Synthesis, C-H bond functionalisation and cycloadditions of 6-styryl-1,2-oxathiine 2,2-dioxides.

A series of 6-styryl-1,2-oxathiine 2,2-dioxides have been efficiently obtained by a two-step protocol from readily available (1E,4E)-1-(dimethylamino)-5-arylpenta-1,4-dien-3-ones involving a regioselective sulfene addition and subsequent Cope elimination. Pd-Mediated direct C-H bond functionalisation of the 6-styryl-1,2-oxathiine 2,2-dioxides and a wider selection of 5,6-diaryl substituted 1,2-oxathiine 2,2-dioxides proceeded smoothly to afford C-3 (hetero)aryl substituted analogues and the results are contrasted with those of a complementary bromination - Suzuki cross-coupling sequence. Whilst the cycloaddition of benzyne, derived from in situ fluoride initiated decomposition of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, to the substituted 1,2-oxathiine 2,2-dioxides resulted in low yields of substituted naphthalenes, the addition of 4-phenyl-1,2,4-triazoline-3,5-dione to the 6-styryl-1,2-oxathiine 2,2-dioxides afforded novel 5,9-dihydro-1H-[1,2]oxathiino[5,6-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione 8,8-dioxides through a silica-mediated isomerisation of the initial [4 + 2] adducts.

Synthesis and Photochromism of Novel Pyridyl-Substituted Naphthopyrans.

Multitarget synthetic strategies to access novel photochromic 3H-naphtho[2,1-b]pyrans decorated with pyridyl units are described. The new pyridyl-substituted 3H-naphtho[2,1-b]pyrans display good photochromic properties with reversible generation of photomerocyanines, which exhibit mainly orange/red hues. Photochromic parameters including photocolorability and persistence of color vary tremendously on structural modification of the naphthopyran core.

Base-Mediated Ring-Contraction of Pyran Systems Promoted by Palladium and Phase-Transfer Catalysis.

A study of the ring-contraction of a model 3H-naphtho[2,1-b]pyran is described to elucidate and optimize the ring-contraction of naphthopyrans. Two efficient base-mediated protocols to access multiple naphthofurans, naphthodifurans, and a benzo-fused indole in generally good yields are reported. Furthermore, a protocol to selectively prepare (hetero)aryl-substituted naphthofurans via a Suzuki-coupling-ring-contraction process is presented. An additional protocol that allows Suzuki cross-coupling reactions to be performed on bromo-substituted naphthopyrans without the ring-contraction side reaction is reported.

Synthesis and photochromism of some mono and bis (thienyl) substituted oxathiine 2,2-dioxides.

1,2-Oxathiine 2,2-dioxides have been obtained from their respective 3,4-dihydro-4-dimethylamino precursors, for the first time, by a mild Cope elimination of the 4-dimethylamino function. The application of the 1,2-oxathiine 2,2-dioxide scaffold in materials chemistry is exemplified by the efficient P-type photochromism of the 5,6-bis(2,5-dimethyl-3-thienyl) substituted oxathiine 2,2-dioxides.

Expedient synthesis of highly substituted 3,4-dihydro-1,2-oxathiine 2,2-dioxides and 1,2-oxathiine 2,2-dioxides: revisiting sulfene additions to enaminoketones.

Diversely substituted 1,2-oxathiine 2,2-dioxides, including 3,5,6-triaryl-, 3,6-diaryl-, 3,5-diaryl-, 5,6-diaryl- and selected fused heterocyclic analogues, have been efficiently obtained by the application of a mild Cope elimination of a 4-amino moiety from the requisite 4-amino-3,4-dihydro-1,2-oxathiine 2,2-dioxides, which themselves were readily obtained by the addition of sulfenes to enaminoketones.

Impact of mutations within the [Fe-S] cluster or the lipoic acid biosynthesis pathways on mitochondrial protein expression profiles in fibroblasts from patients.

