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Logan, G.

Publications and source records attributed to Logan, G..

5 recordsLinked to original sources

Mutant KRAS dosage contributes to heterogeneity in lung cancer therapeutic response

Oncogenic KRAS mutations promote tumorigenesis by constitutive activation of multiple, well-characterised signalling pathways. However, there is significant heterogeneity across mutant KRAS tumours in terms of mutation present, mutant allele abundance and downstream signalling strength. It is unclear whether these variations can impact responses to specific therapies. Here, we demonstrate that [~]20% of lung adenocarcinomas (LUAD) show an increase in mutant KRAS dosage (KRASmutant allele fraction > KRASwild-type). Furthermore, we show that KRAS mutant dosage can directly influence clinical outcome and therapeutic susceptibilities in lung cancer. Our findings show that mutant KRAS copy gains specifically affect platinum lung cancer response, promoting resistance to this standard-of-care therapy. Importantly, increases in KRAS mutant dosage are also associated with an increased vulnerability to pS6K inhibition, due to the unique metabolic rewiring of these cells. Together, we show that mutant KRAS dosage contributes to the phenotypic heterogeneity of mutant KRAS NSCLC and that assessment of mutant KRAS content or signalling strength can help optimise treatments strategies for these patients.

cancer biology↗

Diet High in Soybean Oil Increases Susceptibility to Colitis in Mice

The current American diet is high in soybean oil (SO), which consists of unsaturated fatty acids, most notably linoleic acid (LA, C18:2 omega-6). While LA is an essential fatty acid that must be obtained from the diet, high LA consumption has been linked to the development of inflammatory bowel disease (IBD) in humans. Here, we show that a high fat diet (HFD) based on soybean oil increases susceptibility to colitis in wild-type and IL10 knockout mice. It causes immune dysfunction, decreases colon and crypt length and increases intestinal epithelial barrier permeability; these effects were not observed in low LA HFDs. The SO diet also disrupts the balance of isoforms encoded by the IBD susceptibility gene Hepatocyte Nuclear Factor 4 (HNF4). Both the SO diet and an LA gavage cause gut dysbiosis: the SO diet increases the abundance of an adherent, invasive Escherichia coli (AIEC), which can use LA as a carbon source, and the LA gavage decreases the beneficial bacteria Lactobacillus murinus. Metabolomic analysis of both host-associated and cultured bacteria shows that SO increases levels of LA and oxylipins while decreasing eicosapentaenoic acid (EPA, C20:5 omega-3) and endocannabinoids. Our results suggest that excess LA, obtained from a diet high in soybean oil, increases susceptibility to colitis by alterations in intestinal HNF4, gut microbiota and bioactive metabolites.

physiology↗

A Diaphanous and Enabled dependent asymmetric actin cable array repositions nuclei during Drosophila oogenesis

Cells reposition their nuclei for a diversity of specialized functions through a wide variety of cytoskeletal mechanisms. To complete oogenesis, Drosophila nurse cells employ novel actin cable arrays to reposition their nuclei. During oogenesis, 15 nurse cells connected by ring canals contract to "dump" their cytoplasmic contents into the oocyte. Just prior to dumping, actin cables initiate from the nurse cell cortex and elongate toward their nuclei, pushing them away from the ring canals to prevent obstruction. How the actin cable arrays generate directional nuclear movement is not known. We found regional differences in the actin cable growth rate that are dependent on the differential localization of the actin assembly factors Enabled (Ena) and Diaphanous (Dia). Mislocalization of Ena resulted in actin cable arrays with a uniform growth rate. In the absence of growth rate asymmetry, nuclear relocation was significantly altered and cytoplasmic dumping was incomplete. This novel mechanism for nuclear repositioning relies on the regulated cortical localization of Dia and Ena producing asymmetric actin cable arrays that push the nuclei away from the ring canals, enabling successful oogenesis. Summary statementThis work demonstrates that an asymmetric actin cable array regulated by the differential localization of Diaphanous and Enabled is necessary to reposition nurse cell nuclei and complete oogenesis in Drosophila.

developmental biology↗

Ecological and genomic attributes of novel bacterial taxa that thrive in subsurface soil horizons

