Correction to: Whole-Genome sequencing and comparative genomics of Mycobacterium spp. from farmed Atlantic and coho salmon in Chile

Antonie van Leeuwenhoek -     

Computational Investigation of Pkcβ Inhibitors for the Treatment of Diabetic Retinopathy

Diabetic Retinopathy (DR) is one of the attenuating complications of diabetes mellitus. The key gene responsible for causing diabetic retinopathy is protein kinase C beta (PKCβ). Protein kinase C is a family of protein kinase enzymes which are involved in controlling the function of other proteins through phosphorylation mechanism and plays a crucial role in signal transduction mechanisms. Among all the PKC isoenzymes, PKCβ could be a significant isoenzyme involved in vascular dysfunction during hyperglycemia. Studies show that oral administration of PKCβ inhibitor Ruboxistaurin ({"type":"entrez-nucleotide","attrs":{"text":"LY333531","term_id":"1257370768","term_text":"LY333531"}}LY333531), decreases vessel permeability and improves retinal condition. Thus compounds that decrease the PKCβ activation would be helpful in the treatment of diabetic retinopathy. The compounds similar to Ruboxistaurin are taken from Super Target database and docking analysis was performed. Maleimide derivative 3 showed highest binding affinities compared to Ruboxistaurin and so we advise that compound may be utilized in the treatment of diabetic retinopathy.     

Synthesis of densely functionalised C-glycosides by a tandem oxy Michael addition-Wittig olefination pathway

Wittig olefination of 5,6-dideoxy-5,6-anhydro-6-nitro-d-glucofuranose (5) triggered a concomitant cyclisation via oxy Michael addition of the C2-hydroxyl group resulting in the formation of C-vinyl glycosides with Z-olefinic geometry.     

Utilizing peptidic ordering in the design of hierarchical polyurethane/ureas

One of the key design components of nature is the utilization of hierarchical arrangements to fabricate materials with outstanding mechanical properties. Employing the concept of hierarchy, a new class of segmented polyurethane/ureas (PUUs) was synthesized containing either a peptidic, triblock soft segment, or an amorphous, nonpeptidic homoblock block soft segment with either an amorphous or a crystalline hard segment to investigate the effects of bioinspired, multiple levels of organization on thermal and mechanical properties. The peptidic soft segment was composed of poly(benzyl-l-glutamate)-block-poly(dimethylsiloxane)-block-poly(benzyl-l-glutamate) (PBLG-b-PDMS-b-PBLG), restricted to the β-sheet conformation by limiting the peptide segment length to <10 residues, whereas the amorphous soft segment was poly(dimethylsiloxane) (PDMS). The hard segment consisted of either 1,6-hexamethylene diisocyanate (crystalline) or isophorone diisocyanate (amorphous) and chain extended with 1,4-butanediol. Thermal and morphological characterization indicated microphase separation in these hierarchically assembled PUUs; furthermore, inclusion of the peptidic segment significantly increased the average long spacing between domains, whereas the peptide domain retained its β-sheet conformation regardless of the hard segment chemistry. Mechanical analysis revealed an enhanced dynamic modulus for the peptidic polymers over a broader temperature range as compared with the nonpeptidic PUUs as well as an over three-fold increase in tensile modulus. However, the elongation-at-break was dramatically reduced, which was attributed to a shift from a flexible, continuous domain morphology to a rigid, continuous matrix in which the peptide, in conjunction with the hard segment, acts as a stiff reinforcing element.     

<Superscript>13</Superscript>C-Methyl isocyanide as an NMR probe for cytochrome P450 active sites

The cytochromes P450 (CYPs) play a central role in many biologically important oxidation reactions, including the metabolism of drugs and other xenobiotic compounds. Because they are often assayed as both drug targets and anti-targets, any tools that provide: (a) confirmation of active site binding and (b) structural data, would be of great utility, especially if data could be obtained in reasonably high throughput. To this end, we have developed an analog of the promiscuous heme ligand, cyanide, with a ¹³CH₃-reporter attached. This ¹³C-methyl isocyanide ligand binds to bacterial (P450cam) and membrane-bound mammalian (CYP2B4) CYPs. It can be used in a rapid 1D experiment to identify binders, and provides a qualitative measure of structural changes in the active site. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The low-affinity phosphate transporter PitA is dispensable for in vitro growth of Mycobacterium smegmatis

Background  

Mycobacteria have been shown to contain an apparent redundancy of high-affinity phosphate uptake systems, with two to four copies of such systems encoded in all mycobacterial genomes sequenced to date. In addition, all mycobacteria also contain at least one gene encoding the low-affinity phosphate transporter, Pit. No information is available on a Pit system from a Gram-positive microorganism, and the importance of this system in a background of multiple other phosphate transporters is unclear.     

