Conformational steering in dicarboxy acids: the native structure of succinic acid

Succinic acid, a dicarboxylic acid molecule, has been investigated spectroscopically with computational support to elucidate the complex aspects of its conformational composition. Due to the torsional freedom of the carbon backbone and hydroxy groups, a large number of potentially plausible conformers can be generated with an indication that the gauche conformer is favored over the trans form. The microwave and millimeter wave spectra have been analyzed and accurate spectroscopic constants have been derived that correlate best with those of the lowest energy gauche conformer. For an unambiguous conformational identification measurements were extended to the monosubstituted isotopologues, precisely determining the structural properties. Besides bond distances and angles, particularly the dihedral angle has been determined to be 67.76(11)°, confirming the anomalous tendency of the methylene units to favor gauche conformers when a short aliphatic segment is placed between two carbonyl groups.Spanish Ministry of Science and Innovation/CTQ2011-22923Spanish Ministry of Science and Innovation/CGL2011-2244

MW SPECTROSCOPY COUPLED WITH ULTRAFAST UV LASER VAPORIZATION: SUCCINIC ACID IN THE GAS PHASE

Author Institution: Departamento de Quimica Fisica, Facultad de Ciencia y Tecnologia, Universidad del Pais Vasco (UPV/EHU), Ap.644, E-48940, Bilbao, Spain; School of Chemistry, Box 23 Victoria 3800 Monash University, Australia; Institut fur Physikalische Chemie und Elektrochemie, Gottfried-Wilhelm-Leibniz-Universitat, 30167 Hannover, GermanyRecent lab and field measurements have indicated critical roles of organic acids in enhancing new atmospheric aerosol formation. In order to understand the nucleation process, here we report an experimental and theoretical investigation of chemical structure of succinic acid. We have used the technique of Fourier Transform Microwave Spectroscopy (FTMW). Succinic acid was vaporized by UV ultrafast laser ablation to suppress thermal decomposition processes$^a$ and seeded into an expanding stream of Ne forming a supersonic jet. The rotational spectrum detected the presence of a single most stable conformation in the cm- mm- wave regions for which accurate rotational and centrifugal distortion parameters have been determined. The study was extended to all monosubstituted isotopic species ($^{13}C$, $^{18}O$, $D(O)$), which were positively identified, leading to an accurate determination of the effective and substitution structures of the molecule. The experimental study was supplemented by \emph{ab initio} (MP2) and DFT (M06-2X and B3LYP) calculations. $^{a}$ E. J. Cocinero, A. Lesarri, P. Ecija, F. J. Basterretxea, J. U. Grabow, J. A. Fernandez and F. Casta\~{n}o, \emph{Angew. Chem. Int. Ed.}, 51, 3119-3124, 2012

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. OBJECTIVE: To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. METHODS: NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. RESULTS: A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. CONCLUSIONS: We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tool