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961.
Mara Suleiman Lorella Marselli Miriam Cnop Decio L. Eizirik Carmela De Luca Francesca R. Femia Marta Tesi Silvia Del Guerra Piero Marchetti 《International journal of molecular sciences》2022,23(13)
Type 2 diabetes (T2D) has been considered a relentlessly worsening disease, due to the progressive deterioration of the pancreatic beta cell functional mass. Recent evidence indicates, however, that remission of T2D may occur in variable proportions of patients after specific treatments that are associated with recovery of beta cell function. Here we review the available information on the recovery of beta cells in (a) non-diabetic individuals previously exposed to metabolic stress; (b) T2D patients following low-calorie diets, pharmacological therapies or bariatric surgery; (c) human islets isolated from non-diabetic organ donors that recover from “lipo-glucotoxic” conditions; and (d) human islets isolated from T2D organ donors and exposed to specific treatments. The improvement of insulin secretion reported by these studies and the associated molecular traits unveil the possibility to promote T2D remission by directly targeting pancreatic beta cells. 相似文献
962.
We introduce a model of generalized Hebbian learning and retrieval in oscillatory neural networks modeling cortical areas such as hippocampus and olfactory cortex. Recent experiments have shown that synaptic plasticity depends on spike timing, especially on synapses from excitatory pyramidal cells, in hippocampus, and in sensory and cerebellar cortex. Here we study how such plasticity can be used to form memories and input representations when the neural dynamics are oscillatory, as is common in the brain (particularly in the hippocampus and olfactory cortex). Learning is assumed to occur in a phase of neural plasticity, in which the network is clamped to external teaching signals. By suitable manipulation of the nonlinearity of the neurons or the oscillation frequencies during learning, the model can be made, in a retrieval phase, either to categorize new inputs or to map them, in a continuous fashion, onto the space spanned by the imprinted patterns. We identify the first of these possibilities with the function of olfactory cortex and the second with the observed response characteristics of place cells in hippocampus. We investigate both kinds of networks analytically and by computer simulations, and we link the models with experimental findings, exploring, in particular, how the spike timing dependence of the synaptic plasticity constrains the computational function of the network and vice versa. 相似文献
963.
Silvia Cardarelli Adriana Erica Miele Federica Campolo Mara Massimi Patrizia Mancini Stefano Biagioni Fabio Naro Mauro Giorgi Michele Saliola 《International journal of molecular sciences》2022,23(15)
3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionarily conserved cAMP and/or cGMP hydrolyzing enzymes, components of transduction pathways regulating crucial aspects of cell life. Among them, cGMP-specific PDE5—being a regulator of vascular smooth muscle contraction—is the molecular target of several drugs used to treat erectile dysfunction and pulmonary hypertension. Production of full-length murine PDE5A isoforms in the milk-yeast Kluyveromyces lactis showed that the quaternary assembly of MmPDE5A1 is a mixture of dimers and tetramers, while MmPDE5A2 and MmPDE5A3 only assembled as dimers. We showed that the N-terminal peptide is responsible for the tetramer assembly of MmPDE5A1, while that of the MmPDE5A2 is responsible for its mitochondrial localization. Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)+/NAD(P)H balance and induces a metabolic switch from oxidative to fermentative. In particular, the mitochondrial localization of MmPDE5A2 unveiled the existence of a cAMP-cGMP signaling cascade in this organelle, for which we propose a metabolic model that could explain the role of PDE5 in some cardiomyopathies and some of the side effects of its inhibitors. 相似文献
964.
Nelly Condori-Fernández 《计算机科学技术学报》2007,22(3):358-370
This paper introduces a measurement procedure, called RmFFP, which describes a set of operations for modelling and estimating the size of object-oriented software systems from high-level specifications using the OO-Method Requirement Model. OO-Method is an automatic software production method. The contribution of this work is to systematically define a set of rules that allows estimating the functional size at an early stage of the software production process, in accordance with COSMIC-FFP. To do this, we describe the design, the application, and the analysis of the proposed measurement procedure following the steps of a process model for software measurement. We also report initial results on the evaluation of RmFFP in terms of its reproducibility. 相似文献
965.
We present a class of maximally entangled states generated by a high-dimensional generalisation of the cnot gate. The advantage of our constructive approach is the simple algebraic structure of both entangling operator and resulting entangled states. In order to show that the method can be applied to any dimension, we introduce new sufficient conditions for global and maximal entanglement with respect to Meyer and Wallach’s measure. 相似文献
966.
