BROX haploinsufficiency in familial nonmedullary thyroid cancer.

BACKGROUND: The familial nonmedullary thyroid cancer (FNMTC) is suspected to be a Mendelian condition in up to 3-8% of thyroid cancers. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. The inheritance of FNMTC appears to be autosomal dominant with incomplete penetrance and variable expressivity. The finding of the causative gene of FNMTC and the identification of patients at risk that need genetic testing were our aim. METHODS: We analyzed by whole-exome sequencing patients and non-affected relatives of five families with at least two family members affected by papillary thyroid cancer, selecting for new or extremely rare variants with predicted pathogenic value. RESULTS: A family showed, in all three affected members, a new loss-of-function variant (frameshift deletion) in BROX gene at 1q41 that was absent from all internal and external databases. In a second family with three affected relatives, we found an additional new BROX variant. The smaller families presented no variants in BROX or in the other causative genes studied. CONCLUSIONS: BROX could be a new causative gene for FNMTC. Variants in BROX may result in the haploinsufficiency of a key gene involved in the morphogenesis of MVBs, in the endosomal sorting of cargo proteins, and in EGFR. Functional studies are needed to support this result. The thorough genomic analysis by NGS in all families with three or more affected members should become a routine approach to obtain a comprehensive genetic view and find confirmative second cases.

Current driven transition from Abrikosov-Josephson to Josephson-like vortex in mesoscopic lateral S/S'/S superconducting weak links.

Vortices are topological defects accounting for many important effects in superconductivity, superfluidity, and magnetism. Here we address the stability of a small number of such excitations driven by strong external forces. We focus on Abrikosov-Josephson vortex that appears in lateral superconducting S/S'/S weak links with suppressed superconductivity in S'. In such a system the vortex is nucleated and confined in the narrow S' region by means of a small magnetic field and moves under the effect of a force proportional to an applied electrical current with a velocity proportional to the measured voltage. Our numerical simulations show that when a slow moving Abrikosov-Josephson vortex is driven by a strong constant current it becomes unstable with respect to a faster moving excitation: the Josephon-like vortex. Such a current-driven transition explains the structured dissipative branches that we observe in the voltage-current curve of the weak link. When vortex matter is strongly confined phenomena as magnetoresistance oscillations and reentrance of superconductivity can possibly occur. We experimentally observe these phenomena in our weak links.

Nonequilibrium fluctuations as a distinctive feature of weak localization.

Two-dimensional materials, such as graphene, topological insulators, and two-dimensional electron gases, represent a technological playground to develop coherent electronics. In these systems, quantum interference effects, and in particular weak localization, are likely to occur. These coherence effects are usually characterized by well-defined features in dc electrical transport, such as a resistivity increase and negative magnetoresistance below a crossover temperature. Recently, it has been shown that in magnetic and superconducting compounds, undergoing a weak-localization transition, a specific low-frequency 1/f noise occurs. An interpretation in terms of nonequilibrium universal conductance fluctuations has been given. The universality of this unusual electric noise mechanism has been here verified by detailed voltage-spectral density investigations on ultrathin copper films. The reported experimental results validate the proposed theoretical framework, and also provide an alternative methodology to detect weak-localization effects by using electric noise spectroscopy.

A single Abrikosov vortex trapped in a mesoscopic superconducting cylindrical surface.

We investigate the behaviour of a single Abrikosov vortex trapped in a mesoscopic superconducting cylindrical surface with a magnetic field applied transverse to its axis. In the framework of the time-dependent Ginzburg-Landau formalism we show that, provided the transport current and the magnetic field are not large, the vortex behaves as an overdamped quasi-particle in a tilted washboard potential. The cylindrical thin strip with the trapped vortex exhibits E(J) curves and time-dependent electric fields very similar to the ones exhibited by a resistively shunted Josephson weak link.

Crystal structure of the non-regulatory A(4 )isoform of spinach chloroplast glyceraldehyde-3-phosphate dehydrogenase complexed with NADP.

