Virtual screening-driven identification of human carbonic anhydrase inhibitors incorporating an original, new pharmacophore

Combinated ligand- and pharmacophore-based virtual screening approaches were used to discover novel potential pharmacophores acting as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs). A free database of commercially available compounds was screened through drug-like filters using a four-point pharmacophore, and followed by docking calculation within the active site of an X-ray structure of isoform CA II. One compound, bearing a trifluoro-dihydroxy-propanone moiety, showed an interesting, selective inhibitory activity in low micromolar range against this isoform versus CA I. The chemical originality of this new pharmacophore can represent an important bioisosteric alternative to the sulfonamido-based functionalities, thus leading to the development of a new class of CAIs.     

Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by hamartomatous neurological lesions that exhibit abnormal cell proliferation and differentiation. Hyperactivation of mTOR pathway by mutations in either the Tsc1 or Tsc2 gene underlies TSC pathogenesis, but involvement of specific neural cell populations in the formation of TSC-associated neurological lesions remains unclear. We deleted Tsc1 in Emx1-expressing embryonic telencephalic neural stem cells (NSCs) and found that mutant mice faithfully recapitulated TSC neuropathological lesions, such as cortical lamination defects and subependymal nodules (SENs). These alterations were caused by enhanced generation of SVZ neural progeny, followed by their premature differentiation and impaired maturation during both embryonic and postnatal development. Notably, mTORC1-dependent Akt inhibition and STAT3 activation were involved in the reduced self-renewal and earlier neuronal and astroglial differentiation of mutant NSCs. Thus, finely tuned mTOR activation in embryonic NSCs may be critical to prevent development of TSC-associated brain lesions.     

Espresso Coffee Consumption and Risk of Coronary Heart Disease in a Large Italian Cohort

Background

The relationship between coffee consumption and coronary heart disease (CHD) has been investigated in several studies with discrepant results. We examined the association between Italian-style (espresso and mocha) coffee consumption and CHD risk.

Methods

We investigated 12,800 men and 30,449 women without history of cardiovascular disease recruited to the EPICOR prospective cohort study. Coffee consumption was assessed at baseline. In a random sub-cohort of 1472 subjects, plasma triglycerides, and total, LDL and HDL cholesterol were determined to investigate the effect of coffee consumption on plasma lipids.

Results

After a mean follow up of 10.9 years, 804 cases of CHD (500 acute events, 56 fatal events and 248 revascularizations, all first events) were identified. Multivariable adjusted hazard ratios for CHD were: 1.18 (95% CI 0.87–1.60) for drinking 1–2 cups/day, 1.37 (95% CI 1.03–1.82) for >2–4 cups/day and 1.52 (95% CI 1.11–2.07) for over 4 cups/day (P trend <0.001) compared to reference (<1 cup/day). Plasma triglycerides, and total, LDL and HDL cholesterol did not vary significantly (ANOVA) with coffee consumption.

Conclusion

Consumption of over 2 cups/day of Italian-style coffee is associated with increased CHD risk, but coffee consumption was not associated with plasma lipid changes, so the adverse effect of consumption appears unrelated to lipid profile.     

Hybrid Toroidal Resonance Response in Planar Core-Shell THz Metasurfaces

Toroidal resonance of planar structure is feasible and interesting for many appealing applications. We numerically and experimentally investigated the toroidal resonances in a planar metamaterial comprising core-shell structures and its constituent core and shell components at THz frequencies. The investigated structure demonstrated sharp toroidal and hybrid toroidal resonance modes in 0.2–0.3 THz range. Our analysis showed that these modes could be explained by the interaction of resonance toroidal modes of the shell and core components. The response of the investigated planar core-shell toroidal metasurface is notably geometry dependent and can be easily tuned by tailoring the device geometry. Presented work can be used for advanced THz photonics applications, including precise bio-sensing, narrow-band filters, fast-switching, and modulation.

     

Rare Primary Mitochondrial DNA Mutations and Probable Synergistic Variants in Leber's Hereditary Optic Neuropathy

Background

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined.

Methodology/Principal Findings

In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I.

Conclusions/Significance

Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.     

