Analysis of the Secondary Structure of the Catalytic Domain of Mouse Ras Exchange Factor CDC25Mm

The minimal active domain GEF domain. of the mouse Ras exchange factor CDC25Mm was purified to homogeneity from recombinant Escherichia coli culture. The 256 amino acids polypeptide shows high activity in vitro and forms a stable complex with H-ras p21 in absence of guanine nucleotides. Circular dichroism CD. spectra in the far UV region indicate that this domain is highly structured with a high content of a-helix 42%.. Near UV CD spectra evidenced good signal due to phenylalanine and tyrosine while a poor contribution was elicited by the three tryptophan residues contained in this domain. The tryptophan fluorescence signal was scarcely affected by denaturation of the protein or by formation of the binary complex with H-ras p21, suggesting that the Trp residues, which are well conserved in the GEF domain of several Ras-exchange factors, were exposed to the surface of the protein and they are not most probably directly involved in the interaction with Ras proteins. q1998 Elsevier Science B.

Synthesis and biological evaluation of new 3-amino-2-azetidinone derivatives as anticolorectal cancer agents

Several synthetic combretastatin A4 (CA-4) derivatives were recently prepared to increase the drug efficacy and stability of the natural product isolated from the South African tree Combretum caffrum. A group of ten 3-amino-2-azetidinone derivatives, as combretastatin A4 analogues, was selected through docking experiments, synthesized and tested for their anti-proliferative activity against the colon cancer SW48 cell line. These molecules, through the formation of amide bonds in position 3, allow the synthesis of various derivatives that can modulate the activity with great resistance to hydrolytic conditions. The cyclization to obtain the 3-aminoazetidinone ring is highly diastereoselective and provides a trans biologically active isomer under mild reaction conditions with better yields than the 3-hydroxy-2-azetidinone synthesis. All compounds showed IC50 values ranging between 14.0 and 564.2 nM, and the most active compound showed inhibitory activity against tubulin polymerization in vitro, being a potential therapeutic agent against colon cancer

Insulin and serine metabolism as sex-specific hallmarks of Alzheimer's disease in the human hippocampus

Healthy aging is an ambitious aspiration for humans, but neurodegenerative disorders, such as Alzheimer's disease (AD), strongly affect quality of life. Using an integrated omics approach, we investigate alterations in the molecular composition of postmortem hippocampus samples of healthy persons and individuals with AD. Profound differences are apparent between control and AD male and female cohorts in terms of up- and downregulated metabolic pathways. A decrease in the insulin response is evident in AD when comparing the female with the male group. The serine metabolism (linked to the glycolytic pathway and generating the N-methyl-D-aspartate [NMDA] receptor coagonist D-serine) is also significantly modulated: the D-Ser/total serine ratio represents a way to counteract age-related cognitive decline in healthy men and during AD onset in women. These results show how AD changes and, in certain respects, almost reverses sex-specific proteomic and metabolomic profiles, highlighting how different pathophysiological mechanisms are active in men and women

New Eco-gas mixtures for the Extreme Energy Events MRPCs: results and plans

The Extreme Energy Events observatory is an extended muon telescope array, covering more than 10 degrees both in latitude and longitude. Its 59 muon telescopes are equipped with tracking detectors based on Multigap Resistive Plate Chamber technology with time resolution of the order of a few hundred picoseconds. The recent restrictions on greenhouse gases demand studies for new gas mixtures in compliance with the relative requirements. Tetrafluoropropene is one of the candidates for tetrafluoroethane substitution, since it is characterized by a Global Warming Power around 300 times lower than the gas mixtures used up to now. Several mixtures have been tested, measuring efficiency curves, charge distributions, streamer fractions and time resolutions. Results are presented for the whole set of mixtures and operating conditions, %. A set of tests on a real EEE telescope, with cosmic muons, are being performed at the CERN-01 EEE telescope. The tests are focusing on identifying a mixture with good performance at the low rates typical of an EEE telescope.Comment: 8 pages, 6 figures, proceedings for the "XIV Workshop on Resistive Plate Chambers and Related Detectors" (19-23 February 2018), Puerto Vallarta, Jalisco State, Mexic

The Extreme Energy Events HECR array: status and perspectives

The Extreme Energy Events Project is a synchronous sparse array of 52 tracking detectors for studying High Energy Cosmic Rays (HECR) and Cosmic Rays-related phenomena. The observatory is also meant to address Long Distance Correlation (LDC) phenomena: the network is deployed over a broad area covering 10 degrees in latitude and 11 in longitude. An overview of a set of preliminary results is given, extending from the study of local muon flux dependance on solar activity to the investigation of the upward-going component of muon flux traversing the EEE stations; from the search for anisotropies at the sub-TeV scale to the hints for observations of km-scale Extensive Air Shower (EAS).Comment: XXV ECRS 2016 Proceedings - eConf C16-09-04.

A simulation tool for MRPC telescopes of the EEE project

The Extreme Energy Events (EEE) Project is mainly devoted to the study of the secondary cosmic ray radiation by using muon tracker telescopes made of three Multigap Resistive Plate Chambers (MRPC) each. The experiment consists of a telescope network mainly distributed across Italy, hosted in different building structures pertaining to high schools, universities and research centers. Therefore, the possibility to take into account the effects of these structures on collected data is important for the large physics programme of the project. A simulation tool, based on GEANT4 and using GEMC framework, has been implemented to take into account the muon interaction with EEE telescopes and to estimate the effects on data of the structures surrounding the experimental apparata.A dedicated event generator producing realistic muon distributions, detailed geometry and microscopic behavior of MRPCs have been included to produce experimental-like data. The comparison between simulated and experimental data, and the estimation of detector resolutions is here presented and discussed

Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.

There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders antifungal-resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating the protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for treating fungal infectious disease that evades resistance

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286

A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE

In this small note we are concerned with the solution of Forward-Backward Stochastic Differential Equations (FBSDE) with drivers that grow quadratically in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem is a comparison result that allows comparing componentwise the signs of the control processes of two different qgFBSDE. As a byproduct one obtains conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio

Transverse sphericity of primary charged particles in minimum bias proton-proton collisions at s=0.9\sqrt{s}=0.9, 2.76 and 7 TeV

Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at $\sqrt{s}=0.9$, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with $p_{\rm T}\geq0.5$ GeV/c in $|\eta|\leq0.8$. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity ($N_{\rm ch}$) is reported for events with different $p_{\rm T}$ scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low $N_{\rm ch}$, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean $p_{\rm T}$ with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.Comment: 21 pages, 9 captioned figures, 3 tables, authors from page 16, published version, figures from http://aliceinfo.cern.ch/ArtSubmission/node/308