Here, we report the first crystal structure of a photosynthetic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) complexed with NADP. The enzyme, purified from spinach chloroplasts, is constituted of a single type of subunit (A) arranged in homotetramers. It shows non-regulated NADP-dependent and NAD-dependent activities, with a preference for NADP. The structure has been solved to 3.0 A resolution by molecular replacement. The crystals belong to space group C222 with three monomers in the asymmetric unit. One of the three monomers generates a tetramer using the space group 222 point symmetry and a very similar tetramer is generated by the other two monomers, related by a non-crystallographic symmetry, using a crystallographic 2-fold axis. The protein reveals a large structural homology with known GAPDHs both in the cofactor-binding domain and in regions of the catalytic domain. Like all other GAPDHs investigated so far, the A(4)-GAPDH belongs to the Rossmann fold family of dehydrogenases. However, unlike most dehydrogenases of this family, the adenosine 2'-phosphate group of NADP does not form a salt-bridge with any positively charged residue in its surroundings, being instead set in place by hydrogen bonds with a threonine residue belonging to the Rossmann fold and a serine residue located in the S-loop of a symmetry-related monomer. While increasing our knowledge of an important photosynthetic enzyme, these results contribute to a general understanding of NADP versus NAD recognition in pyridine nucleotide-dependent enzymes. Although the overall structure of A(4)-GAPDH is similar to that of the cytosolic GAPDH from bacteria and eukaryotes, the chloroplast tetramer is peculiar, in that it can actually be considered a dimer of dimers, since monomers are bound in pairs by a disulphide bridge formed across Cys200 residues. This bridge is not found in other cytosolic or chloroplast GAPDHs from animals, bacteria, or plants other than spinach.

Structural basis of the drastically increased initial electron transfer rate in the reaction center from a Rhodopseudomonas viridis mutant described at 2.00-A resolution.

It has previously been shown that replacement of the residue His L168 with Phe (HL168F) in the Rhodopseudomonas viridis reaction center (RC) leads to an unprecedented drastic acceleration of the initial electron transfer rate. Here we describe the determination of the x-ray crystal structure at 2.00-A resolution of the HL168F RC. The electron density maps confirm that a hydrogen bond from the protein to the special pair is removed by this mutation. Compared with the wild-type RC, the acceptor of this hydrogen bond, the ring I acetyl group of the "special pair" bacteriochlorophyll, D(L), is rotated, and its acetyl oxygen is found 1.1 A closer to the bacteriochlorophyll-Mg(2+) of the other special pair bacteriochlorophyll, D(M). The rotation of this acetyl group and the increased interaction between the D(L) ring I acetyl oxygen and the D(M)-Mg(2+) provide the structural basis for the previously observed 80-mV decrease in the D(+)/D redox potential and the drastically increased rate of initial electron transfer to the accessory bacteriochlorophyll, B(A). The high quality of the electron density maps also allowed a reliable discussion of the mode of binding of the triazine herbicide terbutryn at the binding site of the secondary quinone, Q(B).

Crystallization and preliminary X-ray study of chloroplast glyceraldehyde-3-phosphate dehydrogenase.

Glyceraldehyde-3-phosphate dehydrogenase from spinach chloroplasts has been crystallized by vapour diffusion in the pH range 7-8.5 in (NH4)2SO4 and Tris-HCl buffer or potassium phosphate buffer at room temperature. Crystals of the A4 isoform, grown at pH 8.5 in Tris-HCl buffer, diffract to 3.0 A (at 100 K) using synchrotron radiation. The crystals belong to the orthorhombic C222 space group, with unit-cell dimensions a = 145.9, b = 185.9 and c = 106.3 A, and probably contain one tetramer per asymmetric unit. Structure determination by molecular replacement is in progress.

Nonsteroidal antiinflammatory agents. XXIII. Synthesis and activity of stereomeric (+/-)-erythro- and (+/-)-threo-2-(4-biphenylyl)-3-hydroxy-2-methyl-3-phenyl-propionic acids.

In pursuing our research on the NSAIDs, the diastereomeric (+/-)-erythro- and (+/-)-threo-2-(4-biphenylyl)-3-hydroxy-2-methyl-3-phenyl-propionic acids (4 and 5) were synthesized; the last was also resolved in its optical isomers (6 and 7). The attribution of the relative configuration to 4 and 5 was performed by means of X-ray analysis. The compounds were tested for their antiinflammatory activity. The acid 4, which resulted very interesting, was tested also for analgesic and antipyretic activity, as well as for behavioural effects, gastric tolerability and acute toxicity. On the basis of the obtained data, this compound resulted a very promising one.

