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51.
Matteo Surdo Emanuela Balestra Patrizia Saccomandi Fabiola Di Santo Marco Montano Domenico Di Carlo Loredana Sarmati Stefano Aquaro Massimo Andreoni Valentina Svicher Carlo Federico Perno Francesca Ceccherini-Silberstein 《PloS one》2013,8(7)
Background
Dual/mixed-tropic HIV-1 strains are predominant in a significant proportion of patients, though little information is available regarding their replication-capacity and susceptibility against CCR5-antagonists in-vitro. The aim of the study was to analyze the replication-capacity and susceptibility to maraviroc of HIV-1 clinical isolates with different tropism characteristics in primary monocyte-derived-macrophages (MDM), peripheral-blood-mononuclear-cells (PBMC), and CD4+T-lymphocytes.Methods
Twenty-three HIV-1 isolates were phenotipically and genotipically characterized as R5, X4 or dual (discriminated as R5+/X4, R5/X4, R5/X4+). Phenotypic-tropism was evaluated by multiple-cycles-assay on U87MG-CD4+-CCR5+−/CXCR4+-expressing cells. Genotypic-tropism prediction was obtained using Geno2Pheno-algorithm (false-positive-rate [FPR] = 10%). Replication-capacity and susceptibility to maraviroc were investigated in human-primary MDM, PBMC and CD4+T-cells. AMD3100 was used as CXCR4-inhibitor. Infectivity of R5/Dual/X4-viruses in presence/absence of maraviroc was assessed also by total HIV-DNA, quantified by real-time polymerase-chain-reaction.Results
Among 23 HIV-1 clinical isolates, phenotypic-tropism-assay distinguished 4, 17 and 2 viruses with R5-tropic, dual/mixed-, and X4-tropic characteristics, respectively. Overall, viruses defined as R5+/X4-tropic were found with the highest prevalence (10/23, 43.5%). The majority of isolates efficiently replicated in both PBMC and CD4+T-cells, regardless of their tropism, while MDM mainly sustained replication of R5- or R5+/X4-tropic isolates; strong correlation between viral-replication and genotypic-FPR-values was observed in MDM (rho = 0.710;p-value = 1.4e-4). In all primary cells, maraviroc inhibited viral-replication of isolates not only with pure R5- but also with dual/mixed tropism (mainly R5+/X4 and, to a lesser extent R5/X4 and R5/X4+). Finally, no main differences by comparing the total HIV-DNA with the p24-production in presence/absence of maraviroc were found.Conclusions
Maraviroc is effective in-vitro against viruses with dual-characteristics in both MDM and lymphocytes, despite the potential X4-mediated escape. This suggests that the concept of HIV-entry through one of the two coreceptors “separately” may require revision, and that the use of CCR5-antagonists in patients with dual/mixed-tropic viruses may be a therapeutic-option that deserves further investigations in different clinical settings. 相似文献52.
The most commonly preserved soft tissues associated with ornithischian dinosaurs are skin remains. The apparent resistance of hadrosaur skin to decay, and its abundance in the fossil record relative to that of other tetrapods, has been attributed to factors such as thickness and composition. Here we report additional intrinsic factors within hadrosaur skin: 3D-preserved eumelanin-bearing bodies, dermal cells and blood vessel fragments in an organic matrix composed of protein fossilization products. The skin is much thinner than that of living mammals of similar size. It is likely that the preservation of hadrosaur skin is related to the arrangement of the layers composing it. 相似文献
53.
