Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

To meet the ever-growing demand of antibiotic discovery, new chemical matter and antibiotic targets are urgently needed. Many potent natural product antibiotics which were previously discarded can also provide lead molecules and drug targets. One such example is the structurally unique β-lactone obafluorin, produced by Pseudomonas fluorescens ATCC 39502. Obafluorin is active against both Grampositive and -negative pathogens, however the biological target was unknown. We now report that obafluorin targets threonyl-tRNA-synthetase and we identify a homologue, ObaO, which confers self-immunity to the obafluorin producer. Disruption of obaO in P. fluorescens ATCC 39502 results in obafluorin sensitivity, whereas expression in sensitive E. coli strains confers resistance. Enzyme assays demonstrate that E. coli threonyl-tRNA synthetase is fully inhibited by obafluorin, whereas ObaO is only partly susceptible, exhibiting a very unusual partial inhibition mechanism.Altogether, our data highlight the utility of a self-immunity guided approach for the identification of an antibiotic target de novo and will ultimately enable the generation of improved obafluorin variants..

AimThe biogeography of terrestrial organisms across the Florida Keys archipelago is poorly understood. We used population genetics and spatioecological modeling of the Amblypygi Phrynus marginemaculatus to understand the genetic structure and metapopulation dynamics of Keys populations that are otherwise isolated by human development and ocean.LocationThe Florida Keys archipelago and mainland Florida.MethodsWe sequenced a 1,238 bp fragment of mtDNA for 103 individuals of P. marginemaculatus from 13 sites in the Florida Keys and South Florida, binned into four regions. We used population genetic analyses to understand the population structure of the species throughout its US range. Furthermore, we used ecological modeling with climate, habitat, and human development data to develop habitat suitability estimates for the species.ResultsWe found clear genetic structure between localities. The Lower Keys, in particular, support populations separate from those in other regions studied. Ecological modeling and genetic analyses showed the highest habitat suitability and genetic isolation in the Lower Keys, but urban development across the species range has resulted in the loss of most historical habitat.Main conclusionsA mainland‐metapopulation model best fits P. marginemaculatus gene flow patterns in the Florida Keys and mainland. Ocean currents likely play a role in metapopulation dynamics and gene flow for terrestrial Keys species like P. marginemaculatus, and genetic patterns also matched patterns consistent with geologic history. Suitable habitat, however, is limited and under threat of human destruction. The few remaining pockets of the most suitable habitat tend to occur in parks and protected areas. We argue that conservation efforts for this species and others in the terrestrial Florida Keys would benefit from a deeper understanding of the population genetic structure and ecology of the archipelago.

The Caribbean Archipelago is a biodiversity hotspot that plays a key role in developing our understanding of how dispersal ability affects species formation. In island systems, species with intermediate dispersal abilities tend to exhibit greater diversity, as may be the case for many of the salticid lineages of the insular Caribbean. Here, we use molecular phylogenetic analyses to infer patterns of relationships and biogeographic history of the Caribbean endemic Antillattus clade (Antillattus, Truncattus, and Petemethis). We test if the timing of origin of the Antillatus clade in the Greater Antilles is congruent with GAARlandia and infer patterns of diversification within the Antillattus clade among Cuba, Hispaniola, and Puerto Rico. Specifically, we evaluate the relative roles of dispersal over land connections, and overwater dispersal events in diversification within the Greater Antilles. Time tree analysis and model-based inference of ancestral ranges estimated the ancestor of the Antillattus clade to be c. 25 Mya, and the best model suggests dispersal via GAARlandia from northern South America to Hispaniola. Hispaniola seems to be the nucleus from which ancestral populations dispersed into Cuba and Puerto Rico via land connections prior to the opening of the Mona Passage and the Windward Passage. Divergences between taxa of the Antillattus clade from Cuban, Hispaniolan, and Puerto Rican populations appear to have originated by vicariance, founder-events and within-island speciation, while multiple dispersal events (founder-events) between Cuba and Hispaniola during the Middle Miocene and the Late Miocene best explain diversity patterns in the genera Antillattus and Truncattus.

To meet the ever-growing demand of antibiotic discovery, new chemical matter and antibiotic targets are urgently needed. Many potent natural product antibiotics which were previously discarded can also provide lead molecules and drug targets. One such example is the structurally unique β-lactone obafluorin, produced by Pseudomonas fluorescens ATCC 39502. Obafluorin is active against both Grampositive and -negative pathogens, however the biological target was unknown. We now report that obafluorin targets threonyl-tRNA-synthetase and we identify a homologue, ObaO, which confers self-immunity to the obafluorin producer. Disruption of obaO in P. fluorescens ATCC 39502 results in obafluorin sensitivity, whereas expression in sensitive E. coli strains confers resistance. Enzyme assays demonstrate that E. coli threonyl-tRNA synthetase is fully inhibited by obafluorin, whereas ObaO is only partly susceptible, exhibiting a very unusual partial inhibition mechanism.Altogether, our data highlight the utility of a self-immunity guided approach for the identification of an antibiotic target de novo and will ultimately enable the generation of improved obafluorin variants.