X-ray crystal structure and conformational analysis of N-(3-dimethylaminopropyl)-N-(ethylaminocarbonyl)-6-(2-propenyl)er goline -8 beta-carboxamide (Cabergoline): comparison with bromocriptine and lisuride and a hypothesis for its high dopaminergic activity.

The crystal structure of Cabergoline, a potent and long lasting prolactin lowering agent interacting with the D2 dopamine receptors, has been determined by X-ray diffraction data. The structural data represent the starting point for a computational study, where the molecular mechanisms approach was used to explore the motion of all unconstrained torsion angles. Two different conformations related to energetic minima have been found, one of them in agreement with the experimental crystal structure. Both conformations are shape compared with Bromocriptine and Lisuride, two dopaminergic ergoline derivatives with C-8 beta and C-8 alpha substituents of the ergoline ring, respectively. We observe that the C-8 beta Cabergoline assumes the overall three-dimensional features of C-8-alpha-ergolines in one of its low-energy conformations.

Synthesis, muscarinic blocking activity and molecular modeling studies of 4-DAMP-related compounds.

A number of compounds structurally related to 4-DAMP (1) were synthesized and a single crystal X-ray structural study on a representative member of this series was carried out. All the compounds were tested for the antagonist activity in isolated guinea pig atria (M2 muscarinic receptors) and ileum (M3 muscarinic receptors). Affinity values (pA2) for the muscarinic receptor subtypes ranged from 5.39 to 9.71 (M2) and from 5.68 to 9.92 (M3), depending on different structural features of the compounds. A molecular modeling study was performed, with the aim of rationalizing the affinity data for both M2 and M3 muscarinic receptor subtypes. The presence in the series of two highly active, structurally constrained derivatives allowed us to define two different pharmacophoric frames on which all the compounds could be fitted in a satisfactory manner.

Anti-inflammatory drugs: 1-(2-hydroxyethyl)pyrrolidinium salt of diclofenac.

In the solid-state structure of N-(2-hydroxyethyl)pyrrolidinium (2-[(2,6-dichlorophenyl)amino]phenyl)acetate, C6H14NO+. C14H10Cl2NO2-, the asymmetric unit contains two independent ion pairs differing mainly in the conformation of the cation. A complex network of inter- and intramolecular hydrogen bonds is present.

Synthesis of a series of 5-nitro-(benzimidazoles and indoles) as novel antimycotics and evaluation as genotoxins in the Ames test.

Nitrobenzimidazole and nitroindole derivatives, related to oxiconazole and characterized by an oxyiminic function, have been synthesized as novel antimycotics and their mutagenic activity tested in Salmonella typhimurium strains TA100 and TA98 with and without an exogenous metabolizing system. TA98NR and TA98/1,8-DNP6 strains were employed to identify a specific metabolic reaction which governs the mutagenic potency. Active compounds are weak direct-acting mutagens. Only derivatives bearing a nitro group on the phenyl ring linked to the oxyiminic function and lacking halogenated substituents show mutagenic activity. Metabolism by bacterial enzyme systems is important to the expression of genotoxicity. The reductive activation of nitrobenzimidazoles and nitroindoles carried out by the 'classical' nitroreductase of Salmonella, which is defective in TA98NR, is required of mutagenicity. Similarly, the O-acetyltransferase defective in TA98/1,8-DNP6 is required for the efficient production of the ultimate electrophilic nitrogen species, which react with DNA. The role of bacterial metabolism in mutation induction needs careful consideration to assess the potential risk to humans from nitrobenzimidazole and nitroindole antimycotics.

Structure-activity relationship of new 10-13 membered oxygen-nitrogen heterocyclic systems containing two aromatic rings.

The synthesis and biological activity of new 10-13 membered oxygen-nitrogen heterocyclic systems condensed with two aromatic rings is reported. The structure-activity relationship of these new compounds in X-ray investigation has been studied. Pharmacological investigations have shown that the compounds exhibit weak neuroleptic activity.

