27 research outputs found
Integrating transposable elements in the 3D genome
Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or "topography") of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome
Understanding Flavin-Dependent Halogenase Reactivity via Substrate Activity Profiling
The
activity of four native FDHs and four engineered FDH variants on 93
low-molecular-weight arenes was used to generate FDH substrate activity
profiles. These profiles provided insights into how substrate class,
functional group substitution, electronic activation, and binding
affect FDH activity and selectivity. The enzymes studied could halogenate
a far greater range of substrates than have been previously recognized,
but significant differences in their substrate specificity and selectivity
were observed. Trends between the electronic activation of each site
on a substrate and halogenation conversion at that site were established,
and these data, combined with docking simulations, suggest that substrate
binding can override electronic activation even on compounds differing
appreciably from native substrates. These findings provide a useful
framework for understanding and exploiting FDH reactivity for organic
synthesis
One-Pot C–N/C–C Cross-Coupling of Methyliminodiacetic Acid Boronyl Arenes Enabled by Protective Enolization
Iterative cross-coupling is a highly efficient and versatile strategy for modular construction in organic synthesis, though this has historically been demonstrated solely in the context of C–C bond formation. A C–N cross-coupling of haloarene methyliminodiacetic acid (MIDA) boronates with a wide range of aromatic and aliphatic amines is reported. Successful cross-coupling of aliphatic amines was realized only through protective enolization of the MIDA group. This reaction paradigm was subsequently utilized to achieve a one-pot C–N/C–C cross-coupling sequence
MicroCycle: An Integrated and Automated Platform to Accelerate Drug Discovery
We herein describe the development
and application of a modular
technology platform which incorporates recent advances in plate-based
microscale chemistry, automated purification, in situ quantification,
and robotic liquid handling to enable rapid access to high-quality
chemical matter already formatted for assays. In using microscale
chemistry and thus consuming minimal chemical matter, the platform
is not only efficient but also follows green chemistry principles.
By reorienting existing high-throughput assay technology, the platform
can generate a full package of relevant data on each set of compounds
in every learning cycle. The multiparameter exploration of chemical
and property space is hereby driven by active learning models. The
enhanced compound optimization process is generating knowledge for
drug discovery projects in a time frame never before possible