Comparison of dose selection based on target engagement versus inhibition of receptor-ligand interaction for checkpoint inhibitors.

Immune checkpoint inhibitors block the interaction between a receptor on one cell and its ligand on another cell, thus preventing the transduction of an immunosuppressive signal. While inhibition of the receptor-ligand interaction is key to the pharmacological activity of these drugs, it can be technically challenging to measure these intercellular interactions directly. Instead, target engagement (or receptor occupancy) is commonly measured, but may not always be an accurate predictor of receptor-ligand inhibition, and can be misleading when used to inform clinical dose projections for this class of drugs. In this study, a mathematical model explicitly representing the intercellular receptor-ligand interaction is used to compare dose prediction based on target engagement or receptor-ligand inhibition for two checkpoint inhibitors, atezolizumab and magrolimab. For atezolizumab, there is little difference between target engagement and receptor-ligand inhibition, but for magrolimab, the model predicts that receptor-ligand inhibition is significantly less than target engagement. The key variables explaining the difference between these two drugs are the relative concentrations of the target receptors and their ligands. Drug-target affinity and receptor-ligand affinity can also have divergent effects on target engagement and inhibition. These results suggest that it is important to consider ligand-receptor inhibition in addition to target engagement and demonstrate the impact of using modeling for efficacious dose estimation.

The complete mitochondrial genome of the brown pansy butterfly, Junonia stygia (Aurivillius, 1894), (Insecta: Lepidoptera: Nymphalidae).

The brown pansy, Junonia stygia (Aurivillius, 1894) (Lepidoptera: Nymphalidae), is a widespread West African forest butterfly. Genome skimming by Illumina sequencing allowed assembly of a complete 15,233 bp circular mitogenome from J. stygia consisting of 79.5% AT nucleotides. Mitochondrial gene order and composition is identical to other butterfly mitogenomes. Junonia stygia COX1 features an atypical CGA start codon, while ATP6, COX1, COX2, ND4, and ND4L exhibit incomplete stop codons. Phylogenetic reconstruction supports a monophyletic Subfamily Nymphalinae, Tribe Junoniini, and genus Junonia. The phylogenetic tree places Junonia iphita and J. stygia as basal mitogenome lineages sister to the remaining Junonia sequences.

Constructing interethnic conflict and cooperation: why some people harmed Jews and others helped them during the Holocaust in Romania.

The authors draw on a natural experiment to demonstrate that states can reconstruct conflictual interethnic relationships into cooperative relationships in relatively short periods of time. The article examines differences in how the gentile population in each of two neighboring territories in Romania treated its Jewish population during the Holocaust. These territories had been part of tsarist Russia and subject to state-sponsored anti-Semitism until 1917. During the interwar period one territory became part of Romania, which continued anti-Semitic policies, and the other became part of the Soviet Union, which pursued an inclusive nationality policy, fighting against inherited anti-Semitism and working to integrate its Jews. Both territories were then reunited under Romanian administration during World War II, when Romania began to destroy its Jewish population. The authors demonstrate that, despite a uniform Romanian state presence during the Holocaust that encouraged gentiles to victimize Jews, the civilian population in the area that had been part of the Soviet Union was less likely to harm and more likely to aid Jews as compared with the region that had been part of Romania. Their evidence suggests that the state construction of interethnic relationships can become internalized by civilians and outlive the life of the state itself.