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991.
Claudia Galoppini Riccardo Patacchini Stefania Meini Stefania Viganò Mariella Tancredi Laura Quartara Antonio Triolo Carlo A. Maggi Paolo Rovero 《Letters in Peptide Science》1999,6(2-3):123-127
It has recently been shown that the biological activity of the second generation kinin B1 receptor selective antagonist, desArg10 HOE 140, can be improved by specific amino acid substitutions. Starting from this observation, we undertook a systematic structure-activity relationship study of this antagonist, based on the alanine-scan technique, in order to obtain useful information for the rational design of more analogues. Our data indicate that the sequence of desArg10 HOE 140 does not tolerate the replacement by Ala of most of its residues, with the exception of Ser in position 7 and, to a lesser extent, D-Arg in position 1 and Hyp in position 4. The most critical residues appear to be Pro in position 3 and the C-terminal dipeptide DTic-Oic; Ala replacement at these positions resultes in a total loss of activity. Moreover, replacement by Ala of Gly in position 5 reverts the activity of desArg10 HOE 140 to that of an agonist. 相似文献
992.
Rafael E. Ummus Janice Onuki Dieter Drnemann Marisa H. G. Medeiros Paolo Di Mascio 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1999,729(1-2)
In this work we describe a sensitive method for the detection of 4,5-dioxovaleric acid (DOVA). 4,5-Dioxovaleric acid is derivatized with 2,3-diaminonaphthalene to form 3-(benzoquinoxalinyl-2)propionic acid (BZQ), a product with favorable UV absorbance and fluorescence properties. The high-performance liquid chromatographic method with UV absorbance and fluorescence detection is simple and its detection limit is approximately 100 fmol. This method was used to detect 4,5-dioxovaleric acid formation during metal-catalyzed 5-aminolevulinic acid (ALA) oxidation. Iron and ferritin were active in the formation of 4,5-dioxovaleric acid in the presence of 5-aminolevulinic acid. In addition, HPLC–MS–MS assay was used to characterize BZQ. The determination of 4,5-dioxovaleric acid is of great interest for the study of the mechanism of the metal-catalyzed damage of biomolecules by 5-aminolevulinic acid. This reaction may play a role in carcinogenesis after lead intoxication. The high frequency of liver cancer in acute intermittent porphyria patients may also be due to this reaction. 相似文献
993.
Paola Anghileri Paola Branduardi Flora Sternieri Paolo Monti Rosella Visintin Annamaria Bevilacqua Lilia Alberghina Enzo Martegani Maurizio D. Baroni 《Experimental cell research》1999,250(2):510-523
Cell cycle progression of somatic cells depends on net mass accumulation. In Saccharomyces cerevisiae the cAMP-dependent kinases (PKAs) promote cytoplasmic growth and modulate the growth-regulated mechanism triggering the begin of DNA synthesis. By altering the cAMP signal in budding yeast cells we show here that mitotic events can also depend on growth. In fact, the hyperactivation of PKAs permanently inhibited both anaphase and exit from mitosis when cell growth was repressed. In S. cerevisiae the anaphase promoting complex (APC) triggers entry into anaphase by mediating the degradation of Pds1p. The cAMP pathway activation was lethal together with a partial impairment of the Cdc16p APC subunit, causing a preanaphase arrest, and conversely low PKA activity suppressed the lethality of cdc16-1 cells. Deregulated PKAs partially prevented the decrease of Pds1p intracellular levels concomitantly with the anaphase inhibition, and the PKA-dependent preanaphase arrest could be suppressed in pds1(-) cells. Thus, the cAMP pathway and APC functionally interact in S. cerevisiae and Pds1p is required for the cAMP-mediated inhibition of chromosome separation. Exit from mitosis requires APC, Cdc15p, and the polo-like Cdc5p kinase. PKA hyperactivation and a cdc15 mutation were synthetically lethal and brought to a telophase arrest. Finally, a low cAMP signal allowed cell division at a small cell size and suppressed the lethality of cdc15-2 or cdc5-1 cells. We propose that mitosis progression and the M/G1 phase transition specifically depend on cell growth through a mechanism modulated by PKAs and interacting with the APC/CDC15/CDC5 mitotic system. A possible functional antagonism between PKAs and the mitosis promoting factor is also discussed. 相似文献
994.
995.
