Monomolecular G-quadruplex structures with inversion of polarity sites: new topologies and potentiality

In this paper, we report investigations, based on circular dichroism, nuclear magnetic resonance spectroscopy and electrophoresis methods, on three oligonucleotide sequences, each containing one 3- 3 and two 5-5 inversion of polarity sites, and four G-runs with a variable number of residues, namely two, three and four (mTG2T, mTG3T andmTG4T with sequence 3-TGnT-5-5-TGnT-3-3-TGnT-5-5-TGnT-3 in which n = 2, 3 and 4, respectively), in comparison with their canonical counterparts (TGnT)4 (n = 2, 3 and 4). Oligonucleotides mTG3T and mTG4 T have been proven to form very stable unprecedented monomolecular parallel G-quadruplex structures, characterized by three side loops containing the inversion of polarity sites. Both G-quadruplexes have shown an all-syn G-tetrad, while the other guanosines adopt anti glycosidic conformations. All oligonucleotides investigated have shown a noteworthy antiproliferative activity against lung cancer cell line Calu 6 and colorectal cancer cell line HCT-116 p53−/−. Interestingly, mTG3T andmTG4T have proven to be mostly resistant to nucleases in a fetal bovine serum assay. The whole of the data suggest the involvement of specific pathways and targets for the biological activity

The Digital Automatic Coupler (DAC): An Effective Way to Sustainably Increase the Efficiency of Freight Transport in Europe

This paper employs and improves TrainDy software to simulate the in-train forces of single and coupled freight trains with a Digital Automatic Coupler (DAC), having a length from 740 m to 1500 m and hauled mass between 1600 t and 8000 t. Software improvements have focused on the ability to natively simulate the electro-pneumatic (EP) brake, which will be a feature of the future DAC. The various types of DAC and their main features are outlined in the paper. The study shows that it is also possible to increase the trains hauled mass by using radio communication between traction units (TUs). The “relative approach” method is used to demonstrate the safety of these new trains. The paper’s main results are reported in the conclusions and demonstrate the effectiveness of both technologies in increasing freight transport efficiency, even when applied to coupled trains where one train is “classic” and the other is equipped with mechanical DAC

Latanoprost ophthalmic solution in the treatment of open angle glaucoma or raised intraocular pressure: a review

Latanoprost is a prostaglandin F2-alpha isopropyl ester prodrug which is rapidly hydrolyzed by esterases in the cornea to the biologically active latanoprost acid. When latanoprost is topically administered into the eye, the cornea seems to act like as a slow-release depot to the anterior segment. One hour after administration maximum concentration is found in the iris, followed by the anterior chamber and the ciliary body. Despite extensive research, controversy remains about the real mechanism of action of this drug. Immunohistochemical data have shown that the intraocular pressure (IOP) reduction with topical prostaglandin F2-alpha is associated with a reduction of collagens within the uveoscleral outflow pathway. Evidence from several experimental and clinical studies suggests that latanoprost is a valuable addition first-line treatment alternatives for glaucoma, ocular hypertension and even angle-closure glaucoma. Strong points are its efficacy, which is demonstrated to be higher than that of brimonidine, dorzolamide and timolol with fewer systemic adverse effects; a convenient administration schedule; and the IOP-controlling pattern, which is relatively flat compared with timolol and dorzolamide, and enables better control in glaucoma progression, since large fluctuations may be associated with the risk of developing glaucoma in untreated ocular hypertensive subjects

Gender Prejudice Within the Family: The Relation Between Parents' Sexism and Their Socialization Values