Gianluca
E.M. Boari Giulia Chiarini Silvia Bonetti Paolo Malerba Gianluca Bianco Cristina Faustini Federico Braglia-Orlandini Daniele Turini Vittoria Guarinoni Michele Saottini Sara Viola Giulia Ferrari-Toninelli Giancarlo Pasini Cristina Mascadri Bianca Bonzi Paolo Desenzani Claudia Tusi Eros Zanotti Matteo Nardin Damiano Rizzoni 《Bioscience reports》2020,40(12)
The aim of the present study was to simultaneously assess several potential predictors of outcome (co-morbidity, previous and in-hospital treatment, radiologic Brixia score) in patients with COVID-19.This retrospective cohort study included 258 consecutive patients with confirmed COVID-19 admitted to a medical ward at Montichiari Hospital, Brescia, Italy from February 28th to April 30rd, 2020. Patients had SARS-CoV-2 related pneumonia with respiratory failure, and were treated with hydroxychloroquine and lopinavir plus ritonavir. In some patients, additional treatment with tocilizumab, dexamethasone and enoxaparin was adopted. Outcomes (death or recovery) were assessed at the end of the discharge period or at the end of the follow-up (August 2020).During hospitalization, 59 patients died, while 6 died after discharge. The following variables were demonstrated to be associated with a worse prognosis: Radiologic Brixia score higher than 8, presence at baseline of hypertension, diabetes, chronic obstructive pulmonary disease, heart disease, cancer, previous treatment with ACE-inhibitors or anti-platelet drugs. Anticoagulant treatment during hospital admission with enoxaparin at a dose higher than 4000 U once daily was associated with a better prognosis.In conclusion, our study demonstrates that some co-morbidities and cardiovascular risk factors may affect prognosis. The radiologic Brixia score may be a useful tool to stratify the risk of death at baseline. Anticoagulant treatment with enoxaparin might be associated to a clinical benefit in terms of survival in patients with COVID-19. 相似文献
54.
Sara Chiarella Antonella De Cola Giovanni Luca Scaglione Erminia Carletti Vincenzo Graziano Daniela Barcaroli Carlo Lo Sterzo Adele Di Matteo Carmine Di Ilio Brunangelo Falini Alessandro Arcovito Vincenzo De Laurenzi Luca Federici 《Nucleic acids research》2013,41(5):3228-3239
Nucleophosmin (NPM1) is an abundant nucleolar protein implicated in ribosome maturation and export, centrosome duplication and response to stress stimuli. NPM1 is the most frequently mutated gene in acute myeloid leukemia. Mutations at the C-terminal domain led to variant proteins that aberrantly and stably translocate to the cytoplasm. We have previously shown that NPM1 C-terminal domain binds with high affinity G-quadruplex DNA. Here, we investigate the structural determinants of NPM1 nucleolar localization. We show that NPM1 interacts with several G-quadruplex regions found in ribosomal DNA, both in vitro and in vivo. Furthermore, the most common leukemic NPM1 variant completely loses this activity. This is the consequence of G-quadruplex–binding domain destabilization, as mutations aimed at refolding the leukemic variant also result in rescuing the G-quadruplex–binding activity and nucleolar localization. Finally, we show that treatment of cells with a G-quadruplex selective ligand results in wild-type NPM1 dislocation from nucleoli into nucleoplasm. In conclusion, this work establishes a direct correlation between NPM1 G-quadruplex binding at rDNA and its nucleolar localization, which is impaired in the acute myeloid leukemia-associated protein variants. 相似文献
55.
Matteo Nadai Giovanna Sattin Giorgio Palù Manlio Palumbo Sara N. Richter 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
G-quadruplexes are polymorphic non-canonical nucleic acid conformations involved both in physiological and pathological processes. Given the high degree of folding heterogeneity and comparable conformational stabilities, different G-quadruplex forms can occur simultaneously, hence rendering the use of basic instrumental methods for structure determination, like X-ray diffraction or NMR, hardly useful. Footprinting techniques represent valuable and relatively rapid alternative to characterize DNA folding. The natural diterpenoid clerocidin is an alkylating agent that specifically reacts at single-stranded DNA regions, with different mechanisms depending on the exposed nucleotide.Methods
Clerocidin was used to footprint G-quadruplex structures formed by telomeric and oncogene promoter sequences (c-myc, bcl-2, c-kit2), and by the thrombin binding aptamer.Results
The easy modulability of CL reactivity towards DNA bases permitted to discriminate fully and partially protected sites, highlights stretched portions of the G-quadruplex conformation, and discriminate among topologies adopted by one sequence in different environmental conditions. Importantly, CL displayed the unique property to allow detection of G-quadruplex folding within a duplex context.Conclusions
CL is a finely performing new tool to unveil G-quadruplex arrangements in DNA sequences under genomically relevant conditions.General significance
Nucleic acid G-quadruplex structures are an emerging research field because of the recent indication of their involvement in a series of key biological functions, in particular in regulation of proliferation-associated gene expression. The use of clerocidin as footprinting agent to identify G-quadruplex structures under genomically relevant conditions may allow detection of new G-quadruplex-based regulatory regions. 相似文献56.
