Accurate spectroscopic characterization of ethyl mercaptan and dimethyl sufide isotopologues : a rute toward their astrophysical detection

Using state-of-the-art computational methodologies, we predict a set of reliable rotational and torsional parameters for ethyl mercaptan and dimethyl sulfide monosubstituted isotopologues. This includes rotational, quartic, and sextic centrifugal-distortion constants, torsional levels, and torsional splittings. The accuracy of the present data was assessed from a comparison to the available experimental data. Generally, our computed parameters should help in the characterization and the identification of these organo-sulfur molecules in laboratory settings and in the interstellar medium.This research was supported by a Marie Curie International Research Staff Exchange Scheme Fellowship within the 7th European Community Framework Program under grant No. PIRSES-GA-2012-31754, the COST Action CM1002 CODECS, and the FIS2011-28738-C02-02 project (MINECO, Spain). In Bologna, this work was supported by MIUR (PRIN 2012 funds under the project "STAR: Spectroscopic and computational Techniques for Astrophysical and atmospheric Research") and by the University of Bologna (RFO funds). M.L.S., M.H., and M.A.M. acknowledge the Deanship of Scientific Research at King Saud University for its funding through the Research Group RGP-VPP-333

Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype

Purpose: Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype-phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease. Methods: This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years. Results: (i) 15% of published patients do not fulfill the current ­inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient"s genotypic class; and (vi) disease progression rate might depend on genotypic class. Conclusion: New genotype-phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome

Wolfram Syndrome: New Mutations, Different Phenotype

BACKGROUND: Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym "DIDMOAD". The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. METHODOLOGY/PRINCIPAL FINDINGS: We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. CONCLUSIONS/SIGNIFICANCE: Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA)

Determination of Specific Electrocatalytic Sites in the Oxidation of Small Molecules on Crystalline Metal Surfaces

The identification of active sites in electrocatalytic reactions is part of the elucidation of mechanisms of catalyzed reactions on solid surfaces. However, this is not an easy task, even for apparently simple reactions, as we sometimes think the oxidation of adsorbed CO is. For surfaces consisting of non-equivalent sites, the recognition of specific active sites must consider the influence that facets, as is the steps/defect on the surface of the catalyst, cause in its neighbors; one has to consider the electrochemical environment under which the “active sites” lie on the surface, meaning that defects/steps on the surface do not partake in chemistry by themselves. In this paper, we outline the recent efforts in understanding the close relationships between site-specific and the overall rate and/or selectivity of electrocatalytic reactions. We analyze hydrogen adsorption/desorption, and electro-oxidation of CO, methanol, and ammonia. The classical topic of asymmetric electrocatalysis on kinked surfaces is also addressed for glucose electro-oxidation. The article takes into account selected existing data combined with our original works.M.J.S.F. is grateful to PNPD/CAPES (Brazil). J.M.F. thanks the MCINN (FEDER, Spain) project-CTQ-2016-76221-P

Theoretical spectroscopic characterization at low temperatures of detectable sulfurorganic compounds : ethyl mercaptan and dimethyl sulfide

Highly correlated ab initio methods are used for the spectroscopic characterization of ethyl mercaptan (CH3CH2 (32)SH, ETSH) and dimethyl sulfide (CH3 (32)SCH3, DMS), considering them on the vibrational ground and excited torsional states. Since both molecules show non-rigid properties, torsional energy barriers and splittings are provided. Equilibrium geometries and the corresponding rotational constants are calculated by means of a composite scheme based on CCSD(T) calculations that accounts for the extrapolation to the complete basis set limit and core-correlation effects. The ground and excited states rotational constants are then determined using vibrational corrections obtained from CCSD/cc-pVTZ force-field calculations, which are also employed to determine anharmonic frequencies for all vibrational modes. CCSD(T) and CCSD force fields are employed to predict quartic and sextic centrifugal-distortion constants, respectively. Equilibrium rotational constants are also calculated using CCSD(T)-F12. The full-dimensional anharmonic analysis does not predict displacements of the lowest torsional excited states due to Fermi resonances with the remaining vibrational modes. Thus, very accurate torsional transitions are calculated by solving variationally two-dimensional Hamiltonians depending on the CH3 and SH torsional coordinates of ethyl mercaptan or on the two methyl groups torsions of dimethyl-sulfide. For this purpose, vibrationally corrected potential energy surfaces are computed at the CCSD(T)/aug-cc-pVTZ level of theory. For ethyl mercaptan, calculations show large differences between the gauche (g) and trans (t) conformer spectral features. Interactions between rotating groups are responsible for the displacements of the g-bands with respect to the t-bands that cannot therefore be described with one-dimensional models. For DMS, the CCSD(T) potential energy surface has been semi-empirically adjusted to reproduce experimental data. New assignments are suggested for the methyl torsion bands of ETSH and a reassignment is proposed for the infrared bands of DMS (0 3 → 0 4 and 1 0 → 1 1). Our accurate spectroscopic data should be useful for the analysis of the microwave and far infrared spectra of ETSH and DMS recorded, at low temperatures, either in laboratory or in the interstellar medium.This research was supported by a Marie Curie International Research Staff Exchange Scheme Fellowship within the 7th European Community Framework Program under Grant No. PIRSES-GA-2012-31754, the COST Action CM1002 CODECS, and the FIS2011-28738-C02-02 project (MINECO, Spain). In Bologna, this work was supported by MIUR (PRIN 2009 funds) and by the University of Bologna (RFO funds)

An analysis of 6 Leber mutations in 31 individuals with optic atrophy. A study of its transmission in 5 families

