dNTP imbalances, which cannot be compensated by RNR or other enzymatic activities. Moreover, Gln3 inactivation links nutrient deprivation to increased mutagenesis. Our results suggest that similar genetic interactions could drive mutator phenotypes in cancer cells.
    Type of Publication: Journal article published
    PubMed ID: 28416670
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  • 9
    Keywords: Desmin, Intermediate filament protein, Myofibrillar myopathy, Assembly, Transfection
    Abstract: The intermediate filament protein desmin generates an extra-sarcomeric network in myocytes. Mutations in the desmin gene cause myofibrillar myopathy characterized by desmin-positive aggregates and myofibrillar dissolution. Past analysis revealed that the non-alpha-helical amino-terminal "head" domain of desmin is a vital coordinator of protein assembly. We have now characterized assembly and network-forming properties of five recently discovered myopathy-causing mutations residing in this domain. In vitro analyses with recombinant proteins show that two mutant variants residing in a conserved nonapeptide motif "SSYRRTFGG" - Ser13Phe and Arg16Cys - interfere with assembly by forming filamentous aggregates. Consistent with in vitro data, both mutant proteins are unable to generate a bona fide filament system in cells lacking an intermediate filament cytoskeleton.
    Type of Publication: Journal article published
    PubMed ID: 19763525
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  • 10
    Keywords: APOPTOSIS ; CANCER ; PATHWAY ; GROWTH-FACTOR RECEPTOR ; resistance ; microenvironment ; RADIORESISTANCE ; EGFRVIII ; MALIGNANT MAMMARY ; AKT ACTIVATION
    Abstract: Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. This study evaluated the prognostic value of the phosphorylation status of AKT on Ser473 and Thr308 for the clinical outcome of patients with advanced HNSCC on radiotherapy. Furthermore, we investigated the impact of AKT(Ser473) phosphorylation [p-AKT(Ser473)] in the context of radioresistance using ex vivo tissue cultures that resemble the complex tissue architecture and paracrine interaction with the tumor microenvironment. In a cohort of 120 patients with advanced HNSCC, who were treated with primary or adjuvant radiotherapy, a significant association was found between relative p-AKT(Ser473) levels and overall survival (p=0.006) as well as progression-free survival (p=0.021), while no significant correlation was revealed for relative p-AKT(Thr308) levels. In ex vivo tissue cultures p-AKT(Ser473) levels were increased upon irradiation and treatment with the PI3K inhibitor LY294002 inhibited both basal and irradiation induced AKT(Ser473) phosphorylation. Strikingly, pretreatment with LY294002 sensitized tissue cultures derived from primary and recurrent tumors to radiotherapy as determined by impaired tumor cell proliferation and enhanced DNA damage. In conclusion, phosphorylation status of AKT(Ser473) in tumor specimens serves as a novel biomarker to identify patients with advanced HNSCC at high risk for treatment failure following radiotherapy, and our data from ex vivo tissue cultures support the assumption that pharmacological inhibition of AKT(Ser473) phosphorylation might circumvent radioresistance to improve efficiency and reduce toxicity of current treatment modalities. What's new? Patients with head and neck squamous cell cancers often develop resistance to radiotherapy. To figure out how, these authors investigated AKT phosphorylation in the tumor cells. AKT kinase boosts cell proliferation when it is activated by phosphorylation at two possible sites. Could the location of phosphorylation predict whether the tumor will develop resistance? These results suggest it could. The authors show that patients with more phosphorylation at serine 473 had worse survival; furthermore, they showed that reducing phosphorylation at this site increased cancer cells' vulnerability to irradiation. Phosphorylation at the other site, threonine 308, did not affect survival.
    Type of Publication: Journal article published
    PubMed ID: 25388642
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