Lipoic acid (LA) is the cofactor of the E2 subunit of mitochondrial ketoacid dehydrogenases and plays a major role in oxidative decarboxylation. De novo LA biosynthesis is dependent on LIAS activity together with LIPT1 and LIPT2. LIAS is an iron­sulfur (Fe-S) cluster-containing mitochondrial protein, like mitochondrial aconitase (mt-aco) and some subunits of respiratory chain (RC) complexes I, II and III. All of them harbor at least one [Fe-S] cluster and their activity is dependent on the mitochondrial [Fe-S] cluster (ISC) assembly machinery. Disorders in the ISC machinery affect numerous Fe-S proteins and lead to a heterogeneous group of diseases with a wide variety of clinical symptoms and combined enzymatic defects. Here, we present the biochemical profiles of several key mitochondrial [Fe-S]-containing proteins in fibroblasts from 13 patients carrying mutations in genes encoding proteins involved in either the lipoic acid (LIPT1 and LIPT2) or mitochondrial ISC biogenesis (FDX1L, ISCA2, IBA57, NFU1, BOLA3) pathway. Ten of them are new patients described for the first time. We confirm that the fibroblast is a good cellular model to study these deficiencies, except for patients presenting mutations in FDX1L and a muscular clinical phenotype. We find that oxidative phosphorylation can be affected by LA defects in LIPT1 and LIPT2 patients due to excessive oxidative stress or to another mechanism connecting LA and respiratory chain activity. We confirm that NFU1, BOLA3, ISCA2 and IBA57 operate in the maturation of [4Fe-4S] clusters and not in [2Fe-2S] protein maturation. Our work suggests a functional difference between IBA57 and other proteins involved in maturation of [Fe-S] proteins. IBA57 seems to require BOLA3, NFU1 and ISCA2 for its stability and NFU1 requires BOLA3. Finally, our study establishes different biochemical profiles for patients according to their mutated protein.

Processing Binary and Fuzzy Logic by Chaotic Time Series Generated by a Hydrodynamic Photochemical Oscillator.

This work demonstrates the computational power of a hydrodynamic photochemical oscillator based on a photochromic naphthopyran generating aperiodic time series. The chaotic character of the time series is tested by calculating its largest Lyapunov exponent and the correlation dimension of its attractor after building its phase space through the Takens' theorem. Then, the chaotic dynamic is shown to be suitable to implement all the fundamental Boolean two-inputs-one-output logic gates. Finally, the strategy to implement fuzzy logic systems (FLSs) based on the time series is described. Such FLSs promise to be useful in the field of computational linguistics, which is concerned with the development of artificial intelligent systems able to transform collections of numerical data into natural language texts.

Optical Communication among Oscillatory Reactions and Photo-Excitable Systems: UV and Visible Radiation Can Synchronize Artificial Neuron Models.

Neuromorphic engineering promises to have a revolutionary impact in our societies. A strategy to develop artificial neurons (ANs) is to use oscillatory and excitable chemical systems. Herein, we use UV and visible radiation as both excitatory and inhibitory signals for the communication among oscillatory reactions, such as the Belousov-Zhabotinsky and the chemiluminescent Orban transformations, and photo-excitable photochromic and fluorescent species. We present the experimental results and the simulations regarding pairs of ANs communicating by either one or two optical signals, and triads of ANs arranged in both feed-forward and recurrent networks. We find that the ANs, powered chemically and/or by the energy of electromagnetic radiation, can give rise to the emergent properties of in-phase, out-of-phase, anti-phase synchronizations and phase-locking, dynamically mimicking the communication among real neurons.

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

Hip torques and the effect of posture in side-stepping with elastic resistance.

BACKGROUND: The way movement-based exercises affect targeted muscles is not always obvious. Side stepping with an elastic band around the forefeet is aimed at strengthening hip abductors and lateral rotator muscles, with the premise that it creates an external torque of adduction and medial rotation of the femur around the pelvis that needs to be counteracted by hip muscles. However, hip torques during this exercise have not been previously quantified. RESEARCH QUESTION: Is the premise that the side-stepping exercise creates an external torque of adduction and medial rotation of the femur around the pelvis correct? METHODS: Thirty-six adults performed the exercise in an upright and a squat posture while 3D kinetic and kinematic data were collected. Hip muscle torques were calculated using inverse dynamics. The effect of posture and potential interactions with sex, side-stepping phases, and trailing/leading directions were analyzed using Pearson correlation and mixed-model ANOVAs. RESULT: A hip net muscle torque of extension, abduction and medial rotation was required to perform the exercise, regardless of phase and direction. The net muscle torque towards medial rotation required during the exercise was smaller (P < 0.001) in the upright (0.05-0.12 N m kg-1 m-1 across phases) compared to the squat posture (0.10-0.24 N m kg-1 m-1). In contrast, hip abductor torque was not affected by posture. When averaged across phases and directions, the normalized hip medial rotator muscle torque was highly correlated with knee flexion (r = 0.93, P < 0.001). SIGNIFICANCE: The assumption that the side-stepping with the elastic band on the forefeet creates an external hip torque of medial rotation is erroneous. The resistance imposed to the hip during this exercise is consistent with the goal of strengthening the muscles that contribute to hip abduction and hip medial (not lateral) rotation. Changing the knee flexion angle is an effective way to manipulate hip rotator torque when prescribing this exercise in strength training and rehabilitation programs.

Quenching of the phosphorescence of thermally reversible photochromic naphthopyran Re(i) complexes initiated by either visible or ultraviolet radiation.

