The role of arsenic in the hydrolysis and DNA metalation processes in an arsenous acid-platinum(ii) anticancer complex.

Platinum(ii)-based molecules are the most commonly used anticancer drugs in the chemotherapeutic treatment of tumours but possess serious side effects and some cancer types exhibit resistance with respect to these compounds (e.g. cisplatin). For these reasons, the research of new compounds that can bypass this limitation is in continuous development. Recently, mixed Pt(ii)-As(iii) systems have been synthesized and tested as potential anticancer agents. The mechanism of action of these kinds of drugs is unclear. Since in other platinum(ii) containing drugs, hydrolysis plays an important role in the activation of the compound before it reaches DNA, we have explored the aquation process using density functional theory (DFT), focusing our attention on the arsenoplatin complex, [Pt(µ-NHC(CH3)O)2ClAs(OH)2]. As DNA is believed to be the cellular target for Pt anticancer drugs, the metalation mechanism of DNA purine bases has been also investigated. Also for this new drug it appears that guanine is the preferred site with respect to adenine as with other platinum-containing compounds. A comparison with cisplatin is performed in order to highlight the contribution of arsenic in the anticancer activity of this new proposed anticancer agent.

Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome.

Tatton-Brown-Rahman syndrome (TBRS) was recently described in 13 isolated cases with de novo mutations in the DNMT3A gene. This autosomal dominant condition is characterized by tall stature, intellectual disability and a distinctive facial appearance. Here, we report six cases of inherited TBRS caused by novel DNMT3A germline mutations. The affected individuals belong to two sib-ships: four from an Old Order Amish family in America and two from a French Canadian family in Canada. All of them presented with characteristic features of TBRS, including dysmorphic facial features, increased height, intellectual disability, and variable additional features. We performed clinical exome sequencing and identified two mutations in the DNMT3A gene, a c.2312G>A (p.Arg771Gln) missense mutation in the Amish family and a c.2296_2297delAA (p.Lys766Glufs*15) small deletion in the French Canadian family. Parental DNA analysis by Sanger sequencing revealed that the Amish mutation was inherited from the healthy mosaic father. This study reflects the first cases with inherited TBRS and expands the phenotypic spectrum of TBRS.

Mechanistic investigation of trimethylamine-N-oxide reduction catalysed by biomimetic molybdenum enzyme models.

In this paper, we report a theoretical investigation of the reduction reaction mechanism of Me3NO using molybdenum containing systems that are functional and structural analogues of trimethylamine N-oxide reductase mononuclear molybdenum enzyme. The reactivity of the monooxomolybdenum(IV) benzenedithiolato complex and its derivatives to carbamoyl (t-BuNHCO) and acylamino (t-BuCONH) substituents on the benzene rings in both cis and trans arrangements was explored. The calculated energy profiles describing the steps of two mechanisms of attack considered viable (named cis- and trans-attack) by the Me3NO substrate at cis and trans positions with respect to the oxo ligand show that the attack on cis is energetically more favourable than the attack on trans. Along the pathway for the cis-attack the first step of the reaction, that is rate-determining for all the studied compounds, is the approach of the substrate to the Mo centre in cis to the oxo ligand that causes a distortion of the initial square-pyramidal geometry of the complex. The reaction steps involved in the trans position attack were also explored. Calculations confirm that, as previously suggested, the introduction of ligands able to form intramolecular NH···S hydrogen bonds accelerates the reduction of the Me3NO substrate and contributes to the tuning of the reactivity of molybdoenzyme models.

The working mechanism of the ß-carbonic anhydrase degrading carbonyl sulphide (COSase): a theoretical study.

In order to give insights into the working mechanism of the novel characterized enzyme carbonyl sulphide hydrolase (COSase), which efficiently converts COS into H2S and CO2, we have performed a detailed theoretical investigation using the framework of density functional theory (using B3LYP and M06 exchange-correlation functionals) by the cluster model approach. In the final part of the reaction the metal ion is unable to form a pentacoordinated species. The B3LYP-D3 and M06 potential energy surfaces have a very similar shape. The elucidation of the catalytic reduction of COS is important in view of its role in environmental chemistry.

Insight into the promiscuous activity of human carbonic anhydrase against the cyanic acid substrate from a combined QM and QM/MM investigation.

The promiscuous activity of human carbonic anhydrase (hCAII) against a non-physiological cyanic acid substrate has been investigated by using a combined QM and QM/MM level of theory. Results show that the hCAII is able to hydrate the cyanic acid by a reaction mechanism similar to that of the CO2 native substrate. The energy barrier for the nucleophilic attack is found to be 15.6 and 4.3 kcal mol(-1) at QM and QM/MM levels, respectively. This result underlines the importance of taking into account the surrounding residues around the active site in the presence of the substrate having small molecular sizes. The carbamate is strongly stabilized with respect to the bicarbonate of the native substrate indicating a more difficult release of the reaction product.