Mattia Mazzoli Emanuele Pepe David Mateo Ciro Cattuto Laetitia Gauvin Paolo Bajardi Michele Tizzoni Alberto Hernando Sandro Meloni Jos J. Ramasco 《PLoS computational biology》2021,17(10)
Assessing the impact of mobility on epidemic spreading is of crucial importance for understanding the effect of policies like mass quarantines and selective re-openings. While many factors affect disease incidence at a local level, making it more or less homogeneous with respect to other areas, the importance of multi-seeding has often been overlooked. Multi-seeding occurs when several independent (non-clustered) infected individuals arrive at a susceptible population. This can lead to independent outbreaks that spark from distinct areas of the local contact (social) network. Such mechanism has the potential to boost incidence, making control efforts and contact tracing less effective. Here, through a modeling approach we show that the effect produced by the number of initial infections is non-linear on the incidence peak and peak time. When case importations are carried by mobility from an already infected area, this effect is further enhanced by the local demography and underlying mixing patterns: the impact of every seed is larger in smaller populations. Finally, both in the model simulations and the analysis, we show that a multi-seeding effect combined with mobility restrictions can explain the observed spatial heterogeneities in the first wave of COVID-19 incidence and mortality in five European countries. Our results allow us for identifying what we have called epidemic epicenter: an area that shapes incidence and mortality peaks in the entire country. The present work further clarifies the nonlinear effects that mobility can have on the evolution of an epidemic and highlight their relevance for epidemic control. 相似文献
996.
Targeted Disruption of CDK4 Delays Cell Cycle Entry with Enhanced p27Kip1 Activity 总被引:16,自引:0,他引:16
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Tateki Tsutsui Bahar Hesabi David S. Moons Pier Paolo Pandolfi Kimberly S. Hansel Andrew Koff Hiroaki Kiyokawa 《Molecular and cellular biology》1999,19(10):7011-7019
The mechanism by which cyclin-dependent kinase 4 (CDK4) regulates cell cycle progression is not entirely clear. Cyclin D/CDK4 appears to initiate phosphorylation of retinoblastoma protein (Rb) leading to inactivation of the S-phase-inhibitory action of Rb. However, cyclin D/CDK4 has been postulated to act in a noncatalytic manner to regulate the cyclin E/CDK2-inhibitory activity of p27(Kip1) by sequestration. In this study we investigated the roles of CDK4 in cell cycle regulation by targeted disruption of the mouse CDK4 gene. CDK4(-/-) mice survived embryogenesis and showed growth retardation and reproductive dysfunction associated with hypoplastic seminiferous tubules in the testis and perturbed corpus luteum formation in the ovary. These phenotypes appear to be opposite to those of p27-deficient mice such as gigantism and gonadal hyperplasia. A majority of CDK4(-/-) mice developed diabetes mellitus by 6 weeks, associated with degeneration of pancreatic islets. Fibroblasts from CDK4(-/-) mouse embryos proliferated similarly to wild-type embryonic fibroblasts under conditions that promote continuous growth. However, quiescent CDK4(-/-) fibroblasts exhibited a substantial ( approximately 6-h) delay in S-phase entry after serum stimulation. This cell cycle perturbation by CDK4 disruption was associated with increased binding of p27 to cyclin E/CDK2 and diminished activation of CDK2 accompanied by impaired Rb phosphorylation. Importantly, fibroblasts from CDK4(-/-) p27(-/-) embryos displayed partially restored kinetics of the G(0)-S transition, indicating the significance of the sequestration of p27 by CDK4. These results suggest that at least part of CDK4's participation in the rate-limiting mechanism for the G(0)-S transition consists of controlling p27 activity. 相似文献
997.
Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching.
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998.
