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111.
Maria Amprazi Dina Kotsifaki Mary Providaki Evangelia G. Kapetaniou Georgios Fellas Ioannis Kyriazidis Javier Pérez Michael Kokkinidis 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(30):11049-11054
The dimeric Repressor of Primer (Rop) protein, a widely used model system for the study of coiled-coil 4-α-helical bundles, is characterized by a remarkable structural plasticity. Loop region mutations lead to a wide range of topologies, folding states, and altered physicochemical properties. A protein-folding study of Rop and several loop variants has identified specific residues and sequences that are linked to the observed structural plasticity. Apart from the native state, native-like and molten-globule states have been identified; these states are sensitive to reducing agents due to the formation of nonnative disulfide bridges. Pro residues in the loop are critical for the establishment of new topologies and molten globule states; their effects, however, can be in part compensated by Gly residues. The extreme plasticity in the assembly of 4-α-helical bundles reflects the capacity of the Rop sequence to combine a specific set of hydrophobic residues into strikingly different hydrophobic cores. These cores include highly hydrated ones that are consistent with the formation of interchain, nonnative disulfide bridges and the establishment of molten globules. Potential applications of this structural plasticity are among others in the engineering of bio-inspired materials.Recurrent motifs of tertiary structure are convenient model systems for studying protein folding and potentially also for the design of bio-inspired materials. For protein design purposes, structural plasticity is an important, although poorly understood, parameter to be considered, as it is among the main reasons that the re-engineering of proteins toward novel materials is not yet satisfactorily manageable (1, 2).The present study focuses on the structural plasticity associated with the 4-α-helical bundle (4HB) motif. 4HBs consist of four amphipathic α-helices packed in a parallel or antiparallel fashion (3, 4). Their folding is largely determined by a repeating pattern of hydrophobic and hydrophilic residues, organized on the basis of seven-residue repeats (heptads) (5). Being the simplest tertiary motif, 4HBs have been subject to numerous protein-folding studies; attempts have been made to exploit them as building blocks for bio-inspired materials (6).A paradigm of a highly regular 4HB is the RNA-binding ColE1 Repressor of Primer (Rop) protein (7–9), also referred to as RNA-one-modulator (ROM). Each monomer is an α-helical hairpin consisting of two antiparallel α-helices connected by a short loop. The sequence of Rop displays a heptad repeats pattern that is interrupted only in the loop region.Structural simplicity makes Rop an attractive model system for the study of the folding of 4HBs. The loop region and the hydrophobic core have thereby attracted particular attention, as these regions are linked with the remarkable ability of Rop mutants to adopt altered topologies and properties (10–15). Striking examples of loop variants include mutant Loopless Rop (LLR), in which an uninterrupted pattern of heptad repeats is established through a five-residue deletion in the loop. In this “loopless” mutant, the α-helical hairpin of the monomer is converted into a single helix (15, 16). The complete LLR molecule is a tetramer that is completely reorganized relative to the dimeric wild-type (WT) Rop, thereby becoming a hyper-thermostable protein (16). On the other hand, establishment of an uninterrupted heptad periodicity through a two-residue insertion in the loop produces minimal changes relative to WT in terms of structure and properties (12). Thus, these two mutants with uninterrupted patterns of heptads reveal that there is a considerable structural plasticity inherent to the Rop sequence, but the relationship between heptad periodicity and the structural/physicochemical properties is complex.Extreme structural plasticity producing completely altered 4HB topologies is also associated with point mutations in the loop region. Replacement of loop residue Ala31 by Pro (17) results in a complete reorganization of the entire protein, which is converted from the canonical left-handed, all-antiparallel form into a right-handed mixed-parallel and antiparallel 4-α-helical bundle, displaying a “bisecting U” topology that is to a large extent determined by the local conformation at residue 31 (18). Mutant A31P displays two variations of the bisecting U topology; these differ in the relative juxtaposition of the α-helices (19). These conformations crystallize in different space groups (orthorhombic and monoclinic); both space groups have been occasionally observed in the same crystallization drop, indicating the coexistence of the two forms in solution. Molecular dynamics simulations for A31P have demonstrated a potential for the interconversion between the two conformations (14).Hydrophobic core mutants occasionally also display structural plasticity producing a new (“syn”) topology (20) that results from the “anti”-topology of WT through a 180° flip of one monomer around the dyad axis normal to the long axis of WT. The competition between the anti and syn topologies and the mixture of the two structures have been studied in detail for some Rop mutants (21, 22).Apart from structural plasticity, a closely related issue associated with the folding of Rop is the role of Cys residues (Cys-38 and Cys-52). Both residues are buried in the hydrophobic core and are not involved in the formation of disulfide bridges in any of the known structures of WT and its mutants. Surprisingly, however, a Cys-free variant (CYSfree) that conserves the structure, stability, and in vivo activity of WT exhibits dramatically faster unfolding kinetics (23).The present study focuses on the role of the loop region and Cys residues in the structural plasticity of Rop. To explore the conversion of the WT anti-topology into the bisecting U topology of A31P, the three double mutants D30P/A31G (PG), D30G/A31P (GP), and D30P/A31P (PP) have been constructed for loop positions 30 and 31. These mutations combine the effects of the most constrained amino acid (Pro) and of the least constrained one (Gly). In addition, the potential role of Cys residues in Rop folding is explored by following the effects of reducing agents. 相似文献
112.
