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81.
Prof. Arun K. Ghosh Prof. Margherita Brindisi Dana Shahabi Mackenzie E. Chapman Prof. Andrew D. Mesecar 《ChemMedChem》2020,15(11):907-932
The COVID-19 pandemic caused by SARS-CoV-2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID-19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell-surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA-dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high-throughput screening efforts have led to the identification of diverse lead structures, including natural product-derived molecules. This review highlights past and present drug discovery and medicinal-chemistry approaches against SARS-CoV, MERS-CoV and COVID-19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID-19 and other pathogenic coronaviruses. 相似文献
82.
Zotta T Ricciardi A Guidone A Sacco M Muscariello L Mazzeo MF Cacace G Parente E 《International journal of food microbiology》2012,155(1-2):51-59
The growth of Lactobacillus plantarum WCFS1 and of its ΔccpA ery mutant, WCFS1-2, was compared in batch fermentations in a complex medium at controlled pH (6.5) and temperature (30°C) with or without aeration, in order to evaluate the effect of ccpA inactivation and aeration on growth, metabolism and stress resistance. Inactivation of ccpA and, to a lesser extent, aeration, significantly affected growth, expression of proteins related to pyruvate metabolism and stress, and tolerance to heat, oxidative and cold/starvation stresses. The specific growth rate of the mutant was ca. 60% of that of the wild type strain. Inactivation of ccpA and aerobic growth significantly affected yield and production of lactic and acetic acid. Stationary phase cells were more stress tolerant than exponential phase cells with little or no effect of inactivation of ccpA or aeration. On the other hand, for exponential phase cells inactivation of ccpA impaired both heat stress and cold/starvation stress, but increased oxidative stress tolerance. For both strains, aerobically grown cells were more tolerant of stresses. Evidence for entry in a viable but non-culturable status upon prolonged exposure to cold and starvation was found. Preliminary results of a differential proteomic study further confirmed the role of ccpA in the regulation of carbohydrate catabolism and class I stress response genes and allow to gain further insight on the role of this pleiotropic regulator in metabolism and stress. This is the first study in which the impact of aerobic growth on stress tolerance of L. plantarum is evaluated. Although aerobic cultivation in batch fermentations does not improve growth it does improve stress tolerance, and may have significant technological relevance for the preservation of starter and probiotic cultures. 相似文献
83.
Grasso M Fuso A Dovere L de Rooij DG Stefanini M Boitani C Vicini E 《Reproduction (Cambridge, England)》2012,143(3):325-332
In mice and other mammals, spermatogenesis is maintained by spermatogonial stem cells (SSCs), a cell population belonging to undifferentiated type A spermatogonia. In the accepted model of SSC self-renewal, Asingle (As) spermatogonia are the stem cells, whereas paired (Apaired (Apr)) and chained (Aaligned (Aal)) undifferentiated spermatogonia are committed to differentiation. This model has been recently challenged by evidence that As and chained (Apr and Aal), undifferentiated spermatogonia are heterogeneous in terms of gene expression and function. The expression profile of several markers, such as GFRA1 (the GDNF co-receptor), is heterogeneous among As, Apr and Aal spermatogonia. In this study, we have analysed and quantified the distribution of GFRA1-expressing cells within the different stages of the seminiferous epithelial cycle. We show that in all stages, GFRA1+ chained spermatogonia (Apr to Aal) are more numerous than GFRA1+ As spermatogonia. Numbers of chained GFRA1+ spermatogonia are sharply reduced in stages VII-VIII when Aal differentiate into A1 spermatogonia. GFRA1 expression is regulated by GDNF and in cultures of isolated seminiferous tubules, we found that GDNF expression and secretion by Sertoli cells is stage-dependent, being maximal in stages II-VI and decreasing thereafter. Using qRT-PCR analysis, we found that GDNF regulates the expression of genes such as Tex14, Sohlh1 and Kit (c-Kit) known to be involved in spermatogonial differentiation. Expression of Kit was upregulated by GDNF in a stage-specific manner. Our data indicate that GDNF, besides its crucial role in the self-renewal of stem cells also functions in the differentiation of chained undifferentiated spermatogonia. 相似文献
84.
Vinceti M Venturelli M Sighinolfi C Trerotoli P Bonvicini F Ferrari A Bianchi G Serio G Bergomi M Vivoli G 《The Science of the total environment》2007,373(1):77-81
A role of cadmium exposure in prostate cancer etiology has been suggested by epidemiologic and laboratory studies, but conclusive evidence on this topic is still lacking. We investigated the relation between cadmium exposure, estimated by determining toenails cadmium levels, and prostate cancer risk in forty patients newly diagnosed with prostate cancer and fifty-eight hospital controls recruited in two provinces from southern and northern Italy. We found an excess cancer risk in subjects in the third and fourth (highest) quartiles of toenail cadmium concentration (odds ratio 1.3 and 4.7, respectively) compared with subjects in the bottom quartile. Results were basically unchanged when limiting the analysis to each province or entering toenail cadmium concentrations as continuous values in the regression model (P=0.004). Despite the limited statistical stability of the point estimates, these findings appear to support the hypothesis that cadmium exposure increases prostate cancer risk. 相似文献
85.