Re(i) complexes bearing thermally reversible photochromic naphthopyran axial ligands undergo highly efficient, reversible phosphorescence quenching actuated by either visible or UV irradiation. The photoinduced quenching of the triplet metal-to-ligand charge-transfer (3MLCT) emission is interpreted based on changes in the relative energies of the excited states.

The influence of a 1,1-diarylvinyl moiety on the photochromism of naphthopyrans.

1,1,3-Triarylpent-4-en-1-yn-3-ols, efficiently obtained in two steps from 1,1,3-triarylprop-2-yn-1-ols by a Meyer-Schuster rearrangement and subsequent addition of lithium trimethylsilylacetylide, react with either a 1- or 2- naphthol to afford photochromic 1,1-diarylvinyl substituted naphtho[1,2-b]- or naphtho[2,1-b]-pyrans respectively. Irradiation of solutions of these naphthopyrans results in reversible electrocyclic ring-opening to afford photomerocyanines which possess an extended conjugated system and show a bathochromically-shifted λ(max) relative to the non-vinyl substituted analogues.

Ring contraction during the 6pi-electrocyclisation of naphthopyran valence tautomers.

The thermal and photochemical ring-opening of spiro(3H-naphtho[2,1-b]pyran-3,9'-thioxanthene-10,10-dioxide) results in the facile ring-contraction to 9-(naphtho[2,1-b]furan-2-yl)-9H-thioxanthene-10,10-dioxide . Similar behaviour is displayed by the isomeric spiro(2H-naphtho[1,2-b]pyran-2,9'-thioxanthene-10,10-dioxide) affording 9-(naphtho[1,2-b]furan-2-yl)-9H-thioxanthene-10,10-dioxide , though more severe reaction conditions were required. The comparative ease of this rearrangement for the isomers and was rationalised on the basis of the relative isomer populations of the ring-opened naphthopyrans. The rearrangement of simple mono- and bis-methylsulfonylphenyl substituted photochromic naphthopyrans , was examined; the former failed to rearrange whereas the latter could be induced to rearrange only under prolonged UV irradiation. The photochromism of diastereoisomerically pure sulfoxides derived from the oxidation of spiro(3H-naphtho[2,1-b]pyran-3,9'-thioxanthene) and spiro(2H-naphtho[1,2-b]pyran-2,9'-thioxanthene) resulted in conversion to the most thermodynamically stable trans-isomer in each case.

Chronic Diarrhea in L-Amino Acid Decarboxylase (AADC) Deficiency: A Prominent Clinical Finding Among a Series of Ten French Patients.

Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism, affecting catecholamines and serotonin biosynthesis. Cardinal signs consist in psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms. PATIENTS AND METHODS: We present a retrospective descriptive multicentric study concerning ten French children with a biochemical and molecular confirmed diagnosis of AADC deficiency. RESULTS: Clinical presentation of most of our patients was consistent with the previous descriptions from the literature (hypotonia (nine children), autonomic signs (nine children), sleep disorders (eight children), oculogyric crises (eight children), motor disorders like hypertonia and involuntary movements (seven children)). We described however some phenotypic particularities. Two patients exhibited normal intellectual abilities (patients already described in the literature). We also underlined the importance of digestive symptoms like diarrhea, which occurred in five among the ten patients. We report in particular two children with chronic diarrhea, complicated by severe failure to thrive. Vanillactic acid (VLA) elevation in urines of one of these two patients led to suspect the diagnosis of AADC deficiency, as in two other patients from our population. CONCLUSION: Some symptoms like chronic diarrhea were atypical and have been poorly described in the literature up to now. Diagnosis of the AADC deficiency is sometimes difficult because of the phenotypic heterogeneity of the disease and VLA elevation in urines should suggest the diagnosis.

Extending human perception of electromagnetic radiation to the UV region through biologically inspired photochromic fuzzy logic (BIPFUL) systems.

Photochromic fuzzy logic systems have been designed that extend human visual perception into the UV region. The systems are founded on a detailed knowledge of the activation wavelengths and quantum yields of a series of thermally reversible photochromic compounds. By appropriate matching of the photochromic behaviour unique colour signatures are generated in response differing UV activation frequencies.

Urate transport in human red blood cells. Activation by ATP.

Urate transport in human erythrocytes were measured and compared to previous observations by other authors regarding inorganic anions, especially chloride. Conclusions wwere as follows: 1. Urate influx as a function of increasing concentrations showed saturation kinetics. 2. The effects of pH and of several passive anion transport inhibitors such as dinitrofluorobenzene, sodium salicylate, sodium benzoate and phenylbutazone suggest that urate and chloride are transported by different mechanisms. 3. Urate influx seems to depend on intracellular glycolysis. The results obtained on red blood cells after glycolysis inhibition agree with those obtained on ghosts where metabolism does not take place. 4. The large drop in urate influxes into erythrocytes in the presence of a glycolysis inhibitor and of a passive ion transport inhibitor seems to argue in favour of a dual urate transport mechanism, one for passive diffusion and the other connected with glycolysis. 5. The drop in the urate influx into ghosts in the absence of ATP suggests that the latter might intervene in urate transport by human red cell membranes.