Silvia Attardo Olimpia Musumeci Daniele Velardo Antonio Toscano 《International journal of molecular sciences》2022,23(15)
Statins are drugs widely prescribed in high-risk patients for cerebrovascular or cardiovascular diseases and are, usually, safe and well tolerated. However, these drugs sometimes may cause neuromuscular side effects that represent about two-third of all adverse events. Muscle-related adverse events include cramps, myalgia, weakness, immune-mediated necrotizing myopathy and, more rarely, rhabdomyolysis. Moreover, they may lead to peripheral neuropathy and induce or unmask a preexisting neuromuscular junction dysfunction. A clinical follow up of patients assuming statins could reveal early side effects that may cause neuromuscular damage and suggest how to better modulate their use. In fact, statin dechallenge or cessation, or the alternative use of other lipid-lowering agents, can avoid adverse events. This review summarizes the current knowledge on statin-associated neuromuscular adverse effects, diagnosis, and management. It is conceivable that the incidence of neuromuscular complications will increase because, nowadays, use of statins is even more diffused than in the past. On this purpose, it is expected that pharmacogenomic and environmental studies will help to timely predict neuromuscular complications due to statin exposure, leading to a more personalized therapeutic approach. 相似文献
967.
Silvia Paukovcekova Maria Krchniakova Petr Chlapek Jakub Neradil Jan Skoda Renata Veselska 《International journal of molecular sciences》2022,23(15)
Anticancer therapy by anthracyclines often leads to the development of multidrug resistance (MDR), with subsequent treatment failure. Thiosemicarbazones have been previously suggested as suitable anthracycline partners due to their ability to overcome drug resistance through dual Pgp-dependent cytotoxicity-inducing effects. Here, we focused on combining anthracyclines (doxorubicin, daunorubicin, and mitoxantrone) and two thiosemicarbazones (DpC and Dp44mT) for treating cell types derived from the most frequent pediatric solid tumors. Our results showed synergistic effects for all combinations of treatments in all tested cell types. Nevertheless, further experiments revealed that this synergism was independent of Pgp expression but rather resulted from impaired DNA repair control leading to cell death via mitotic catastrophe. The downregulation of checkpoint kinase 1 (CHEK1) expression by thiosemicarbazones and the ability of both types of agents to induce double-strand breaks in DNA may explain the Pgp-independent synergism between anthracyclines and thiosemicarbazones. Moreover, the concomitant application of these agents was found to be the most efficient approach, achieving the strongest synergistic effect with lower concentrations of these drugs. Overall, our study identified a new mechanism that offers an avenue for combining thiosemicarbazones with anthracyclines to treat tumors regardless the Pgp status. 相似文献
968.
Matteo Cassandri Silvia Pomella Alessandra Rossetti Francesco Petragnano Luisa Milazzo Francesca Vulcano Simona Camero Silvia Codenotti Francesca Cicchetti Roberto Maggio Claudio Festuccia Giovanni Luca Gravina Alessandro Fanzani Francesca Megiorni Marialuigia Catanoso Cinzia Marchese Vincenzo Tombolini Franco Locatelli Rossella Rota Francesco Marampon 《International journal of molecular sciences》2021,22(19)
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS. 相似文献
969.
Erika Ponzini Diletta Ami Alessandro Duse Carlo Santambrogio Antonella De Palma Dario Di Silvestre Pierluigi Mauri Fabio Pezzoli Antonino Natalello Silvia Tavazzi Rita Grandori 《International journal of molecular sciences》2021,22(19)
Lacrimal fluid is an attractive source of noninvasive biomarkers, the main limitation being the small sample amounts typically collected. Advanced analytical methods to allow for proteomics profiling from a few microliters are needed to develop innovative biomarkers, with attractive perspectives of applications to precision medicine. This work describes an effective, analytical pipeline for single-tear analysis by ultrahigh-resolution, shotgun proteomics from 23 healthy human volunteers, leading to high-confidence identification of a total of 890 proteins. Highly reproducible quantification was achieved by either peak intensity, peak area, or spectral counting. Hierarchical clustering revealed a stratification of females vs. males that did not emerge from previous studies on pooled samples. Two subjects were monitored weekly over 3 weeks. The samples clustered by withdrawal time of day (morning vs. afternoon) but not by follow-up week, with elevated levels of components of the immune system in the morning samples. This study demonstrates feasibility of single-tear quantitative proteomics, envisaging contributions of this unconventional body fluid to individualized approaches in biomedicine. 相似文献
970.
Natural co-occurrence of fumonisins, deoxynivalenol, zearalenone and aflatoxins in field trial corn in Argentina 总被引:1,自引:0,他引:1
Hector H. L. Gonzalez Elena J. Martinez Ana M. Pacin Silvia L. Resnik Eric W. Sydenham 《Food Additives & Contaminants》1999,16(12):565-569
Corn samples collected from the main production area in Argentina in 1995 were surveyed for the natural occurrence of Fusarium mycotoxins and aflatoxins. Fumonisins B1, B2 and B3 and zearalenone were found in all samples. A positive relationship was found between fumonisins B1, B2 and B3, B1 and B3, and B2 and B . Deoxynivalenol and aflatoxins were not de3 tected. Mycological survey has also revealed the predominance of Fusarium moniliforme . This is the first report on the simultaneous occurrence of fumonisins and zearalenone in corn from the main production area in Argentina. 相似文献