Natural genetic variation affects circadian rhythms across the evolutionary tree, but the underlying molecular mechanisms are poorly understood. We investigated population-level, molecular circadian clock variation by generating >700 tissue-specific transcriptomes of Drosophila melanogaster (w1118) and 141 Drosophila Genetic Reference Panel (DGRP) lines. This comprehensive circadian gene expression atlas contains >1700 cycling genes including previously unknown central circadian clock components and tissue-specific regulators. Furthermore, >30% of DGRP lines exhibited aberrant circadian gene expression, revealing abundant genetic variation–mediated, intertissue circadian expression desynchrony. Genetic analysis of one line with the strongest deviating circadian expression uncovered a novel cry mutation that, as shown by protein structural modeling and brain immunohistochemistry, disrupts the light-driven flavin adenine dinucleotide cofactor photoreduction, providing in vivo support for the importance of this conserved photoentrainment mechanism. Together, our study revealed pervasive tissue-specific circadian expression variation with genetic variants acting upon tissue-specific regulatory networks to generate local gene expression oscillations.

Toll-Like Receptors (TLR) are a large family of proteins involved in the immune system response. Both the activation and the inhibition of these receptors can have positive effects on several diseases, including viral pathologies and cancer, therefore prompting the development of new compounds. In order to provide new indications for the design of Toll-Like Receptor 7 (TLR7)-targeting drugs, the mechanism of interaction between the TLR7 and two important classes of agonists (imidazoquinoline and adenine derivatives) was investigated through docking and Molecular Dynamics simulations. To perform the computational analysis, a new model for the dimeric form of the receptors was necessary and therefore created. Qualitative and quantitative differences between agonists and inactive compounds were determined. The in silico results were compared with previous experimental observations and employed to define the ligand binding mechanism of TLR7.

Resistance to last-resort carbapenem antibiotics is an increasing threat to human health, as it critically limits therapeutic options. Metallo-!-lactamases are the largest family of carbapenemases, enzymes that inactivate these drugs. Among MBLs, New Delhi metallo-!-lactamase 1 has experienced the fastest and largest worldwide dissemination. This success has been attributed to the fact that NDM-1 is a lipidated protein anchored to the outer membrane of bacteria, while all other MBLs are soluble periplasmic enzymes. By means of a combined experimental and computational approach, we show that NDM-1 interacts with the surface of bacterial membranes in a stable, defined conformation, in which the active site is not occluded by the bilayer. Although the lipidation is required for a long-lasting interaction, the globular domain of NDM-1 is tuned to interact specifically with the outer bacterial membrane. In contrast, this affinity is not observed for VIM-2, a natively soluble MBL. Finally, we identify key residues involved in the membrane interaction of NDM-1, which constitute potential targets for developing therapeutic strategies able to combat resistance granted by this enzyme.