Gender inequalities are still persistent despite the growing policy efforts to combat them. Sexism, which is an evaluative tendency leading to different treatment of people based on their sex and to denigration (hostile sexism) or enhancement (benevolent sexism) of certain dispositions as gendered attributes, plays a significant role in strengthening these social inequalities. As it happens with many other attitudes, sexism is mainly transmitted by influencing parental styles and socialization practices. This study focused on the association between parents' hostile and benevolent sexism toward women and their socialization values (specifically, conservation and self-transcendence), that are the values parents would like their children to endorse. We took both parents' and children's sex into account in the analyses. One-hundred-sixty-five Italian parental couples with young adult children participated in the study. Parents, both the mother and the father, individually filled in a self-report questionnaire composed of the Ambivalent Sexism Inventory and the Portrait Values Questionnaire. Findings showed that mothers' benevolent sexism was positively related to their desire to transmit conservation values to their sons and daughters. This result was also found for fathers, but with a moderation effect of children's sex. Indeed, the positive relationship between fathers' benevolent sexism and conservation was stronger in the case of sons than of daughters. Moreover, fathers' benevolent sexism was positively associated with self-transcendence values. Finally, fathers' hostile sexism was positively associated with conservation and negatively with self-transcendence. Limitations of the study, future research developments, and practical implications of the results are discussed

Farmacoeconomia dei COXIB nella patologia osteoarticolare: revisione della letteratura

A new class of anti-inflammatory agents, the selective inhibitors of cyclooxygenase-2 (COXIBs), has been recently introduced into the market for the treatment of osteoarthritis and reumatoid arthritis. Randomized and controlled clinical trials showed a similar efficacy and a better tolerability profile of COXIBs compared with conventional non-steroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to perform a scientific literature review relating to the economic impact produced by COXIBs' introduction. The research of references included the following databases: MEDLINE, EMBASE and the NHS (Economic Evaluation Database) of the York University. A total of 67 in extenso pubblications have been extracted. Of these 13 papers having the specific objective to evaluate the economic implications of COXIBs in comparison to conventional NSAIDs was analysed. In ten cases (77%), cost-effectiveness analyses were performed. The European context was considered in eight cases (62%), while that of North America and Asia were investigated in four and one case, respectively. The analysis of costs took always into account direct costs of the management of arthritis exclusively (drugs, and resources associated with the treatment of gastrointestinal side effects). Indirect and intangible costs were never considered. The results of this review highlight that the higher tollerability profile of COXIBs may generate a cost-saving. This cost-saving seems to be basically due to the reduced frequency of gastroprotective agents coprescription and also to a lesser appearance of severe gastrointestinal side effects compared with conventional NSAIDs. Besides the disease management improving, the cost-saving associated with COXIBs can completely or partially offset the net increase of expense induced by their higher price of purchase

Analisi Costo Minimizzazione delle preparazioni di Interferon Beta per il trattamento della Sclerosi Multipla

The multiple sclerosis (MS) is a neurologic disease that is characterized by a progressive demielinization of the white matter of the central nervous system. In the lasts decades, several therapies have been introduced after randomized, double-blind, placebo controlled trials. These trials supported the efficacy of Interferon-beta (INF- b) in reducing relapsing frequency and slowing the progressive disability, mainly in cases affected by relapsing- remitting MS course. In Italy four different preparations of INF-b are available for MS treatment having different INF-b types (i.e., INF-b1a e INF-b1b), different administration schemes, different INF-b doses and ways of administration. Recently, the biological activity of these preparations have been compared using the same assay system against the same INF-b standard. The aim of this study was to carry out a cost-minimization analysis, on the MS treatments in Italy comparing of the available preparations in terms of cost per microgram standardized by the level of biological activity. The economic evaluation has been conducted adopting the hospital perspective. Health resources have been valued considering euro currency during 2004. According to registered treatment protocol, the results showed that the micrograms per week of INF-b standardized by the level of biological activity ranged from 30mg of Avonex® to 132mg of Rebif44®. Under the same levels of biological activity, Rebif44® resulted the INF-b preparation with the lower cost per micrograms (1.95 euro), followed by Rebif®22 and Betaferon® that had a similar cost (2.90 e 2.97 respectively). Avonex® resulted the INF-b preparation with the highest cost per micrograms (6,37 euro), about three times higher than that of the preparation with the lowest cost

A Systematic Review on Combined [18F]FDG and 68Ga-SSA PET/CT in Pulmonary Carcinoid

