Species-wide whole genome sequencing reveals historical global spread and recent local persistence in Shigella flexneri.

Shigella flexneri is the most common cause of bacterial dysentery in low-income countries. Despite this, S. flexneri remains largely unexplored from a genomic standpoint and is still described using a vocabulary based on serotyping reactions developed over half-a-century ago. Here we combine whole genome sequencing with geographical and temporal data to examine the natural history of the species. Our analysis subdivides S. flexneri into seven phylogenetic groups (PGs); each containing two-or-more serotypes and characterised by distinct virulence gene complement and geographic range. Within the S. flexneri PGs we identify geographically restricted sub-lineages that appear to have persistently colonised regions for many decades to over 100 years. Although we found abundant evidence of antimicrobial resistance (AMR) determinant acquisition, our dataset shows no evidence of subsequent intercontinental spread of antimicrobial resistant strains. The pattern of colonisation and AMR gene acquisition suggest that S. flexneri has a distinct life-cycle involving local persistence

A new hammer to crack an old nut : interspecific competitive resource capture by plants is regulated by nutrient supply, not climate

Peer reviewedPublisher PD

Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors

Abstract ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated the AACR Genie database and identified 34 missense mutations in the ROS1 tyrosine kinase domain for further analysis. Our experiments revealed that these mutations have varying effects on ROS1 kinase function, ranging from complete loss to significantly increased catalytic activity. Notably, Asn and Gly substitutions at Asp2113 in the ROS1 kinase domain were found to be TKI‐sensitive oncogenic variants in cell‐based model systems. In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA‐approved ROS1‐TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA‐approved ROS1‐TKIs

NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations

ROS1 tyrosine kinase inhibitors (TKI) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion–positive cancers, although none of them simultaneously address the need for broad resistance coverage, avoidance of clinically dose-limiting TRK inhibition, and brain penetration. NVL-520 is a rationally designed macrocycle with &gt;50-fold ROS1 selectivity over 98% of the kinome tested. It is active in vitro against diverse ROS1 fusions and resistance mutations and exhibits 10- to 1,000-fold improved potency for the ROS1 G2032R solvent-front mutation over crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib. In vivo, it induces tumor regression in G2032R-inclusive intracranial and patient-derived xenograft models. Importantly, NVL-520 has an ∼100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As a clinical proof of concept, NVL-520 elicited objective tumor responses in three patients with TKI-refractory ROS1 fusion–positive lung cancers, including two with ROS1 G2032R and one with intracranial metastases, with no observed neurologic toxicities.Significance:The combined preclinical features of NVL-520 that include potent targeting of ROS1 and diverse ROS1 resistance mutations, high selectivity for ROS1 G2032R over TRK, and brain penetration mark the development of a distinct ROS1 TKI with the potential to surpass the limitations of earlier-generation TKIs for ROS1 fusion–positive patients.</p

NVL-520 is a selective, TRK-sparing, and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations.

ROS1 tyrosine kinase inhibitors (TKIs) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion-positive cancers, although none simultaneously address the need for broad resistance coverage, avoidance of clinically dose-limiting TRK inhibition, and brain penetration. NVL-520 is a rationally designed macrocycle with \u3e50-fold ROS1 selectivity over 98% of the kinome tested. It is active in vitro against diverse ROS1 fusions and resistance mutations and exhibits 10-to-1,000-fold improved potency for the ROS1 G2032R solvent-front mutation over crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib. In vivo, it induces tumor regression in G2032R-inclusive intracranial and patient-derived xenograft models. Importantly, NVL-520 has a ~100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As clinical proof-of-concept, NVL-520 elicited objective tumor responses in three patients with TKI-refractory ROS1 fusion-positive lung cancers, including two with ROS1 G2032R and one with intracranial metastases, with no observed neurological toxicities

Functional perspectives on tropical tree demography and forest dynamics

Abstract Disentangling the processes that drive population, community and whole forest structure and dynamics is a challenge. It becomes a grand challenge in the tropics where there are a large number of species, small population sizes, less research infrastructure, and a relatively smaller number of researchers compared to the temperate zone. Tackling this grand challenge, we argue, requires detailed knowledge of the functioning of individuals and species. To this end, researchers frequently employ plant functional traits to study tree populations and communities. Here, we review this approach by first providing a basic background regarding the major trait axes generally of interest. We then discuss how these axes may be or have been applied from ecosystem to community and population studies. In doing so, we highlight where the functional trait research program has failed in tropical tree ecology and where it can be improved or strengthened. Finally, we provide a perspective regarding how functional trait and emerging ‘omics approaches can be integrated to address large questions facing the field. Our intention throughout is to provide an entryway into this literature for an early career researcher rather than a comprehensive review of all possible studies that have taken place in tropical forests