Metabolite identification of small interfering RNA duplex by high-resolution accurate mass spectrometry

On-line liquid chromatography/electrospray ionization high-resolution mass spectrometry (LC/ESI-HRMS) using an LTQ-Orbitrap mass spectrometer was employed to investigate the metabolite profiles of a model siRNA duplex designated HBV263. The HBV263 duplex was incubated in rat and human serum and liver microsomes in vitro. The siRNA drug and its metabolites were then extracted using a liquid-liquid extraction followed by solid-phase extraction (LLE-SPE), and analyzed by LC/ESI-MS. High-resolution accurate mass data enabled differentiation between two possible metabolite sequences with a monoisotopic molecular mass difference of less than 1 Da. ProMass deconvolution software was used to provide semi-automated data processing. In vitro serum and liver microsome incubation samples afforded different metabolite patterns: the antisense strand of the duplex was degraded preferentially in rat and human serum, while the sense strand of the duplex was less stable in rat and human liver microsomes.     

Crystal structure and spectroscopy of 4-N-benzylaminocoumarin

The structure of 4-N-benzylaminocoumarin (C₁₆H₁₃NO₂) has been determined by X-ray diffraction and the Ft-ir,¹H- and¹³C-nmr spectra of the compound were recorded. Crystals of the compound are monoclinic, space group P2₁/c, with cell dimensiona=8.077(2),b=14.598(4),c=10.890(3) Å, and =97.76(3)°. The Ft-ir and nmr spectra indicate that the nitrogen atom is in the amino form in solution. The crystal structure is consistent with this observation, but the C(3)–C(4) double bond is clearly delocalized to include the lone pair on the nitrogen atom.     

Poly(9‐undecyl‐9‐methyl‐fluorene) and poly(9‐pentadecyl‐9‐methyl‐fluorene): Synthesis,solution structure,and effect of side chain asymmetry on aggregation behavior

We report on solution aggregates and backbone conformation of poly(9‐undecyl‐9‐methyl‐fluorene) (PF1‐11) and poly(9‐pentadecyl‐9‐methyl‐fluorene) (PF1‐15), having two different side chains compared with poly(9,9‐dihexylfluorene) (PF6) and poly(9,9‐dioctylfluorene) (PF8) with two identical side chains. In the poor solvent methylcyclohexane (MCH), X‐ray scattering indicates that PF1‐11 and PF1‐15 appear as three‐dimensional aggregates (5–10 nm wide and thick), forming ribbon‐like agglomerates (correlation lengths of 100 nm). PF6 and PF8 appear as two‐dimensional aggregates (>10 nm wide and 2–3 nm thick) involving ribbon‐like agglomerates (correlation lengths much greater than 100 nm). Upon heating, all aggregates undergo a gel–sol transition which occurs at lower temperatures for PF1‐11 and PF1‐15 (<60°C) than for PF6 and PF8 (>80°C). In the good solvent toluene, PF1‐11 and PF1‐15 form networks of cylindrical particles. The mesh size and the cylinder radius are smaller in 24°C toluene (60 nm, 0.5 nm) than in 60°C MCH (300 nm, 1–2 nm). Nuclear magnetic resonance spectra in toluene‐d₈ together with density functional theory calculations suggest higher torsion angles between polymer repeat units for PF6, PF8, and PF1‐11 (less planar conformation) and a gauche arrangement of the dihedral angles between the bridge carbon atom and the side chain methylene groups in PF1‐15. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019 , 57, 826–837     

An objective means of diagnosing anorexia nervosa and bulimia nervosa using 15N/14N and 13C/12C ratios in hair

An objective means based on the carbon and nitrogen stable isotope analysis of five hairs per individual is presented for distinguishing between individuals with anorexia nervosa and/or bulimia nervosa from non-clinical individuals (i.e. clinically normal controls). Using discriminant analysis, an algorithm has been developed that provides both sensitivity and specificity of 80% in making diagnoses of individuals with these eating disorders. With further refinements, the results suggest that it may be also possible to distinguish between individuals with anorexia or bulimia. Finally, the study shows the value of conducting blind tests and using larger sample sizes of both control and treatment groups. Both groups are needed to validate the diagnostic value of a method and to provide measures of sensitivity and specificity of any diagnostic test.     

Syntheses of Para-Terphenyl via Reductive Deoxygenation of Quinol Derivatives

Syntheses of para-terphenyl via reductive aromatization of 1,4-dioxygenated-1,4-diaryl-2,5-cyclohexadienes are described¹     

Molecular cluster perturbation theory. I. Formalism

We present second-order molecular cluster perturbation theory (MCPT(2)), a linear scaling methodology to calculate arbitrarily large systems with explicit calculation of individual wave functions in a coupled-cluster framework. This new MCPT(2) framework uses coupled-cluster perturbation theory and an expansion in terms of molecular dimer interactions to obtain molecular wave functions that are infinite order in both the electronic fluctuation operator and all possible dimer (and products of dimers) interactions. The MCPT(2) framework has been implemented in the new SIA/Aces4 parallel architecture, making use of the advanced dynamic memory control and fine-grained parallelism to perform very large explicit molecular cluster calculations. To illustrate the power of this method, we have computed energy shifts, lattice site dipole moments, and harmonic vibrational frequencies via explicit calculation of the bulk system for the polar and non-polar polymorphs of solid hydrogen fluoride. The explicit lattice size (without using any periodic boundary conditions) was expanded up to 1000 HF molecules, with 32,000 basis functions and 10,000 electrons. Our obtained HF lattice site dipole moments and harmonic vibrational frequencies agree well with the existing literature.     

Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc

Background

Developmental dyslexia is a specific cognitive disorder in reading acquisition that has genetic and neurological origins. Despite histological evidence for brain differences in dyslexia, we recently demonstrated that in large cohort of subjects, no differences between control and dyslexic readers can be found at the macroscopic level (MRI voxel), because of large variances in brain local volumes. In the present study, we aimed at finding brain areas that most discriminate dyslexic from control normal readers despite the large variance across subjects. After segmenting brain grey matter, normalizing brain size and shape and modulating the voxels' content, normal readers' brains were used to build a 'typical' brain via bootstrapped confidence intervals. Each dyslexic reader's brain was then classified independently at each voxel as being within or outside the normal range. We used this simple strategy to build a brain map showing regional percentages of differences between groups. The significance of this map was then assessed using a randomization technique.

Results

The right cerebellar declive and the right lentiform nucleus were the two areas that significantly differed the most between groups with 100% of the dyslexic subjects (N = 38) falling outside of the control group (N = 39) 95% confidence interval boundaries. The clinical relevance of this result was assessed by inquiring cognitive brain-based differences among dyslexic brain subgroups in comparison to normal readers' performances. The strongest difference between dyslexic subgroups was observed between subjects with lower cerebellar declive (LCD) grey matter volumes than controls and subjects with higher cerebellar declive (HCD) grey matter volumes than controls. Dyslexic subjects with LCD volumes performed worse than subjects with HCD volumes in phonologically and lexicon related tasks. Furthermore, cerebellar and lentiform grey matter volumes interacted in dyslexic subjects, so that lower and higher lentiform grey matter volumes compared to controls differently modulated the phonological and lexical performances. Best performances (observed in controls) corresponded to an optimal value of grey matter and they dropped for higher or lower volumes.

Conclusion

These results provide evidence for the existence of various subtypes of dyslexia characterized by different brain phenotypes. In addition, behavioural analyses suggest that these brain phenotypes relate to different deficits of automatization of language-based processes such as grapheme/phoneme correspondence and/or rapid access to lexicon entries.