Effects of selection stringency on the outcomes of directed evolution.

Directed evolution makes mutant lineages compete in climbing complicated sequence-function landscapes. Given this underlying complexity it is unclear how selection stringency, a ubiquitous parameter of directed evolution, impacts the outcome. Here we approach this question in terms of the fitnesses of the candidate variants at each round and the heterogeneity of their distributions of fitness effects.

Effects of selection stringency on the outcomes of directed evolution.

Directed evolution makes mutant lineages compete in climbing complicated sequence-function landscapes. Given this underlying complexity it is unclear how selection stringency, a ubiquitous parameter of directed evolution, impacts the outcome. Here we approach this question in terms of the fitnesses of the candidate variants at each round and the heterogeneity of their distributions of fitness effects.

Extrasynaptic δGABAA receptors mediate resistance to migraine-like phenotype in rats.

Background: GABA, a key inhibitory neurotransmitter, has synaptic and extrasynaptic receptors on the postsynaptic neuron. Background GABA, which spills over from the synaptic cleft, acts on extrasynaptic delta subunit containing GABAA receptors. The role of extrasynaptic GABAergic input in migraine is unknown.

Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses.

Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model.

Comparison of Mutations in Myelodysplasia and Acute Leukemia Suggests Divergent Roles in Initiation and Progression.

mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations impact disease biology, and whether they differ between disease categories, remain unknown. We analyzed mutations in four myeloid neoplasm subtypes (MDS, AML, AML with myelodysplasia-related changes (AML-MRC), and therapy-related acute myeloid leukemia (tAML)), and identified differences in mutation types, spectrum, and hotspots between disease categories and compared to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC compared to MDS.