Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities.

Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes.

Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression.

Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin.

Normal development of mice lacking PAXX, the paralogue of XRCC4 and XLF.

DNA repair consists of several cellular pathways which recognize and repair damaged DNA. The classical nonhomologous DNA end-joining (NHEJ) pathway repairs double-strand breaks in DNA. It is required for maturation of both B and T lymphocytes by supporting V(D)J recombination as well as B-cell differentiation during class switch recombination (CSR).

Effects of microgravity simulation on zebrafish transcriptomes and bone physiology-exposure starting at 5 days post fertilization.

Physiological modifications in near weightlessness, as experienced by astronauts during space flight, have been the subject of numerous studies. Various animal models have been used on space missions or in microgravity simulation on ground to understand the effects of gravity on living animals. Here, we used the zebrafish larvae as a model to study the effect of microgravity simulation on bone formation and whole genome gene expression.

Stem Cells toward the Future: The Space Challenge.

Astronauts experience weightlessness-induced bone loss due to an unbalanced process of bone remodeling that involves bone mesenchymal stem cells (bMSCs), as well as osteoblasts, osteocytes, and osteoclasts. The effects of microgravity on osteo-cells have been extensively studied, but it is only recently that consideration has been given to the role of bone MSCs. These live in adult bone marrow niches, are characterized by their self-renewal and multipotent differentiation capacities, and the published data indicate that they may lead to interesting returns in the biomedical/bioengineering fields.

The challenging environment on board the International Space Station affects endothelial cell function by triggering oxidative stress through thioredoxin interacting protein overexpression: the ESA-SPHINX experiment.

Exposure to microgravity generates alterations that are similar to those involved in age-related diseases, such as cardiovascular deconditioning, bone loss, muscle atrophy, and immune response impairment. Endothelial dysfunction is the common denominator. To shed light on the underlying mechanism, we participated in the Progress 40P mission with Spaceflight of Human Umbilical Vein Endothelial Cells (HUVECs): an Integrated Experiment (SPHINX), which consisted of 12 in-flight and 12 ground-based control modules and lasted 10 d.

Oxidative stress and alterations in actin cytoskeleton trigger glutathione efflux in Saccharomyces cerevisiae.

A marked deficiency in glutathione (GSH), the most abundant antioxidant in living systems, plays a major role in aging and the pathogenesis of diseases ranging from neurological disorders to early atherosclerosis and the impairment of various immunological functions. In an attempt to shed light on GSH homeostasis, we carried out the space experiment SCORE (Saccharomyces cerevisiae oxidative stress response evaluation) during the FOTON-M3 mission. Microgravity and hyperoxic conditions induced an enormous extracellular release of GSH from S.

Effects of gravity on proliferation and differentiation of adipose tissue-derived stem cells.

Recent studies have demonstrated that culturing stem cells under altered gravity conditions modulates their proliferation and differentiation. In the current study we focused on osteogenesis. In an attempt to induce high proliferation rates and low differentiation of adipose tissue-derived stem cells (AT-MSCs), we exposed them to simulated microgravity (sim-microg) and hypergravity.

Assessment of water-soluble pi-extended squaraines as one- and two-photon singlet oxygen photosensitizers: design, synthesis, and characterization.

Singlet oxygen sensitization by organic molecules is a topic of major interest in the development of both efficient photodynamic therapy (PDT) and aerobic oxidations under complete green chemistry conditions. We report on the design, synthesis, biology, and complete spectroscopic characterization (vis-NIR linear and two-photon absorption spectroscopy, singlet oxygen generation efficiencies for both one- and two-photon excitation, electrochemistry, intrinsic dark toxicity, cellular uptake, and subcellular localization) of three classes of innovative singlet oxygen sensitizers pertaining to the family of symmetric squaraine derivatives originating from pi-excessive heterocycles. The main advantage of pi-extended squaraine photosensitizers over the large number of other known photosensitizers is their exceedingly strong two-photon absorption enabling, together with sizable singlet oxygen sensitization capabilities, for their use at the clinical application relevant wavelength of 806 nm.

Alterations of the actin cytoskeleton and increased nitric oxide synthesis are common features in human primary endothelial cell response to changes in gravity.