Role of the mitochondrial DNA and calmitine in myopathies.

We present data on mitochondrial DNA deletions and mitochondrial diseases. The mechanism of their occurrence is discussed on the basis of deletion breakpoints and particularly with the slippage mispairing hypothesis. As the correlation between the genotypes and the phenotypes is not always straightforward, a classification of mitochondrial diseases is suggested according to the genotype (deletions, depletions and duplications, mutations affecting structural genes or tRNA genes) rather than the phenotype. The effect of mitochondrial DNA alterations on the expression of nuclear encoded proteins is presented, and the nucleus can be found to respond differently but in a coordinate way according to the kind of mitochondrial DNA alteration. The search for a nuclear gene affecting the expression of Leber's disease could not show any correlation between the alleles of TAP2 (transporter antigen peptide) and the expression of the disease. Finally, we present new data on another class of myopathies, namely Duchenne muscular dystrophy (DMD), where mitochondria could play an unexpected role in the metabolism of calcium. In some patients with DMD a mitochondrial calcium binding protein that is mainly located in the mitochondrial matrix and which is named 'calmitine' was found to disappear. We have thus cloned its cDNA and found that it was identical with to calsequestrine which is a high-capacity but low-affinity Ca2+ binding protein from the sarcoplasmic reticulum.

Spectroscopic studies (FT-IR, FT-Raman, UV-Visible), normal co-ordinate analysis, first-order hyperpolarizability and HOMO, LUMO studies of 3,4-dichlorobenzophenone by using Density Functional Methods.

The vibrational frequencies of 3,4-dichlorobenzophenone (DCLBP) were obtained from the FT-IR and Raman spectral data, and evaluated based on the Density Functional Theory using the standard method B3LYP with 6-311+G(d,p) as the basis set. On the basis of potential energy distribution together with the normal-co-ordinate analysis and following the scaled quantum mechanical force methodology, the assignments for the various frequencies were described. The values of the electric dipole moment (µ) and the first-order hyperpolarizability (ß) of the molecule were computed. The UV-absorption spectrum was also recorded to study the electronic transitions. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. The NBO analysis, to study the intramolecular hyperconjugative interactions, was carried out. Mulliken's net charges were evaluated. The MEP and thermodynamic properties were also calculated. The electron density-based local reactivity descriptor, such as Fukui functions, was calculated to explain the chemical selectivity or reactivity site in 3,4-dichlorobenzophenone.

[Association between the presence of antiphospholipid antibodies and the occurrence of autism spectrum disorder in childhood]. / Lien entre trouble du spectre autistique de l'enfant et anticorps antiphospholipides : une étude cas-témoin.

OBJECTIVES: To evaluate the association between the presence of antiphospholipid (APL) antibodies and the occurrence of autism spectrum disorder (ASD) in childhood. METHODS: A prospective, monocentric case-control study from February 2012 to August 2014 comparing the APL antibodies of children with ASD (group 1) and children without ASD (group 2). RESULTS: Group 1 consisted of 44 children with ASD defined by clinical, genetic, metabolic, and morphological criteria. Group 2 consisted of 26 control children without ASD. One of children with ASD (2.3 %) had persistent anticardiolipin (ACL) antibodies, five of them (11.4 %) had persistent APL antibodies, one of them (2.3 %) had antiannexin V (AAV) antibodies, and two of them (4.5 %) had antiphosphatidylethanolamine (APE) antibodies. Two of the control children (7.7 %) had persistent APL antibodies. None of them had persistent ACL, AAV, or APE antibodies. Comparing group 1 and 2 children, no significant difference was found between the presence and the titers of conventional and non conventional antibodies (P<0.05). Furthermore, one mother of an autistic child (3 %) had persistent APL antibodies. CONCLUSION: ASD had no significant relation with the presence of APL antibodies.

Five novel frameshift mutations in exon 3 and 4 of the MECP2 gene identified in Rett patients: Consequences for the molecular diagnosis strategy.

Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in 70-85% of RTT cases. We report here five novel frameshift mutations (named 345delC, 895del202, 989ins18del8, 996insAG and 1124del53) in exon 3 and 4 of the MECP2 gene. To avoid the missing of few small deletions in RTT patients using classical mutation screening approaches, we suggest that screening of the mutations in the MECP2 gene in RTT girls should include at least a large PCR to amplify exon 4 entirely.