Synthesis of trans-L/D-2-(Tert-butoxycarbonyl- aminomethyl)-4-(thymin-1-yl) Pyrrolidin-1-yl Acetic Acid

Abstract

To delineate the binding preferences of stereochemically divergent pyrrolidine PNAs, synthesis of all four diastreomeric monomers of I and the systematic complexation studies of the resultant PNAs with complementary DNA/RNA is essential. We herein report the synthesis of trans-L/D-2-(tert-butoxycarbonylaminomethyl)-4-(thymin-1-yl) pyrrolidin-1-yl acetic acids I, their incorporation in PNA oligomers and DNA binding studies will be presented.     

Fluorinated Peptide Nucleic Acid

Abstract

The fluorinated olefinic peptide nucleic acid analogue (F-OPA) monomer containing the base thymine was synthesised in 13 steps. PNAs containing this unit were prepared and their pairing properties assessed by means of UV-melting experiments.     

Building Blocks for Polyamide Nucleic Acids: Facile Synthesis Using Potassium Fluoride Doped Natural Phosphate as Basic Catalyst

Abstract

Potassium fluoride doped natural phosphate, inexpensive and environmentally friendly catalyst, is shown to be an efficient basic catalyst for the N1/N9 alkylation of different nucleobases as synthons for PNAs.     

DNA-PHONA-PNA Chimeric Molecules: Contributions to Binding Against Complementary DNA

Abstract

The synthesis of a DNA-PHONA-PNA chimeric molecule using the Mmt protection strategy is described. The chimeric oligomer shows duplex binding properties that are comparable to PNA. Obviously, PHONA building blocks can be incorporated into PNAs without distortion of the PNA structure

     

Attending a social event and consuming alcohol is associated with changes in serum microRNA: a before and after study in healthy adults

Abstract

Purpose: Circulating microRNAs represent a reservoir for biomarker discovery. Our objective was to profile the change in human circulating microRNA associated with recreational use of alcohol at a social event.

Material and methods: Blood was collected from healthy volunteers (N?=?16) before and after recreational consumption of alcohol (ethanol). Biochemistry, hematology and ethanol measurements were performed. The change in the serum small RNA fraction was quantified by RNA sequencing.

Results: Blood ethanol was undetectable at study entry in all subjects [<10?mg/dL]. After consuming alcohol the median concentration was 89?mg/dL [IQR: 71–138. Min–max 20–175]. There were no changes in biochemistry and hematology parameters. Serum RNA sequencing identified 1371 small RNA species (1305 microRNAs). There were significant increases [adjusted p-value <0.05, fold increase 2 or more] in 265 microRNAs, around a fifth of the total [median fold increase 2.3 [IQR: 2.1–2.5; Max: 3.7]]. miR-185-5p decreased following alcohol exposure [adjusted p-value <0.05, fold decrease 2 or more].

Conclusions: The microRNA composition of human serum is dynamic and environmental factors may have a significant impact. Within its context of use the fold change ‘signal’ of a microRNA must be large enough to negate the risk of false results due to background ‘noise’.     

Inhibition of Gene Expression by Peptide Nucleic Acids in Cultured Cells

Abstract

We have tested in cultured cells the capacity of antisense and antigene PNAs to inhibit, in a sequence specific manner, the expression of oncogenes in leukaemia and pancreatic carcinoma cells. The results observed appeared promising and suggest that PNA may play in the future an important role in targeting disease-related genes.     

Analysis of the neuromuscular activity during rising from a chair in water and on dry land

PurposeThe purpose of the present study was to analyze the neuromuscular responses during the performance of a sit to stand [STS] task in water and on dry land.Scope10 healthy subjects, five males and five females were recruited for study. Surface electromyography sEMG was used for lower limb and trunk muscles maximal voluntarty contraction [MVC] and during the STS task.ResultsMuscle activity was significantly higher on dry land than in water normalized signals by MVC from the quadriceps-vastus medialis [17.3%], the quadriceps – rectus femoris [5.3%], the long head of the biceps femoris [5.5%], the tibialis anterior [13.9%], the gastrocnemius medialis [3.4%], the soleus [6.2%]. However, the muscle activity was higher in water for the rectus abdominis [?26.6%] and the erector spinae [?22.6%].ConclusionsThis study for the first time describes the neuromuscular responses in healthy subjects during the performance of the STS task in water. The differences in lower limb and trunk muscle activity should be considered when using the STS movement in aquatic rehabilitation.     

