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Nanoindentation of Molecular Crystals: Lessons Learned from Aspirin.

ABSTRACT: Nanoindentation enables the measurement of mechanical properties from single crystals with dimensions of a few micrometers. This experimental technique, however, has only recently been applied to molecular crystals. Key differences between the application of this technique to molecular crystals and metals and other inorganics are identified. From this, protocols for the measurement of hardness and elastic modulus of molecular crystals of pharmaceutical interest are proposed. Using form I aspirin as a model system, the impact of single crystal sample surface preparation (washing and cleaving) on the surface roughness is explored. We show the importance of using a calibration sample with hardness and stiffness close to that of molecular crystals for the acquisition of more accurate data. The issue of solvent occlusions formed during crystal growth is discussed as a source of material property variation as well as tip contamination. It is proposed that this in part explains the significantly larger variation of the measured mechanical properties among different single crystals compared to those performed on a unique sample. Because both the indentation modulus and the hardness can vary significantly for low depth indents, samples were tested over a wide range of depths, which revealed that a minimum depth of penetration is required for the acquisition of data. This experiment is crucial and needs to be carried out for every system under study since it allows for the determination of the minimum-working load. Post-indentation imaging combined with crystallographic analysis and molecular simulations allows for the characterization and rationalization of the material plastic deformation mechanisms.

SUBMITTER: Gabriele BPA

PROVIDER: S-EPMC7587144 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Nanoindentation of Molecular Crystals: Lessons Learned from Aspirin.

Gabriele Benjamin P A BPA Williams Craig J CJ Lauer Matthias Eckhard ME Derby Brian B Cruz-Cabeza Aurora J AJ

Crystal growth & design 20200805 9

Nanoindentation enables the measurement of mechanical properties from single crystals with dimensions of a few micrometers. This experimental technique, however, has only recently been applied to molecular crystals. Key differences between the application of this technique to molecular crystals and metals and other inorganics are identified. From this, protocols for the measurement of hardness and elastic modulus of molecular crystals of pharmaceutical interest are proposed. Using form I aspirin ...[more]

PMID: 33122971

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Project description:BackgroundMolecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans.MethodsWe describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels.ResultsThe study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results.ConclusionsMolecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.

Dataset Information

Nanoindentation of Molecular Crystals: Lessons Learned from Aspirin.

Publications

Nanoindentation of Molecular Crystals: Lessons Learned from Aspirin.

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