[Correlation between hormonal and metabolic profiles in women with polycystic ovary syndrome]. / Correlazioni tra assetto ormonale e metabolico in donne con sindrome dell'ovaio policistico.

To investigate the sex hormone status of women with polycystic ovary syndrome (PCO) and to relate this to serum levels of glucose, insulin, lipids and lipoproteins, 90 women with PCO (30 obese: BMI greater than 30 kg/m2; 30 overweight: BMI greater than 25- less than 30 kg/m2; 30 non obese: BMI less than 25 kg/m2) and 60 normal ovulatory women (20 obese; 20 overweight; 20 non obese) were studied. The women with PCO had significantly increased LH, FSH and androgen levels and significantly decreased SHBG levels compared to the normal women. Obese women with PCO had higher concentrations of fasting glucose, fasting insulin, incremental glucose area, incremental insulin area and lipid than overweight and non obese women with PCO and overweight and non obese control subjects, but were similar in obese normal women. There were decreases in high-density lipoproteins levels in both the obese groups (obese PCO and obese control women). Lipid and lipoprotein concentrations did not differ in the obese, overweight and non obese PCO women compared to the normal groups while HDL cholesterol were decreased in obese PCO and obese control women. The correlations between hormone, glucose, insulin, lipid and lipoprotein levels were different among the six groups. Non obese PCO women had: inverse correlations between free testosterone and incremental glucose area (r = -0.5128, P = 0.03); positive correlations between SHBG and alpha-lipoproteins (r = 0.9159, P = 0.001). Non obese normal women had: positive correlations between fasting insulin and total testosterone (r = 0.5272, P = 0.043) and between SHBG and beta-lipoproteins (r = 0.7445, P = 0.014) and LDL cholesterol (r = 0.7360, P = 0.010).(ABSTRACT TRUNCATED AT 250 WORDS)

Structure and molecular orbital study of ergoline derivatives. 1-(6-Methyl-8 beta-ergolinylmethyl)imidazolidine-2,4-dione (I) and 2-(10-methoxy-1,6-dimethyl-8 beta-ergolinyl)ethyl 3,5-dimethyl-1H-2-pyrrolecarboxylate toluene hemisolvate (II) and comparison with nicergoline (III).

(I): C19H22N4O2 (Registry No. 95688-34-9), m.p. greater than 573 K, Mr = 338.4, orthorhombic, P2(1)2(1)2(1), a = 8.392 (2), b = 13.004 (2), c = 15.676 (5) A, V = 1710.7 (7) A3, Z = 4, Dx = 1.31 Mg m-3, Mo Ka radiation, lambda = 0.71069 A, mu = 0.08 mm-1, F(000) = 720, T = 293 K, final R = 0.051 for 990 independent reflexions. (II): C26H33N3O3.1/2C7H8 (Registry No. 54370-23-9), m.p. 427-429 K, Mr = 481.64, monoclinic, P2(1), a = 11.595 (4), b = 14.274 (2), c = 16.103 (4) A, beta = 100.19 (3) degrees, V = 2623 (1) A3, Z = 4, Dx = 1.22 Mg m-3, Mo Ka radiation, lambda = 0.71069 A, mu = 0.07 mm-1, F(000) = 1036, T = 293 K, final R = 0.064 for 2738 independent reflexions. Two independent molecules constitute the asymmetric unit, together with a toluene molecule. Parallel investigations of the title compounds by single-crystal X-ray analysis and theoretical calculations have converged in showing an extended configuration of the side chain attached at the C8 atom of the ergoline nucleus.

Synthesis and antimycotic activity of some benzyloxyimino compounds.

Some benzyloxyimio compounds, related to oxiconazole and having a 1H-indole or 1H-benzimidazole moiety, have been synthesized and tested in vitro for their antimycotic activity against Candida tropicalis and C. albicans. The most active was showed to be 0-(2,4-dichlorobenzyl)-1-benzyl-5-nitro-1H-benzimidazole-2-carboxaldehyd e oxime (MIC: 25 micrograms/ml against both microorganisms). A structural feature important for the biological activity of the series appears to be presence of a benzimidazole nucleus substituted by an electron withdrawing group.