Because endothelial cells are fundamental to the maintenance of the functional integrity of the vascular wall, endothelial modifications in altered gravity conditions might offer some insights into the mechanisms leading to circulatory impairment in astronauts. We cultured human endothelial cells in a dedicated centrifuge (MidiCAR) to generate hypergravity and in two different devices, namely the Rotating Wall Vessel and the Random Positioning Machine, to generate hypogravity. Hypogravity stimulated endothelial growth, did not affect migration, and enhanced nitric oxide production.

Novel nontoxic mitochondrial probe for confocal fluorescence microscopy.

We propose a 2,5-Bis[1-(4-N-methylpyridinium)ethen-2-yl)]-N-methylpyrrole ditriflate (PEPEP) as a novel nontoxic, nonpotentiometric mitochondrial probe for confocal fluorescence microscopy. PEPEP is a representative chromophore of a large family of heterocyclic fluorescent dyes that show fluorescence emission in aqueous media and great DNA affinity. We check its cytotoxicity and intracellular localization in mammalian and yeast cell cultures.

A NMR-compatible and reduced gravity simulation based (NRG) bioreactor for on-line monitoring cell culture metabolism.

We developed a NMR-compatible microgravity-based bioreactor (NRG[R]) that offers the advantage of an analytical non-invasive approach associated to the effects of an optimized suspension culture. The simulated microgravity conditions reached in the bioreactor are analogous to those of commercial apparatus like the Rotating Wall Vessel (RWV) system. The faster proliferation of endothelial cells cultured in the NRG bioreactor (doubling time : 28 +/- 1.

New pi-extended water-soluble squaraines as singlet oxygen generators.

[graph: see text] Condensation of squaric acid with a number of differently substituted 2-pyrrolyl derivatives afforded three new classes of squaraines. Their sharp and intense absorption bands in the biological window (700-900 nm), inherent singlet oxygen generation capabilities, together with proper functionalization allowing good water solubility make them suitable candidates as new non-porphyrinic singlet oxygen photosensitizers for photodynamic therapy (PDT).

Cardiovascular protective effects of resveratrol.

Resveratrol (3,4',5-trihydroxy-trans-stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that at low doses (such as consumed in the common diet) resveratrol may have cardioprotective activity. In this article we describe recent in vitro and in vivo studies in animal models.

Simulated weightlessness in the design and exploitation of a NMR-compatible bioreactor.

Mammalian cells cultured in simulated weightlessness take advantage of a favorable environment, experiencing low shear stress and reduced turbulence. NMR spectroscopy allows the on-line noninvasive monitoring of cell growth and metabolism. With this in mind, we developed a novel bioreactor that fits into a NMR instrument and in which the simulated weightlessness conditions are obtained by a suitable medium and a flow-lift suspension.

Novel coordinating motifs for lanthanide(III) ions based on 5-(2-pyridyl)tetrazole and 5-(2-pyridyl-1-oxide)tetrazole. Potential new contrast agents.

Water-soluble and neutral Ln(III) and Zn (II) complexes of pyridine- and (pyridine-1-oxide)tetrazole have been synthesized and the Gd derivatives have great potential as high-relaxivity low-osmolarity MRI contrast agents.

Modulation of human endothelial cell behaviour in simulated microgravity.

Eukaryotic organisms are influenced by gravitational forces in their environment. The low gravitational forces endured by organisms in space alter cellular processes in cultured mammalian cells. Endothelial cells represent an interesting model to study because of their crucial role in the pathogenesis of various diseases, from atherosclerosis to inflammation to any situation characterized by dysregulated angiogenesis.

A distinctive example of the cooperative interplay of structure and environment in tuning of intramolecular charge transfer in second-order nonlinear optical chromophores.

The strongly enhanced cooperative influence of medium polarity and organic structural design on the first hyperpolarizability beta of a novel family of highly polarizable azinium-(CH=CH-thienyl)-dicyanomethanido chromophores 1-3 is described. The dyes can be efficiently synthesized by regioselective protonation/alkylation of the corresponding bidentate anion precursors. Consecutive annelation of the pyridyl ring of 1 (pyridine-->quinoline-->acridine) and medium polarity effects are responsible for an extraordinarily variable range of intramolecular charge transfer (ICT), leading to a large set of pi-electron distribution patterns.

Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism.

We used two experimental models to prove that resveratrol (trans-3,4',5-trihydroxystilbene) reduces cardiac ischemic-reperfusion injury by means of a nitric oxide- and adenosine-dependent mechanism. (1). ACUTE EX VIVO: resveratrol (10 microM, 10 min) infusion in Langendorff-perfused normoxic rat hearts significantly increased adenosine release and coronary flow compared with baseline.

Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction?

The aim of this study was to understand the mechanism of action through which carnosine (beta-alanyl-L-histidine) acts as a quencher of cytotoxic alpha,beta-unsaturated aldehydes, using 4-hydroxy-trans-2,3-nonenal (HNE) as a model aldehyde. In phosphate buffer solution (pH 7.4), carnosine was 10 times more active as an HNE quencher than L-histidine and N-acetyl-carnosine while beta-alanine was totally inactive; this indicates that the two constitutive amino acids act synergistically when incorporated as a dipeptide and that the beta-alanyl residue catalyzes the addition reaction of the histidine moiety to HNE.

Production of lovastatin examined by an integrated approach based on chemometrics and DOSY-NMR.

Microbial secondary metabolites are one of the sources of therapeutic molecules in the pharmaceutical industry. Product quality and high yields of secondary metabolites are the main goals for the commercial success of a fermentation process. Our novel approach was based on the decision-tree algorithm to determine the key variables correlated with the process outcome and on DOSY-NMR to identify both co-metabolites and impurities, and it improves fermentation systems and speeds up bioprocess development.

Metal chelation aptitudes of bis(o-azaheteroaryl)methanes as tuned by heterocycle charge demands.

We describe the synthesis of a number of 1,3-azol-2-yl-, 1,3-benzazol-2-yl-, and azinyl-based bis(o-azaheteroaryl)methanes (LH, L(-) = Het(2)CH(-)) and their coordinating properties toward divalent transition metals (Zn, Cu, Co, Ni, Hg, Pd). This extended investigation includes both symmetrical and unsymmetrical ligands based on several substituted and/or unsubstituted thiazole, benzothiazole, benzoxazole, benzimidazole, pyridine, and quinoline derivatives. Depending on the structure and electron properties of the ligand, a vast set of neutral chelates ML(2) were obtained, where the ligand is present in its carbanionic form L(-).

Pyridoneimines and pyridonemethides: substituent- and solvent-tunable intramolecular charge transfer and geometric isomerism.

We have prepared and fully characterized by means of multinuclear NMR and UV-vis spectroscopy a series of pyridoneimines and pyridonemethides in order to show how it is possible to finely tune pi-electron structure properties by properly exploiting substituent and solvent effects. Substituents with different electron-withdrawing capacities were introduced in pyridoneimines 2-4, pyridonemethides 5 and 6, and pyridine sulfonamido derivatives 7-9. The anisochrony of the carbon position of the azinium ring (geometric isomerism) and the exploitation of previously reported (13)C and (15)N shift/pi-electron density relationships allowed the investigation of the extent of intramolecular charge transfer from the donor group to the acceptor pyridinium moiety.

Diheteroarylmethanes. 8.(1) Mapping Charge and Electron-Withdrawing Power of the 1,2,4-Triazol-5-yl Substituent.

Three new triazolyl derivatives, bis(1H-1-phenyl-1,2,4-triazol-5-yl)methane (11), 1H-1-phenyl-5-(beta-styryl)-1,2,4-triazole (12), and 1H-5-benzyl-1-phenyl-1,2,4-triazole (13) have been synthesized and the carbanions 11(-)() and 13(-)() investigated in DMSO by multinuclear NMR spectroscopy. By applying previously proposed and widely used pi-charge/(13)C shift relationships on the spectra of the anions, it is possible to rank the pi electron-withdrawing power of the 1,2,4-triazol-5-yl group in terms of charge demand c(X), a quantity that represents the fraction of pi negative charge delocalized by the heterocyclic ring. Our results indicate that the charge demand c(X) of this heterocycle is considerably greater than that of other 1,3-azoles (2-imidazolyl, 2-oxazolyl, 2-benzoimidazolyl), being close to that of some mono- and diazinyl substituents.