Self-organized-criticality model consistent with statistical properties of edge turbulence in a fusion plasma

The statistical properties of the intermittent signal generated by a recent model for self-organized criticality are examined. A successful comparison is made with previously published results of the equivalent quantities measured in the electrostatic turbulence at the edge of a fusion plasma. This result reestablishes self-organized criticality as a potential paradigm for transport in magnetic fusion devices, overriding shortcomings pointed out in earlier works [E. Spada, Phys. Rev. Lett. 86, 3032 (2001)10.1103/PhysRevLett.86.3032; V. Antoni, Phys. Rev. Lett. 87, 045001 (2001)10.1103/PhysRevLett.87.045001].     

Tumor Carbohydrate Associated Antigen Analogs as Potential Binders for Siglec-7

We investigated two recently synthesized and characterized sialyl derivatives, bearing the Neu5Ac-α-(2-6)-Gal epitope, as promising binders for Siglec-7, an inhibitory Siglec mainly found on natural killer cells. A variety of sialoglycan structures can be recognized by Siglec-7 with implications in the modulation of immune responses. Notably, overexpression of sialylated glycans recognized by Siglec-7 can be associated with the progression of several tumors, including melanoma and renal cell carcinoma. NOE-based NMR techniques, including Saturation Transfer Difference and transferred-NOESY NMR, together with molecular docking and dynamic simulations were combined to shed light on the molecular basis of Siglec-7 recognition of two conformationally constrained Sialyl-Tn antigen analogs. We, therefore, identify the ligands epitope mapping and their conformational features and propose 3D models accurately describing the protein-ligand complexes. We found that the binding site of Siglec-7 can accommodate both synthetic analogs, with the sialic acid mainly involved in the interaction. Moreover, the flexibility of Siglec-7 loops allows a preferred accommodation of the more rigid compound bearing a biphenyl moiety at position 9 of the sialic acid that contributed to the interaction to a large extent. Our findings provided insights for developing potential novel high affinity ligands for Siglec-7 to hinder tumor evasion.     

New Chemotypes for the Inhibition of (p)ppGpp Synthesis in the Quest for New Antimicrobial Compounds

Antimicrobial resistance (AMR) poses a serious threat to our society from both the medical and economic point of view, while the antibiotic discovery pipeline has been dwindling over the last decades. Targeting non-essential bacterial pathways, such as those leading to antibiotic persistence, a bacterial bet-hedging strategy, will lead to new molecular entities displaying low selective pressure, thereby reducing the insurgence of AMR. Here, we describe a way to target (p)ppGpp (guanosine tetra- or penta-phosphate) signaling, a non-essential pathway involved in the formation of persisters, with a structure-based approach. A superfamily of enzymes called RSH (RelA/SpoT Homolog) regulates the intracellular levels of this alarmone. We virtually screened several fragment libraries against the (p)ppGpp synthetase domain of our RSH chosen model Rel_Seq, selected three main chemotypes, and measured their interaction with Rel_Seq by thermal shift assay and STD-NMR. Most of the tested fragments are selective for the synthetase domain, allowing us to select the aminobenzoic acid scaffold as a hit for lead development.     

TRH-like antidepressant peptide, pyroglutamyltyroslyprolineamide, occurs in rat brain

We have previously reported the occurrence of pGlu-Glu-Pro-NH(2)(Glu-TRH, EEP), Val-TRH, Tyr-TRH, Leu-TRH, Phe-TRH, and Trp-TRH in rat brain using a combination of HPLC and radioimmunoassays with antibodies that cross-react with the general structure pGlu-X-Pro-NH(2) where 'X' maybe any amino acid residue (Peptides 2004; 25 : 647). This new family of TRH-like peptides, along with TRH (pGlu-His-Pro-NH(2)), has neuroprotective, anticonvulsant, antidepressant, euphoric, anti-amnesic, and analeptic effects. We now report that a combination of affinity chromatography using a rabbit antibody specific for Tyr-TRH and Phe-TRH, along with HPLC and tandem mass spectrometry operating in the multiple reaction monitoring (MRM) mode, provide conclusive evidence for the presence of Tyr-TRH in rat brain. Furthermore, synthetic Tyr-TRH is active in the Porsolt Swim Test suggesting that it is a fourth member of this family of in vivo neuroregulatory agents that have psychopharmacotherapeutic properties.     

Superstatistics and temperature fluctuations

Superstatistics [Beck and Cohen (2003) [1]] is a formalism aimed at describing statistical properties of a generic extensive quantity E in complex out-of-equilibrium systems in terms of a linear superposition of equilibrium canonical distributions. The weight function $P(\beta )$ is argued to be provided by the statistics of the intensive thermodynamic quantity β conjugate to E [Beck (2011) [14]], and therefore is expected to be determined by the spatiotemporal dynamics alone of the system under consideration. In this paper, recalling a previous work [Beck (2006) [21]], I show by examples that, in some cases fulfilling all the conditions for the superstatistics formalism to be applicable, $P(\beta )$ cannot be defined uniquely, but rather depends upon the way the measurement of E is performed.     

Direct measurement of tertiary contact cooperativity in RNA folding

All structured biological macromolecules must overcome the thermodynamic folding problem to populate a unique functional state among a vast ensemble of unfolded and alternate conformations. The exploration of cooperativity in protein folding has helped reveal and distinguish the underlying mechanistic solutions to this folding problem. Analogous dissections of RNA tertiary stability remain elusive, however, despite the central biological importance of folded RNA molecules and the potential to reveal fundamental properties of structured macromolecules via comparisons of protein and RNA folding. We report a direct quantitative measure of tertiary contact cooperativity in a folded RNA. We precisely measured the stability of an independently folding P4-P6 domain from the Tetrahymena thermophila group I intron by single molecule fluorescence resonance energy transfer (smFRET). Using wild-type and mutant RNAs, we found that cooperativity between the two tertiary contacts enhances P4-P6 stability by 3.2 +/- 0.2 kcal/mol.     

Water soluble extended naphthalene diimides as pH fluorescent sensors and G-quadruplex ligands

Extended naphthalene diimides (NDIs) fused to 1,4-dihydropyrazine-2,3-dione, containing two solubilizing moieties, have been synthesized. Fluorescence spectra of the new NDIs were remarkably affected by pH, as the second deprotonation of the dihydropyrazinedione moiety (pK(a) 6.9) switched off the emission. Binding to a G-quadruplex folded oligonucleotide and stoichiometry were evaluated by FRET melting assay and CD analysis. G-quadruplex binding was strongly enhanced shifting from pH 7.4 to pH 6.0 as a consequence of the dihydropyrazinedione moiety protonation. Cytotoxicity studies using two human telomerase-positive cell lines (HT29 and A549) revealed that the best G-quadruplex ligand was very active against the colon cell line, with an EC(50) of 300 nM.     

Microtearing modes in reversed field pinch plasmas

In the reversed field pinch RFX-mod strong electron temperature gradients develop when the single-helical-axis regime is achieved. Gyrokinetic calculations show that in the region of the strong temperature gradients microtearing instabilities are the dominant turbulent mechanism acting on the ion Larmor radius scale. The quasilinear evaluation of the electron thermal conductivity is in good agreement with the experimental estimates.