While most bacterial and archaeal taxa living in surface soils remain undescribed, this problem is exacerbated in deeper soils owing to the unique oligotrophic conditions found in the subsurface. Additionally, previous studies of soil microbiomes have focused almost exclusively on surface soils, even though the microbes living in deeper soils also play critical roles in a wide range of biogeochemical processes. We examined soils collected from 20 distinct profiles across the U.S. to characterize the bacterial and archaeal communities that live in subsurface soils and to determine whether there are consistent changes in soil microbial communities with depth across a wide range of soil and environmental conditions. We found that bacterial and archaeal diversity generally decreased with depth, as did the degree of similarity of microbial communities to those found in surface horizons. We observed five phyla that consistently increased in relative abundance with depth across our soil profiles: Chloroflexi, Nitrospirae, Euryarchaeota, and candidate phyla GAL15 and Dormibacteraeota (formerly AD3). Leveraging the unusually high abundance of Dormibacteraeota at depth, we assembled genomes representative of this candidate phylum and identified traits that are likely to be beneficial in low nutrient environments, including the synthesis and storage of carbohydrates, the potential to use carbon monoxide (CO) as a supplemental energy source, and the ability to form spores. Together these attributes likely allow members of the candidate phylum Dormibacteraeota to flourish in deeper soils and provide insight into the survival and growth strategies employed by the microbes that thrive in oligotrophic soil environments.\n\nImportanceSoil profiles are rarely homogeneous. Resource availability and microbial abundances typically decrease with soil depth, but microbes found in deeper horizons are still important components of terrestrial ecosystems. By studying 20 soil profiles across the U.S., we documented consistent changes in soil bacterial and archaeal communities with depth. Deeper soils harbored distinct communities compared to the more commonly studied surface horizons. Most notably, we found that the candidate phylum Dormibacteraeota (formerly AD3) was often dominant in subsurface soils, and we used genomes from uncultivated members of this group to identify why these taxa are able to thrive in such resource-limited environments. Simply digging deeper into soil can reveal a surprising amount of novel microbes with unique adaptations to oligotrophic subsurface conditions.

microbiology↗

A dispensable paralog of succinate dehydrogenase subunit C mediates standing resistance towards a subclass of SDHI fungicides in Zymoseptoria tritici

Succinate dehydrogenase inhibitor (SDHI) fungicides are widely used for the control of a broad range of fungal diseases. This has been the most rapidly expanding fungicide group in terms of new molecules discovered and introduced for agricultural use over the past fifteen years. A particular pattern of differential sensitivity (resistance) to a subclass of chemically-related SDHIs (SHA-SDHIs) was observed in naive Zymoseptoria tritici populations. Class specific SHA-SDHI resistance was confirmed at the enzyme level but did not correlate with the genotypes of the succinate dehydrogenase (SDH) encoding genes. Mapping and characterization of the genetic factor responsible for standing SHA-SDHI resistance in natural field isolates identified a gene (alt-SDHC) encoding a paralog of the C subunit of succinate dehydrogenase. This paralog was not present within our sensitive reference isolates and found at variable frequencies within Z. tritici populations. Using reverse genetics, we showed that alt-SDHC associates with the three other SDH subunits leading to a fully functional enzyme and that a unique Qp-site residue within the alt-SDHC protein confers SHA-SDHI resistance. Enzymatic assays, computational modelling and docking simulations for the two types of SQR enzymes (alt-SDHC, SDHC) enabled us to describe protein-inhibitor interactions at an atomistic level and to propose rational explanations for differential potency and resistance across SHA-SDHIs. European Z. tritici populations displayed a presence (20-30%) / absence polymorphism of alt-SDHC, as well as differences in alt-SDHC expression levels and splicing efficiency. These polymorphisms have a strong impact on SHA-SDHI resistance phenotypes. Characterization of the alt-SDHC promoter in European Z. tritici populations suggest that transposon insertions are associated with the strongest resistance phenotypes. These results establish that a dispensable paralogous gene determines SHA-SDHIs fungicide resistance in natural populations of Z. tritici. This study paves the way to an increased awareness of the role of fungicidal target paralogs in resistance to fungicides and demonstrates the paramount importance of population genomics in fungicide discovery.\n\nAuthor SummaryZymoseptoria tritici is the causal agent of Septoria tritici leaf blotch (STB) of wheat, the most devastating disease for cereal production in Europe. Multiple succinate dehydrogenase inhibitor (SDHI) fungicides have been developed and introduced for the control of STB. We report the discovery and detailed characterization of a paralog of the C subunit of the SDH enzyme conferring standing resistance towards a particular chemical subclass of the SDHIs. The resistance gene is characterized by its presence/absence, expression and splicing polymorphisms which in turn affect resistance levels. The identified mechanism influenced the chemical optimization phase which led to the discovery of pydiflumetofen, exemplifying the importance of population genomics for discovery and rational design of the most adapted solutions.

microbiology↗