Phosphono Peptide Nucleic Acids with a Constrained Hydroxyproline-Based Backbone

Abstract

DNA mimics representing negatively charged analogues of peptide nucleic acids (PNAs), particularly hetero-oligomers constructed from alternating phosphono-PNA residues (pPNA) and monomers on the base of trans-4-hydroxy-L-proline (HypNA) as well as mimics composed of phosphono-HypNA monomers (pHypNA) were tested in a set of in vitro and in vivo assays, and they demonstrated a high potential for the use in nucleic acid based diagnostic, isolation of nucleic acids and antisense experiments.     

Linked Lists and the Method of Lights in Molecular Dynamics Simulation - Search for the Best Method of Forces Evaluation in Sequential MD Codes

Abstract

In this paper two methods of forces evaluation used in the MD codes are presented and compared against the classical linked lists algorithm [3,4] and its modified version [5]. The first algorithm, so called the method of lights is a sequential version of the CYBER 205 vector oriented code [6]. A new algorithm of forces evaluation is also proposed, which incorporates advantages of the method of lights and the linked lists technique.     

Modelling Diffusion in Zeolites by Molecular Dynamics Simulations

Abstract

The diffusion of molecules sorbed in zeolites is of growing interest for understanding the mechanisms of chemical processes with regard to selectivity and reactivity [1].

MD simulations give insight into physical systems on the molecular level allowing to study and visualize the motion of molecules even beyond the possibilities of experiments [2,3]. Single system parameters can easily be varied to study their influence, also those parameters that are fixed in reality (e.g., the size of particles). We present a cross section of our recent work to illustrate the capabilities of MD: The self diffusion coefficients (D) of a mixture of methane and xenon in silicalite show remarkable deviations from those of the pure species. This is shown and confirmed by PFG NMR experiments [4].

Simulating ethane in zeolite A the mechanism of diffusion has been studied. The effects of rotation on the diffusion lead to cases where D decreases with growing temperature [5].

The independence of self diffusion on lattice vibrations is proven even for zeolites with windows of guest particle size comparing simulations with rigid and vibrating zeolite lattice [6].     

Pre-procedural elevated cardiac troponin predict risk of long-term all-cause mortality after transcatheter aortic valve replacement: a meta-analysis of prospective studies

Abstract

Background: The purpose of this meta-analysis was to evaluate the relationship between elevated cardiac troponin pre-transcatheter aortic valve replacement (TAVR) and long-term all-cause mortality.

Methods: Prospective studies with the endpoint of all-cause mortality were included. We primarily used the fixed-effect model weighted by inverse variance. Meta-regression and subgroup analyses were conducted to explore the potential sources of heterogeneity by specified study characteristics.

Results: Seven prospective studies comprising of 3049 subjects were included in our meta-analysis. Pre-procedural elevated cardiac troponin was associated with increased risk of long-term mortality post TAVR [hazard ratio (HR) 2.25, 95% CI 1.83–2.78, p?=?0.000, I² = 30.3%, p for heterogeneity 0.197]. In addition, subgroup analyses have shown that the group with an younger age (<82?y) seemed to have a higher risk of all-cause mortality than the group with older age (≥82?y) [HR 4.08 (2.41 to 6.89) VS 2.01 (1.60 to 2.53), p?=?0.016 for subgroup difference].

Conclusions: Pre-procedural elevated cardiac troponin was associated with increased long-term all-cause mortality in patients undergoing TAVR.     

The synthesis of 2-nitroaryl-1,2,3,4-tetrahydroisoquinolines, nitro-substituted 5,6-dihydrobenzimidazo[2,1-a]isoquinoline N-oxides and related heterocycles as potential bioreducible substrates for the enzymes NAD(P)H: quinone oxidoreductase 1 and E. coli nitroreductase

A series of 2-nitroaryl-1,2,3,4-tetrahydroisoquinolines 10 and nitro-substituted 5,6-dihydrobenzimidazo[2,1-a]isoquinoline N-oxides 11 have been synthesised and evaluated as potential bioreducible substrates for the enzymes NAD(P)H: quinone oxidoreductase 1 (NQO1) and Escherichia coli nitroreductase (NR). Also prepared and evaluated were 2-(3,5-dinitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline 12 and 5,6-dihydro-10-nitropyrido[3″,2″:4′,5′]imidazo[2′,1′-a]isoquinoline 12-oxide 13. Both compounds 10b and 13 were reduced faster by human NQO1 than by CB-1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide].     