57.
Marco Cucurachi Matteo Busconi Mariangela Marudelli Giovanna Soffritti Corrado Fogher 《Molecular biology reports》2013,40(7):4317-4325
Eight genes encoding cellulolytic enzymes were obtained by direct PCR amplification of genomic DNA recovered from woodland soil samples. The direct amplifications were carried out by using primers designed from available online cellulase nucleotide sequences. The isolated genes were all different from each other and homologous to endo-β-1,4-glucanases of Bacillus subtilis. The cellulases were functionally expressed in Escherichia coli and tested on soluble substrate at 37 and 60 °C, showing different cellulolytic activities. Among these, the enzyme renamed CelWS6 exhibited good activity at higher temperatures. Further analysis of CelWS6 showed a high performance in acid environments (between pH 4.0 and 6.0) and at elevated temperatures with its maximum activity at pH 5.0 and 50 °C. At the optimum pH, it was very stable since more than 80 % of its original activity was maintained after an incubation of 120 min at 60 °C. Because the cellulases had different cellulolytic activities, but similar amino acid sequences, it was possible to assess the relationship between sequence and protein function. 相似文献
58.
59.
Geun-Shik Lee Yuanzheng He Edward J. Dougherty Maria Jimenez-Movilla Matteo Avella Sean Grullon David S. Sharlin Chunhua Guo John A. Blackford Jr. Smita Awasthi Zhenhuan Zhang Stephen P. Armstrong Edra C. London Weiping Chen Jurrien Dean S. Stoney Simons Jr. 《The Journal of biological chemistry》2013,288(21):15167-15180
TTLL5/STAMP (tubulin tyrosine ligase-like family member 5) has multiple activities in cells. TTLL5 is one of 13 TTLLs, has polyglutamylation activity, augments the activity of p160 coactivators (SRC-1 and TIF2) in glucocorticoid receptor-regulated gene induction and repression, and displays steroid-independent growth activity with several cell types. To examine TTLL5/STAMP functions in whole animals, mice were prepared with an internal deletion that eliminated several activities of the Stamp gene. This mutation causes both reduced levels of STAMP mRNA and C-terminal truncation of STAMP protein. Homozygous targeted mutant (Stamptm/tm) mice appear normal except for marked decreases in male fertility associated with defects in progressive sperm motility. Abnormal axonemal structures with loss of tubulin doublets occur in most Stamptm/tm sperm tails in conjunction with substantial reduction in α-tubulin polyglutamylation, which closely correlates with the reduction in mutant STAMP mRNA. The axonemes in other structures appear unaffected. There is no obvious change in the organs for sperm development of WT versus Stamptm/tm males despite the levels of WT STAMP mRNA in testes being 20-fold higher than in any other organ examined. This defect in male fertility is unrelated to other Ttll genes or 24 genes previously identified as important for sperm function. Thus, STAMP appears to participate in a unique, tissue-selective TTLL-mediated pathway for α-tubulin polyglutamylation that is required for sperm maturation and motility and may be relevant for male fertility. 相似文献
60.
Valeria Zanollo Matteo Griggio Jeremy Robertson Sonia Kleindorfer 《Ethology : formerly Zeitschrift fur Tierpsychologie》2013,119(4):344-352
There is growing evidence that female mate choice could be based on a combination of multiple signals that often involve both ornamental colourful traits and behavioural displays. The Diamond Firetail is an Australian finch with a variable number of white spots on their black flank feathers. The number of white spots is a dimorphic characteristic: females have more spots than males, and males prefer females with many spots. Previously, we found assortative pairing for spot number despite the absence of experimental evidence for female preference for male spot number. Here, we test whether the male behavioural courtship display (bobbing while waving a grass stem) correlates with male spot number and pairing success. We also test whether male spot number predicts the outcome (winner or loser) of intrasexual competition over courtship materials (grass stem, perch, nest site). Males with many spots had higher pairing success, and male spot number correlated with the intensity of courtship display. In a multivariate statistical analysis, male courtship display was the stronger predictor of male pairing success. Finally, male spot number predicted the outcome of intrasexual interactions: males with many spots consistently won contests over grass stems, perches and nest sites. We suggest that intrasexual selection could favour male spot number, whereas courtship intensity appears to be under stronger intersexual selection. 相似文献