Erica Andreotti Chiara Brofferio Luca Foggetta Andrea Giuliani Benno MargesinClaudia Nones Marisa PedrettiClaudia Rusconi Chiara Salvioni Margherita Tenconi 《Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment》2012,664(1):161-170
86.
Simone Panigada Margherita Zanardelli Monique MacKenzie Carl Donovan Frédéric Mélin Philip S. Hammond 《Remote sensing of environment》2008,112(8):3400-3412
One of the needs of the Pelagos Sanctuary for the Conservation of Mediterranean Marine Mammals is information on critical habitats for cetaceans. This study modelled habitat use and preferences of fin whales and striped dolphins (the two most abundant species in the area) with the aim of providing this information, using sighting data collected between 1993 and 1999. The study area was divided into a 2′ latitude by 2′ longitude grid. The explanatory variables considered in the models were physiographic variables (mean, range and standard deviation of depth and slope, and distance from the nearest coastline) and remotely-sensed data (Sea Surface Temperature and Chlorophyll-a concentration). The former were calculated for each cell using GIS tools, while the latter were obtained from AVHRR and SeaWiFS sensors. Generalized Additive Models (GAMs) with multidimensional smoothers were used to model the distribution of fin whales and striped dolphins in relation to these variables, and Classification And Regression Trees were used for habitat characterization and predictive models. The GAMs were coupled with Generalized Estimating Equations (GEEs) to account for temporal autocorrelation in the errors and to help ensure model selection was reliable; the QIC statistic was used alongside GEE-based p-values. Bathymetric features were the most valuable predictors in the Pelagos Sanctuary area for both species. Sea Surface Temperature values were indicators of striped dolphin and fin whale presence, with both species showing a tendency to prefer colder waters (21–24 °C). Chl-a levels were selected by the GAM models only for striped dolphins, and with large associated uncertainty; this may be related to the relatively brief period examined (only 2 years) and/or to any functional relationship operating at a different geographical or temporal scale. The boosted classification trees however indicated an importance of Chl-a for both species. The techniques applied to this dataset proved to be valuable tools to describe habitat use and preferences of cetaceans, and the use of the remotely-sensed data can substantially improve the predictions. The results of this study will be used for assessing critical habitats within the Pelagos Sanctuary and will provide information for conservation and management in the Sanctuary. 相似文献
87.
Effect of Heat Treatment and of Primary Austenite Grain Size on the Minimum Size of Detectable Defect on 26NiCrMoV11.5 High Strength Steel 下载免费PDF全文
88.
Timed tree automata with an application to temporal logic 总被引:1,自引:0,他引:1
Finite automata on -sequences and -trees were introduced in the sixties by Büchi, McNaughton and Rabin. Finite automata on timed -sequences were introduced by Alur and Dill. In this paper we extend the theory of timed -sequences to -trees. The main motivation is the introduction of a new way to specify real-time systems and to study, using automata-theoretic
techniques, branching-time temporal logics with timing constraints. We study closure properties and decision problems for
the obtained classes of timed -tree languages. In particular, we show the decidability of the emptiness problem. As an application of the introduced theory,
we give a new decidable branching time temporal logic (STCTL) whose semantics is based upon timed -trees.
Received: 8 September 1997 / 27 June 2001 相似文献
89.
Annabella Di Mauro Giosu Scognamiglio Gabriella Aquino Margherita Cerrone Giuseppina Liguori Ottavia Clemente Maurizio Di Bonito Monica Cantile Gerardo Botti Salvatore Tafuto Fabiana Tatangelo 《International journal of molecular sciences》2021,22(13)
Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets. 相似文献
90.
Daniela A. Covino Maria G. Desimio Margherita Doria 《International journal of molecular sciences》2021,22(13)
The ‘shock-and-kill’ strategy to purge the latent HIV reservoir relies on latency-reversing agents (LRAs) to reactivate the provirus and subsequent immune-mediated killing of HIV-expressing cells. Yet, clinical trials employing histone deacetylase inhibitors (HDACis; Vorinostat, Romidepsin, Panobinostat) as LRAs failed to reduce the HIV reservoir size, stressing the need for more effective latency reversal strategies, such as 2-LRA combinations, and enhancement of the immune responses. Interestingly, several LRAs are employed to treat cancer because they up-modulate ligands for the NKG2D NK-cell activating receptor on tumor cells. Therefore, using in vitro T cell models of HIV latency and NK cells, we investigated the capacity of HDACis, either alone or combined with a distinct LRA, to potentiate the NKG2D/NKG2D ligands axis. While Bortezomib proteasome inhibitor was toxic for both T and NK cells, the GS-9620 TLR-7 agonist antagonized HIV reactivation and NKG2D ligand expression by HDACis. Conversely, co-administration of the Prostratin PKC agonist attenuated HDACi toxicity and, when combined with Romidepsin, stimulated HIV reactivation and further up-modulated NKG2D ligands on HIV+ T cells and NKG2D on NK cells, ultimately boosting NKG2D-mediated viral suppression by NK cells. These findings disclose limitations of LRA candidates and provide evidence that NK cell suppression of reactivated HIV may be modulated by specific 2-LRA combinations. 相似文献