Abstract: Pulmonary carcinoids (PCs) are part of a spectrum of well-differentiated neuroendocrine neoplasms (NENs) and are classified as typical carcinoid (TC) and atypical carcinoid (AC). TC differ from AC not only for its histopathological features but also for its “functional imaging pattern” and prognosis. ACs are more undifferentiated and characterized by higher aggressiveness. Positron emission tomography/computed tomography (PET/CT) with somatostatin analogs (SSA) labeled with Gallium-68 (68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE) has widely replaced conventional imaging with gamma camera using 111In- or 99mTc-labelled compounds and represents now the gold standard for diagnosis and management of NENs. In this setting, as already described for gastro-entero-pancreatic NENs, 18F-Fluorodeoxiglucose ([18F]FDG) in addition to 68Ga-SSA can play an important role in clinical practice, particularly for ACs that show a more aggressive behavior compared to TCs. The aim of this systematic review is to analyze all original studies collected from the PubMed and Scopus databases regarding PCs in which both 68Ga-SSA PET/CT and [18F]FDG PET/CT were performed in order to evaluate the clinical impact of each imaging modality. The following keywords were used for the research: “18F, 68Ga and (bronchial carcinoid or carcinoid lung)”. A total of 57 papers were found, of which 17 were duplicates, 8 were reviews, 10 were case reports, and 1 was an editorial. Of the remaining 21 papers, 12 were ineligible because they did not focus on PC or did not compare 68Ga-SSA and [18F]FDG. We finally retrieved and analyzed nine papers (245 patients with TCs and 110 patients with ACs), and the results highlight the importance of the combined use of 68Ga-SSA and [18F]FDG PET/CT for the correct management of these neoplasms

Beyond motor scheme: a supramodal distributed representation in the action-observation network

The representation of actions within the action-observation network is thought to rely on a distributed functional organization. Furthermore, recent findings indicate that the action-observation network encodes not merely the observed motor act, but rather a representation that is independent from a specific sensory modality or sensory experience. In the present study, we wished to determine to what extent this distributed and ‘more abstract’ representation of action is truly supramodal, i.e. shares a common coding across sensory modalities. To this aim, a pattern recognition approach was employed to analyze neural responses in sighted and congenitally blind subjects during visual and/or auditory presentation of hand-made actions. Multivoxel pattern analyses-based classifiers discriminated action from non-action stimuli across sensory conditions (visual and auditory) and experimental groups (blind and sighted). Moreover, these classifiers labeled as ‘action’ the pattern of neural responses evoked during actual motor execution. Interestingly, discriminative information for the action/non action classification was located in a bilateral, but left-prevalent, network that strongly overlaps with brain regions known to form the action-observation network and the human mirror system. The ability to identify action features with a multivoxel pattern analyses-based classifier in both sighted and blind individuals and independently from the sensory modality conveying the stimuli clearly supports the hypothesis of a supramodal, distributed functional representation of actions, mainly within the action-observation network

Structural and functional studies of Stf76 from the Sulfolobus islandicus plasmid-virus pSSVx: a novel peculiar member of the winged helix–turn–helix transcription factor family

The hybrid plasmid virus pSSVx from Sulfolobus islandicus presents an open reading frame encoding a 76 aminoacid protein, namely Stf76, that does not show significant sequence homology with any protein with known three-dimensional structure. The recombinant protein recognises specifically two DNA binding sites located in its own promoter, thus suggesting an auto-regulated role of its expression. CD, spectrofluorimetric, light scattering and ITC experiments indicated a 2:1 molar ratio (protein:DNA) upon binding to the DNA target containing a single site. Furthermore, the solution structure of Stf76, determined by nuclear magnetic resonance (NMR) using chemical shift Rosetta software, has shown that the protein assumes a winged helix–turn–helix fold. NMR chemical shift perturbation analysis has been performed for the identification of the residues responsible for DNA interaction. In addition, a model of the Stf76-DNA complex has been built using as template a structurally related homolog