Julien Rohmer Amélie Couteau-Chardon Julie Trichereau Kewin Panel Cyrielle Gesquiere Raouf Ben Abdelali Audrey Bidet Jean-Sébastien Bladé Jean-Michel Cayuela Pascale Cony-Makhoul Vincent Cottin Eric Delabesse Mikaël Ebbo Olivier Fain Pascale Flandrin Lionel Galicier Catherine Godon Nathalie Grardel Aurélien Guffroy Mohamed Hamidou Mathilde Hunault Etienne Lengline Faustine Lhomme Ludovic Lhermitte Irène Machelart Laurent Mauvieux Catherine Mohr Marie-Joelle Mozicconacci Dina Naguib Franck E. Nicolini Jerome Rey Philippe Rousselot Suzanne Tavitian Louis Terriou Guillaume Lefèvre Claude Preudhomme Jean-Emmanuel Kahn Matthieu Groh CEREO GBMHM collaborators 《American journal of hematology》2020,95(11):1314-1323
FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM. 相似文献
113.
Abdel-Rahman Rehab F. El Awdan Sally A. Hegazy Rehab R. Mansour Dina F. Ogaly H. A. Abdelbaset Marwan 《Metabolic brain disease》2020,35(3):427-439
Metabolic Brain Disease - The present study aimed to investigate the role of vascular endothelial growth factor (VEGF) in the neuroprotective effect of Crocus sativus (saffron) against cerebral... 相似文献
114.
115.
Jessica K. Salwen Genna F. Hymowitz K. Daniel O’Leary Aurora D. Pryor Dina Vivian 《Obesity surgery》2014,24(9):1572-1575
The present study evaluated the importance of multimodal assessment of childhood verbal abuse (CVA) in pre-bariatric surgery psychological evaluations, and the role of CVA as a predictor of depression. Data from the psychological evaluations of 184 pre-bariatric surgery patients were retrospectively examined. Using two self-report measures and an interview-based screen, 52.2 % of participants reported experiencing some form of CVA; conversely, assessments of CVA based on only one measure yielded significantly lower prevalence rates. Endorsement of CVA on multiple measures was associated with more severe depressive symptomatology and greater likelihood of mood disorder diagnosis. Based on these data, a self-report measure and interview-based screen for CVA should be included in pre-bariatric psychological evaluations; either of these assessments may be conducted via a single-item screen. Lastly, patients who endorse CVA on multiple measures should be monitored closely for symptoms of depression post-surgery. 相似文献
116.
Brigitte Lueger‐Schuster Dina Weindl Viktoria Kantor Matthias Knefel Tobias Glück Yvonne Moy Asisa Butollo Reinhold Jagsch 《Journal of traumatic stress》2014,27(5):568-575
In recent years, reports of institutional abuse within the Catholic Church have emerged and research on the consequences on mental health is in its beginnings. In this study, we report findings on current mental health and resilience in a sample of adult survivors of institutional abuse (N = 185). We compared 3 groups of survivors that differed regarding their current mental health to investigate aspects of resilience, coping, and disclosure. The majority of the sample was male (76.2%), the mean age was 56.28 (SD = 9.46) years, and more than 50.0% of the sample was cohabiting/married. Most of the survivors reported severe mental health problems. Known protective factors (education, social support, age) were not associated with mental health in our sample. Our findings corroborate that institutional abuse has long‐term effects on mental health. We found that fewer emotional reactions during disclosure, task‐oriented coping, and optimism were associated with better mental health. The study was limited by a cross‐sectional design, but we conclude that the kind of institutional abuse reported is especially adverse, and thus typical protective factors for mental health do not apply. Future research should focus on intrapersonal factors and institutional dynamics to improve treatment for persons affected by institutional abuse. 相似文献
117.