Synthesis of New PMEA Diphosphate Mimics

Abstract

We synthesized and characterized new diphosphate mimics of the acyclic nucleoside phosphonate PMEA [Adefovir, 9-(2-phosphonylmethoxyethyl)adenine].     

Fate of Hydrocarbons During Oily Sludge Disposal in Soil

A 1,280-day laboratory simulation of the “landfarming” process explored the fate in soil of polynuclear aromatics (PNAs) and total extractable hydrocarbon residues originating from the disposal of an oily sludge. In addition to the measurement of CO₂ evolution, periodic analyses of PNAs and hydrocarbons monitored biodegradation activity. The estimation of carbon balance and of soil organic matter assessed the fate of residual hydrocarbons. Seven sludge applications during a 920-day active disposal period were followed by a 360-day inactive “closure” period with no further sludge applications. A burst of CO₂ evolution followed each sludge addition, but substantial amounts of undegraded hydrocarbons remained at the end of the study. Hydrocarbon accumulation did not inhibit biodegradation performance. Conversion of hydrocarbons to CO₂ predominated during active disposal; incorporation into soil organic matter predominated during the closure period. In this sludge, the predominant PNAs were degraded more completely (85%) than total hydrocarbons. Both biodegradation and abiotic losses of three- and four-ring PNAs contributed to this result. Some PNAs with five and six rings were more persistent, but these constituted only a small portion of the PNAs in the sludge. The study confirmed that the microbially mediated processes of mineralization and humification remove sludge hydrocarbons from soils of landfarms with reasonable efficiency.     

Synthesis and MS Analysis of Thiazolium and Pyridinium Derivatives of Peptide Nucleic Acids (PNAs) and Peptides

Abstract

Sensitivity of ESI-MS analysis of crude PNAs is enhanced using their pyridinium or thiazolium derivatives. Identification of the molecular ion of the product is easier when the label contains bromine, based on the isotope distribution. Study of side reactions, occurred upon the synthesis and/or cleavage, is simple with labelling. Sequencing of non-polar peptides is clear as only a_n type ions can be observed during their MS/MS analysis.     

Synthesis of Polyamide Nucleic Acids (Pnas), Pna /Dna-Chimeras and Phosphonic Ester Nucleic Acids (Phonas)

Abstract

The synthesis of polyamide nucleic acids (PNAs) and derivatives thereof by different synthetic routes is described. The first strategy makes use of 9-Fluorenylmethoxycarbonyl (Fmoc)/monomethoxytrityl (Mmt) protected building blocks, whereas the second approach involves the use of Mmt/acyl protected monomers, which allows the preparation of PNADNA chimera. Additionally, a block coupling strategy is presented for the synthesis of novel phosphonic ester nucleic acids (PHONAs).     

Synthesis of new thieno[2,3-b]pyridine derivatives as pim-1 inhibitors

Three series of 5-bromo-thieno[2,3-b]pyridines bearing amide or benzoyl groups at position 2 were prepared as pim-1 inhibitors. All the prepared compounds were tested for their pim-1 enzyme inhibitory activity. Two compounds (3c and 5b) showed moderate pim-1 inhibitory activity with IC₅₀ of 35.7 and 12.71?μM, respectively. Three other compounds (3d, 3g and 6d) showed poor pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on five cell lines [MCF7, HEPG2, HCT116, A549 and PC3]. Compound 3g was the most potent cytotoxic agent on almost all the cell lines tested.     

Recognition of Double-Stranded Dna by Peptide Nucleic Acid

Abstract

Peptide nucleic acid (PNA) is an oligonucleotide mimic in which the backbone of DNA has been replaced by a pseudopeptide. We here show that there are distinct variations as to how PNA oligomers interact with double-stranded DNA depending on choice of nucleobases. Thymine-rich homopyrimidine PNA oligomers recognise double-stranded polynucleotides by forming PNA₂-DNA triplexes with the DNA purine strand. By contrast, cytosine-rich homopyrimidine PNAs add to double-stranded polynucleotides as Hoogsteen strands, forming PNA-DNA₂ triplexes, while homopurine, or alternating thymine-guanine, PNA oligomers invade DNA to form PNA-DNA duplexes.