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder that represents the most frequent cause of visual loss among otherwise healthy young men. We have screened for the most important LHON mutations (primary mutations) and several other previously described mutations (secondary mutations) in 31 Spanish patients suffering from optic atrophy. These individuals fulfilled the clinical criteria for LHON. We have compared the mutation frequencies obtained with those reported in several other countries. We have also followed the segregation of the disease and its associated LHON mutations in five families. The screening has been performed by PCR followed by restriction enzyme digestions and electrophoretic separation. 67.75% of the patients did not harbour any of the studied mutations, whereas 16.13% showed one mutation and the remaining 16.13% carried two Leber mutations in their mitochondrial DNA. The three primary mutations as well as G15257A were the changes most frequently detected (30% each of them). There were no significant differences among the compared populations in terms of frequencies of the primary mutations. In contrast, our patients showed a significantly higher rate of 15257 mutation. The incidence of primary LHON mutations among the Spanish patients is not statistically different from those observed in other Caucasian populations. Transmission of the mutation to the progeny is not necessarily linked to the transmission of the disease. This fact complicates genetic counselling and makes prenatal diagnosis almost impossible for this disease

Diagnóstico y comportamiento clínico de pacientes con sospecha de síndrome de Lynch sin mutación conocida

Resumen: Introducción y objetivos: La sospecha de síndrome de Lynch sin mutación conocida (SSL) se diagnostica cuando existe déficit de expresión de las proteínas reparadoras de ADN pero con estudio genético normal. El comportamiento y el manejo son controvertidos. Presentamos las características de pacientes con SSL y proponemos una vigilancia. Material y métodos: Se realiza análisis inmunohistoquímico (IMH) en familias con sospecha de síndrome de Lynch. Si existe pérdida de expresión, sin mutación BRAF, se procede al análisis germinal. Resultados: De ciento cuarenta y ocho pacientes en los que se realizó IMH, 23 presentaron pérdida de expresión. Siete fueron identificados como SSL: 3 con cáncer de colon, 2 con tumor endometrial y otros 2 sanos con familiar afectado. La edad media fue de 56.9 años y solo uno presentó otro tumor asociado al síndrome de Lynch. Conclusiones: Hasta que conozcamos mejor la etiología de esta entidad heterogénea, una vigilancia intermedia sería una estrategia adecuada. Abstract: Introduction and aims: Lynch-like syndrome is diagnosed when there is an expression deficit in DNA mismatch repair proteins but a normal genetic study. The behavior and management of that pathology are currently a subject of debate. We present herein the characteristics of patients with Lynch-like syndrome, together with a surveillance proposal. Materials and methods: Immunohistochemistry was carried out on families suspected of presenting with Lynch syndrome. Germline analysis was done if there was loss of mismatch repair protein expression and no BRAF mutation. Results: Of the 148 patients that underwent immunohistochemistry testing, 23 presented with loss of mismatch repair protein expression. Seven of those patients were identified as having Lynch-like syndrome: 3 had colon cancer, 2 had endometrial tumor, and 2 were healthy, with an affected relative. Mean patient age was 56.9 years and only one patient presented with another tumor associated with Lynch syndrome. Conclusions: Until there is a better understanding of the etiology of that heterogeneous entity, intermediate surveillance is an adequate strategy. Palabras clave: Sospecha de síndrome de Lynch, Inmunohistoquímica, Análisis genético, Riesgo de cáncer, Vigilancia, Keywords: Suspected Lynch syndrome, Immunohistochemistry, Genetic analysis, Risk for cancer, Surveillanc

α-Synuclein accumulates in huntingtin inclusions but forms independent filaments and its deficiency attenuates early phenotype in a mouse model of Huntington's disease

Huntington's disease (HD) is the most common of nine inherited neurological disorders caused by expanded polyglutamine (polyQ) sequences which confer propensity to self-aggregate and toxicity to their corresponding mutant proteins. It has been postulated that polyQ expression compromises the folding capacity of the cell which might affect other misfolding-prone proteins. α-Synuclein (α-syn) is a small neural-specific protein with propensity to self-aggregate that forms Parkinson's disease (PD) Lewy bodies. Point mutations in α-syn that favor self-aggregation or α-syn gene duplications lead to familial PD, thus indicating that increased α-syn aggregation or levels are sufficient to induce neurodegeneration. Since polyQ inclusions in HD and other polyQ disorders are immunopositive for α-syn, we speculated that α-syn might be recruited as an additional mediator of polyQ toxicity. Here, we confirm in HD postmortem brains and in the R6/1 mouse model of HD the accumulation of α-syn in polyQ inclusions. By isolating the characteristic filaments formed by aggregation-prone proteins, we found that N-terminal mutant huntingtin (N-mutHtt) and α-syn form independent filamentous microaggregates in R6/1 mouse brain as well as in the inducible HD94 mouse model and that N-mutHtt expression increases the load of α-syn filaments. Accordingly, α-syn knockout results in a diminished number of N-mutHtt inclusions in transfected neurons and also in vivo in the brain of HD mice. Finally, α-syn knockout attenuates body weight loss and early motor phenotype of HD mice. This study therefore demonstrates that α-syn is a modifier of polyQ toxicity in vivo and raises the possibility that potential PD-related therapies aimed to counteract α-syn toxicity might help to slow HD. © The Author 2011. Published by Oxford University Press. All rights reserved.Spanish Ministry of Science/MEC/MCINN; CiberNed; Comunidad Autónoma de Madrid; Fundación Ramón ArecesPeer Reviewe

Mitochondrial Haplogroups and Polymorphisms Reveal No Association with Sporadic Prostate Cancer in a Southern European Population

[Background] It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer. [Methodology and Principal Findings] Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage. [Conclusions and Significance] Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results