Donald M. Bushnell Mona L. Martin Michael Scanlon TeChieh Chen Dina Chau Hema N. Viswanathan 《Quality of life research》2014,23(3):897-906
Purpose
To evaluate the equivalence of electronic and paper versions of the Psoriasis Symptom Inventory and to examine measurement properties of the electronic version.Methods
In a prospective, randomized, crossover, non-interventional study in adult subjects (age ≥18 years) with plaque psoriasis conducted over a period of 15 days, subjects were randomized to two groups, completing either the paper or electronic Psoriasis Symptom Inventory daily for 7 consecutive days followed by the alternate version. Equivalence was assessed by the intraclass correlation coefficient (ICC) between both administration modes. Differences in scores were also tested using paired Student’s t test. Measurement properties included internal consistency reliability, test–retest reliability, and convergent and discriminant validity between the Psoriasis Symptom Inventory and (1) disease-specific (Dermatology Life Quality Index) and (2) general health (SF-36v2) status.Results
Eighty subjects [74 % (59/80) moderate-to-severe psoriasis; 26 % (21/80) mild psoriasis receiving systemic treatment] were enrolled from 8 sites in the USA. The two modes were highly concordant for both total (ICC = 0.97) and individual item scores (ICC range = 0.93–0.97). Response bias testing showed no differences based on completion order with all ICC values >0.91. All mean score differences, except for one item (“flaking”), were non-significant (P > 0.05). Minimum values for reliability (>0.70) and validity (convergent, r ≥ 0.40) were exceeded for the electronic Psoriasis Symptom Inventory.Conclusions
Equivalence between paper and electronic versions of the Psoriasis Symptom Inventory and strong measurement properties of the electronic mode indicated a successful migration from paper to electronic format of the Psoriasis Symptom Inventory. 相似文献118.
Scott B. Patten Jeanne V. A. Williams Dina H. Lavorato Andrew G. M. Bulloch Gillian Currie Herb Emery 《Quality of life research》2014,23(1):363-371
Purpose
Preference-weighted HRQoL (utility) ratings are increasingly used to guide clinical and resource allocation decisions, but their performance has not always been adequately explored. We sought to examine patterns of health utility ratings in community populations with depressive disorders and painful conditions.Methods
We used two Canadian cross-sectional health surveys that obtained Comprehensive Health Status Measurement System/Health Utilities Index Mark 3 (HUI3) ratings and identified people with painful conditions and major depression. We estimated the frequency of item endorsements and mean utility ratings in these groups.Results
Interesting differences between health state ratings and diagnostic categories were noted. For example, 71 % of those professionally diagnosed with migraine reported that they usually have “no pain.” Despite this, utility ratings were lower in those respondents with depressive episodes and in those with painful conditions. Greater than additive reductions in HUI3 scores were noted in most instances where both depressive disorders and painful conditions were present.Conclusions
Health utility ratings confirm the clinical impression that painful conditions and depressive disorders magnify each other’s impact. Despite weak alignment between the health state definitions incorporated into utility ratings and the diagnostic concepts examined, the HUI3 appeared to capture HRQoL decrements and negative synergies associated with the co-occurrence of depressive episodes and painful conditions. 相似文献119.
Sara De Biasi Domenico Lo Tartaro Marianna Meschiari Lara Gibellini Caterina Bellinazzi Rebecca Borella Lucia Fidanza Marco Mattioli Annamaria Paolini Licia Gozzi Dina Jaacoub Matteo Faltoni Sara Volpi Jovana Milić Marco Sita Mario Sarti Carlo Pucillo Massimo Girardis Giovanni Guaraldi Cristina Mussini Andrea Cossarizza 《European journal of immunology》2020,50(9):1283-1294
Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM− plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies. 相似文献
120.
Daniela Almeida Renê Gerhard Dina Leitão Cristina Davilla Margarida Damasceno Fernando Schmitt 《Pathology, research and practice》2014
Amplification or deletion of the topoisomerase IIα (TOP2A) gene in breast cancer has been related with responsiveness to anthracyclines-based chemotherapy. The purpose of this study was to evaluate the predictive value of TOP2A gene for the efficacy of neo-adjuvant anthracycline in a population with locally advanced breast cancer. Sixty-two patients were included, and the status of TOP2A gene was determined by in situ hybridization method. Treatment efficacy was determined by clinical and pathological response and overall survival. TOP2A gene alterations were found in 22.6% (21.0% of cases with amplification and 1.6% with deletion), and these tumors were biologically more aggressive, with higher nuclear grade, more frequently with HER2 amplification and inflammatory type. Also in these tumors response to chemotherapy appeared to be increased. There was a higher clinical and pathological response rate (complete pathological response of 21.4% vs. 8.3%), a trend toward longer progression-free survival (82.51 vs. 63.12 months) and a trend to increased overall survival (92.08 months; 95% CI 82.81–101.35 vs. 73.40 months; 95% CI 63.44–83.36; p = 0.113). These results corroborate that the TOP2A gene alterations may play an important role in determining anthracycline sensitivity in breast cancer. 相似文献