Amphiphilic,hydrophilic, or hydrophobic synthetic bacteriochlorins in biohybrid light-harvesting architectures: consideration of molecular designs

Biohybrid light-harvesting architectures can be constructed that employ native-like bacterial photosynthetic antenna peptides as a scaffold to which synthetic chromophores are attached to augment overall spectral coverage. Synthetic bacteriochlorins are attractive to enhance capture of solar radiation in the photon-rich near-infrared spectral region. The effect of the polarity of the bacteriochlorin substituents on the antenna self-assembly process was explored by the preparation of a bacteriochlorin–peptide conjugate using a synthetic amphiphilic bacteriochlorin (B1) to complement prior studies using hydrophilic (B2, four carboxylic acids) or hydrophobic (B3) bacteriochlorins. The amphiphilic bioconjugatable bacteriochlorin B1 with a polar ammonium-terminated tail was synthesized by sequential Pd-mediated reactions of a 3,13-dibromo-5-methoxybacteriochlorin. Each bacteriochlorin bears a maleimido-terminated tether for attachment to a cysteine-containing analog of the Rhodobacter sphaeroides antenna β-peptide to give conjugates β-B1, β-B2, and β-B3. Given the hydrophobic nature of the β-peptide, the polarity of B1 and B2 facilitated purification of the respective conjugate compared to the hydrophobic B3. Bacteriochlorophyll a (BChl a) associates with each conjugate in aqueous micellar media to form a dyad containing two β-peptides, two covalently attached synthetic bacteriochlorins, and a datively bonded BChl-a pair, albeit to a limited extent for β-B2. The reversible assembly/disassembly of dyad (β-B2/BChl)₂ was examined in aqueous detergent (octyl glucoside) solution by temperature variation (15–35 °C). The energy-transfer efficiency from the synthetic bacteriochlorin to the BChl-a dimer was found to be 0.85 for (β-B1/BChl)₂, 0.40 for (β-B2/BChl)₂, and 0.85 for (β-B3/BChl)₂. Thus, in terms of handling, assembly and energy-transfer efficiency taken together, the amphiphilic design examined herein is more attractive than the prior hydrophilic or hydrophobic designs.     

Lidocaine Transdermal Patch: Pharmacokinetic Modeling and <Emphasis Type="Italic">In Vitro</Emphasis>–<Emphasis Type="Italic">In Vivo</Emphasis> Correlation (IVIVC)

The present study aims to develop the correlation between in vitro and in vivo skin permeation of lidocaine in its transdermal patch. In order to minimize the run-to-run variability during in vitro skin permeation studies, release normalized cumulative percent (%Ct _n) was calculated. A suitable polynomial mathematical model was used to establish a correlation between time and %Ct _n. Percent in vivo absorbed was calculated by using numerical deconvolution (NDC) and non-compartmental analysis (NCA) methods. Pharmacokinetic (PK) parameters such as AUC _last and C _max were predicted with the established in vitro–in vivo correlation (IVIVC) models. The minimum prediction errors in NDC method for C _max were found to be ?30.9 and ?25.4% for studies I (in vivo study in human volunteers with one batch of Lidoderm patch; internal validation) and II (in vivo study in human volunteers with another batch of Lidoderm patch; external validation), respectively, whereas minimum prediction errors in NCA method were relatively low (3.9 and 0.03% for studies I and II, respectively) compared to those in NDC method. The prediction errors for AUC _last were found to be less than 2% for both methods and studies. The established method in this study could be a potential approach for predicting the bioavailability and/or bioequivalence for transdermal drug delivery systems.