Methicillin-resistant Staphylococcus aureus hand infections at UP-PGH: A retrospective study from 2005-2010

OBJECTIVES: To determine the incidence of MRSA among admitted hand patients at UP-PGH from 2005 to 2010 and determine the antibiotic susceptibility pattern. METHODS: Records of admitted hand patients of all ages were identified and wound culture results were reviewed. A total of 482 wound cultures from the S-year period were examined. RESULTS AND CONCLUSION: From an initial decreasing trend, there was a sharp increase in incidence of MRSA hand infections from 2008 (11.8%) to 2009 (22.5%).Vancomycin had the highest number of susceptible cases from 2005 to 2008, but dropped quite sharply to the least number of susceptible cases in 2010. Chloramphenicol and erythromycin had the highest number of susceptible MRSA hand cases in recent years.

Couples at risk for spinocerebellar ataxia type 2: the Cuban prenatal diagnosis experience

Cuba reports the highest worldwide prevalence of spinocerebellar ataxia type 2 (SCA2) and the greatest number of descendants at risk. A protocol for genetic counseling, presymptomatic testing, and prenatal diagnosis of hereditary ataxias has been under development since 2001. Considering that the revision of the experience with prenatal diagnosis for SCA2 in Cuba would enable comparison of ours with international findings, we designed a descriptive study, based on the retrospective revision of the medical records belonging to the 58 couples that requested their inclusion in the program, during an 11-year period (2001-2011). Most of the participants in the prenatal diagnosis program were known presymptomatic carriers, diagnosed through the presymptomatic testing in the same period of study, for an uptake among them of 22.87 percent (51 out of 223). In 28 cases, the fetuses were carriers, 20 of these couples (71.43 percent) decided to terminate the pregnancy; the rest continued the pregnancy to term, this resulting in a predictive test for their unborn children. A predominance of females as the at-risk progenitor was observed. Except for a slightly lower average age, the results attained in the Cuban SCA2 prenatal diagnosis program resulted similar to the ones reported for Huntington disease in other countries. It is necessary to have easy access to the Cuban program through its expansion to other genetic centers along the island. Future research is needed to evaluate the long-term impact of both the predictive testing in unborn children and the selection of other reproductive options by the at-risk couples (AU)

A micro-environmental study of the Zn(+2)-Aß1-16 structural properties.

Relying on a combination of classical molecular dynamics and hybrid QM/MM computational methods, we study the influence of the nature of the local physico-chemical environment on the structural features of ß-amyloid peptides complexed with Zn(+2) ions. The analysis is carried out by comparing among themselves different Zn(+2)-ligand force fields and studying their influence on metal coordination and long-range peptide folding. The system in the non-physiological so-called "gas phase" (no solvent) was also simulated with the purpose of identifying to what extent, if at all, the solvent can affect the Zn coordination mode, besides its long-range structural properties. There are two main results of this investigation. The first is that the Zn(+2) coordination mode in classical molecular dynamics simulations markedly depends on the partial charge attributed to the ion and the atoms surrounding it. Comparing with experiments, it is possible to identify the most appropriate Zn(+2) force field for the Zn(+2)-Aß1-16 complex in study. Secondly, although the presence of water naturally influences the peptide folding propensity, it does not affect the structure of the Zn(+2) inner coordination shell. A useful way to validate classical results and in particular those referring to the structural differences visible when different force fields are employed, was to use a hybrid QM/MM optimization step. When the classical system configurations are submitted to such a quantum minimization step, the geometries of the resulting Zn(+2) site turn out to be all very similar and structurally in good agreement with what is experimentally known.

The Cuban program for predictive testing of SCA2: 11 years and 768 individuals to learn from.

Having reported the world's highest prevalence of spinocerebellar ataxia type 2 (SCA2), health professionals in Cuba developed a program for the predictive testing of this condition. Between February 2001 and December 2011, a total of 1050 individuals requested their inclusion in the presymptomatic testing (PST) program. Their medical records were retrospectively analyzed in the present descriptive study. A total of 768 participants completed the protocol, 204 withdrew and 78 were excluded. The PST uptake was 24.91%. Females predominated and 70.96% had negative test results. Their main motivations were risk assessment in their descendants, physical and psychological preparation to cope with the disease and planning for the future. The profile of Cuban participants in the predictive testing program is similar to the one reported for other programs all over the world, nevertheless the genetic counseling practice at the community level is a distinctive aspect, which is valuable in providing at-risk individuals with wide and proper knowledge before their testing inclusion request. The SCA2 predictive testing program has high uptake rates and is renowned in our population. Future research is needed to assess the long-term psychological impact in the participants, their partners and relatives.

On the metal ion (Zn(2+), Cu(2+)) coordination with beta-amyloid peptide: DFT computational study.

As is widely accepted, the crucial event of the progress of Alzheimer's disease is the formation of extracellular neurotoxic amyloid plaques, consisting mainly of 40 or 42 amino acid residues, in the brain. Zinc and copper metal ions are involved in this process, since they enhance the amyloid beta aggregation and are incorporated into plaques. In this paper we have analyzed theoretically the energetics implied in the formation of some complexes of both cations, adopting a number of models that take into account various coordination environments. The aim was to determine which among the coordination patterns examined is the favoured one in order to give better insight in the controversy concerning the metal binding site of amyloid beta peptide.