Expandable tumor prostheses in children

Any surgical resection in the lower extremities in children will cause a leg length discrepancy from physeal resection. To avoid the resulting functional deficit, leg length discrepancy must be reconciled with surgical techniques to approximate equal leg lengths at skeletal maturity. Currently there are several manufacturers who offer options for prosthetic reconstruction with expandable implants. These implants can be expanded to a length projected on the basis of three factors: the length of bone resected, the anticipated future growth of the contralateral extremity, and the estimated discrepancy of limb length at skeletal maturity. In this article, we review the basic principles and guidelines for prediction of remaining bone growth and planning lengthening in children, and present the currently available expandable prostheses and the evolution performed over time.     

Rhodium Plasmonics for Deep-Ultraviolet Bio-Chemical Sensing

Rhodium (Rh) has been recently introduced as a perfect metal for ultraviolet (UV) applications with the advantages of its oxide-free nature and support of strong plasmon resonant modes at very short wavelengths. We report on a simple platform of nanoplasmonic structures to support strong plasmonic Fano resonances across the deep-UV spectrum for biochemical sensing applications. We investigate the plasmonic response of several types of Rh nanoparticles and designed dimer-type antennas using nanorings with geometrical tunability in both symmetric and antisymmetric assemblies. Using numerical and theoretical methods, it is shown that Rh-based dimer antennas with broken symmetry can be tailored to support strong plasmon resonant modes at the deep-UV region (\( E>6\; eV \)). We also propose a complex infinity-shaped structure composed of a pair of split rings with a nanodisk in between with extra degree of tunability to push the plasmon resonant modes further in deep-UV spectrum. Plasmon hybridization theory is used to describe formation of plasmonic Fano-resonant dips in simple nanoscale assemblies. We calculate the corresponding figure of merit for the Rh-based nanostructure around 11.5 which shows an excellent sensitivity to the refractive index perturbations of the surrounding medium at very short wavelengths for sensing applications.     

Antibacterial effect of some essential oils administered alone or in combination with Norfloxacin

The objective of the present study was that of verifying a possible synergistic antibacterial effect between Pelargonium graveolens [Lis-Balchin, M., Deans, S.G., Hart, S., 1996. Bioactive Geranium oils from different commercial sources. J. Essential Oil Res. 8, 281-290.] essential oil (and its main components) and Norfloxacin antibiotic. As a first step growth inhibition by some types of essential oils was assessed in five microbial species. The antimicrobial effects of P. graveolens oil, as well as those of its components, were evaluated by means of the agar dilution method (ADM) against Bacillus cereus ATCC 11778, Bacillus subtilis ATCC 6633, Escherichia coli ATCC 35218, Staphylococcus aureus ATCC 6538 and S. aureus ATCC 29213. The results obtained highlighted the occurrence of a pronounced synergism between P. graveolens essential oil and Norfloxacin against three of the five bacterial species under study with a FIC index in the 0.37-0.50 range. Such antibacterial effects were also shown to increase, although to a lesser extent, when Norfloxacin was given with the main components of P. graveolens essential oil. SIGNIFICANCE AND IMPACT OF THE STUDY: The combination of Norfloxacin with either P. graveolens essential oil, or with some of the main components of this latter, in the treatment of infections caused by some bacterial species is likely to reduce the minimum effective dose of Norfloxacin thus minimizing the side effects of the antibiotic.     

Mitochondrial and Y-chromosome diversity of the Tharus (Nepal): a reservoir of genetic variation

Background  

Central Asia and the Indian subcontinent represent an area considered as a source and a reservoir for human genetic diversity, with many markers taking root here, most of which are the ancestral state of eastern and western haplogroups, while others are local. Between these two regions, Terai (Nepal) is a pivotal passageway allowing, in different times, multiple population interactions, although because of its highly malarial environment, it was scarcely inhabited until a few decades ago, when malaria was eradicated. One of the oldest and the largest indigenous people of Terai is represented by the malaria resistant Tharus, whose gene pool could still retain traces of ancient complex interactions. Until now, however, investigations on their genetic structure have been scarce mainly identifying East Asian signatures.