Human MxA Protein Protects Mice Lacking a Functional Alpha/Beta Interferon System against La Crosse Virus and Other Lethal Viral Infections 总被引:14,自引:0,他引:14
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Hans Peter Hefti Michael Frese Heinrich Landis Claudio Di Paolo Adriano Aguzzi Otto Haller Jovan Pavlovic 《Journal of virology》1999,73(8):6984-6991
The human MxA protein is part of the antiviral state induced by alpha/beta interferon (IFN-alpha/beta). MxA inhibits the multiplication of several RNA viruses in cell culture. However, its antiviral potential in vivo has not yet been fully explored. We have generated MxA-transgenic mice that lack a functional IFN system by crossing MxA-transgenic mice constitutively expressing MxA with genetically targeted (knockout) mice lacking the beta subunit of the IFN-alpha/beta receptor (IFNAR-1(-/-) mice). These mice are an ideal animal model to investigate the unique antiviral activity of human MxA in vivo, because they are unable to express other IFN-induced proteins. Here, we show that MxA confers resistance to Thogoto virus, La Crosse virus, and Semliki Forest virus. No Thogoto virus progeny was detectable in MxA-transgenic mice, indicating an efficient block of virus replication at the primary site of infection. In the case of La Crosse virus, MxA restricted invasion of the central nervous system. In contrast, Semliki Forest virus multiplication in the brain was detectable in both MxA-expressing and nonexpressing IFNAR-1(-/-) mice. However, viral titers were clearly reduced in MxA-transgenic mice. Our results demonstrate that MxA does not need the help of other IFN-induced proteins for activity but is a powerful antiviral agent on its own. Moreover, the results suggest that MxA may protect humans from potential fatal infections by La Crosse virus and other viral pathogens. 相似文献
999.
Localization of a Passively Transferred Human Recombinant Monoclonal Antibody to Herpes Simplex Virus Glycoprotein D to Infected Nerve Fibers and Sensory Neurons In Vivo
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A human recombinant monoclonal antibody to herpes simplex virus (HSV) glycoprotein D labeled with the fluorescent dye Cy5 was administered to mice infected in the cornea with HSV type 1 (HSV-1). The distribution of such antibody in the corneas and trigeminal ganglia of the mice was then investigated by confocal microscopy. The antibody was detected on HSV-infected nerve fibers in the cornea--identified by colocalization with HSV antigens and the neuritic markers neurofilament, GAP-43, synapsin-1, and CNPase--and on the perikarya of sensory neurons in the HSV-1-infected neurons in ipsilateral trigeminal ganglia. Antibodies have been shown to be effective against many neurotropic viruses, often in the absence of obvious cell damage. Observations from experimental HSV infections suggest that antibodies could act in part by interfering with virus expression in the ganglia and/or with axonal spread. The present results provide morphological evidence of the localization of antiviral antibodies at anatomical sites relevant to such putative antibody-mediated protective actions and suggest that viral glycoproteins are accessible to antibodies on infected nerve fibers and sensory neurons. 相似文献
1000.
Paolo Ruzza Arianna Donella-Deana Andrea Calderan Giuseppe Zanotti Luca Cesaro Lorenzo A. Pinna Gianfranco Borin 《Journal of peptide science》1998,4(1):33-45
Two Tyr residues are supposed to play a crucial role in the regulation of protein tyrosine kinases of the Src family. Autophosphorylation of Src Tyr416 correlates with enzyme activation, while phosphorylation of C-terminal Tyr527 by Csk gives rise to inactive forms of Src kinases. It has previously been demonstrated that the Src-like tyrosine kinase expressed by the oncogenelyndisplays a particularly high affinity (Km20 μm ) toward the dimeric linear and cyclic derivatives of the heptapeptide H-Glu-Asp-Asn-Glu-Tyr-Thr-Ala-OH which reproduces the main autophosphorylation site of most of the Src enzymes. Under the experimental conditions used only one Tyr residue of the dimeric sequence can be phosphorylated [P. Ruzza, A. Calderan, B.Filippi, B. Biondi, A. Donella Deana, L. Cesaro, L. A. Pinna & G. Borin (1995) Int. J. Peptide Protein Res. 45, 529–539]. The present study addresses the problem of the efficiency displayed by Lyn towards the two Tyr residues located at positions 5 and 12 of the dimeric peptide. To this purpose, two tetradecapeptides were synthesized by the classical solution method, each containing one of the two Tyr residues alternatively replaced by Phe, and the corresponding univocal cyclic form. A possible correlation between the different structural properties induced by the modifications of the native sequence and the ability of the peptides to act as Lyn substrates was noted. The kinetic data obtained indicate that Lyn phosphorylates the residues located at different positions in the two linear analogues differently. In particular, while the Tyr5, Phe12 derivative presents aKmvalue similar to those obtained for the dimeric linear and cyclic unmodified analogues, theKmvalue of the Phe5, Tyr12 derivative is two-fold higher than those found for the above-mentioned peptides. Moreover, as previously reported for the linear and cyclic dimeric forms of the native sequence, in the mono-tyrosine containing series of dimers the still conformationally flexible cyclic derivative shows a phosphorylation efficiency two-fold higher than those found for the linear derivatives. © 1998 European Peptide Society and John Wiley & Sons, Ltd. 相似文献