Ab initio study of microsolvated Al3+-aromatic amino acid complexes.

The systematic microhydration of Al(3+)-aromatic amino acid complexes is studied by both B3LYP/G03 and PBE/CPMD methods, considering the different binding sites available. The binding affinity of water molecules together with the structural and thermochemical changes triggered by the solvation of the metal are discussed, which are found to be dominated by the charge and size of the metal cation, yielding a very subtle equilibrium between the steric hindrance and the charge transfer to the metal. Some structures previously seen to be unfavored in the gas phase are stabilized upon microhydration, without the need of including bulk solvent effects.

Maternal obesity: the interplay between inflammation, mother and fetus.

Obesity has reached epidemic proportions in our patients who are of childbearing age, with pregnant patients of normal weight being in the minority. The pregnancy-related complications attributable to obesity affect not only the pregnant women, but also her fetus and potentially both mother and child for their lifetimes. Pregnancy is associated with altered immunity. The physiologic state of chronic inflammation in obesity affects systemic immunity and metabolism, and may be associated with several of the complications associated with maternal obesity. The interplay between pregnancy, obesity and inflammation may have far-reaching implications for fertility, pregnancy, the fetus and neonate.

The role of glutathione in cadmium ion detoxification: coordination modes and binding properties--a density functional study.

In this investigation the reduced form of glutathione molecule (GSH) was considered as a model in the coordination chemistry of Cd(2+) and group thiol-containing peptides. Three different forms of GSH, corresponding to the prevalent ones in gas-phase and in aqueous solution, were taken into account in the metallation process. The obtained complexes were characterized at the density functional B3LYP level with the purpose to give better insight in the chelation mechanism of GSH with heavy metal ions in living organisms. Solvent effects, whether with explicit water molecules or with polarizable continuum model (PCM), were considered on the most stable cadmium-complexes obtained by every GSH charged species examined.

Complexation of Al(III) by aromatic amino acids in the gas phase.

The coordination properties of three natural aromatic amino acids (AAAs)-phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp)-to AlIII are studied in this work, devoting special attention to the role of the aromatic side chain. A comparison with aluminum(III)-alanine complexes is also presented. The polarizability arising from the ring has been seen to be a key factor in the stability of the complexes, with the order being Trp-AlIII > Tyr-AlIII > Phe-AlIII, starting from the most stable one. Cation-pi interactions between the metal and the aromatic ring are present in the lowest energy conformers, especially for Trp, which seems to be very well suited for these kinds of interactions, occurring with both the six- and five-membered rings of the indole side chain. The most stable coordination mode for the three AAAs is found to be tricoordinated with the N and O of the backbone chain and the aromatic ring, as was found theoretically and experimentally for other metals.

On the copper(II) ion coordination by prion protein HGGGW pentapeptide model.

The interaction of the octapeptide domain of the prion protein with the transition-metal-ion Cu2+ was studied at the DFT level by using the HGGGW pentapeptide as a model to mimic the PHGGGWGQ octarepeat sequence. Ten complexes, in which the metal ion exhibits different coordinations, were considered. Our results indicate that the lowest-energy structure is characterized by a tetracoordinated metal center and that this tendency of the ion to assume the square planar geometry is strong enough to prevent the addition of a further water molecule in its coordination sphere. The role of tryptophan was found to cause a lowering of the system energy due to the stabilizing effect of the electrostatic interaction between the Trp aromatic indole and histidine imidazole rings.

CO2 Activation by Nb(+) and NbO(+) in the Gas Phase. A Case of Two-State Reactivity Process.

Gas-phase carbon dioxide activation by Nb(+) and NbO(+) was studied at the density functional level of theory using the hybrid exchange correlation functional B3LYP. Three reaction profiles corresponding to the quintet, triplet, and singlet multiplicities were investigated in order to ascertain the presence of some spin inversion during the CO2 reduction. Carbon dioxide activation mediated by metal cations was found to be an exothermic spin-forbidden process resulting from a crossing between quintet and triplet energetic profiles. The endothermic reaction of NbO(+) with carbon dioxide was a barrierless process involving spin inversion. Geometries of minima along potential energy surfaces and reaction heats were in agreement with those from experimental studies carried out by using a guided ion beam tandem mass spectrometer.

Assessment of Approximate Density Functional Methods for the Study of the Interactions of Al(III) with Aromatic Amino Acids.

Four approximate Density Functional Theory methods, the standard hybrid B3LYP functional, the hybrid mPW1PW91 functional designed to account for van der Waals forces, the one-parameter meta hybrid TPSSh functional, the general-purpose meta hybrid MPWB1K functional and one Molecular Orbital Theory method, the standard Moller-Plesset perturbation theory up to second-order MP2, have been assessed for studying the complexation modes of the highly acidic Al(III) cation with the three aromatic amino acids, phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp). Based on their performance toward the prediction of the geometrical structure of a number of lowest energy isomers and their relative binding energies, it is concluded that the B3LYP approximate functional renders the desired accuracy at the minimum computational cost.