Biology subjects

Donovan, L.

Publications and source records attributed to Donovan, L..

3 recordsLinked to original sources

bioRxiv2025

Simple sequence repeats power Staphylococcus aureus adaptation

Understanding Staphylococcus aureus adaptation is foundational for addressing the challenges posed by this pathogen. Using evolutionary convergence analysis on 7099 S. aureus genomes we uncovered frequent, reversible loss-of-function (LoF) mutations caused by simple sequence repeats (SSRs). Functional assays showed SSRs are potent, length-dependent switches that activate and deactivate genes, a mechanism exemplified by frequent LoF mutations in mutL (DNA mismatch repair) that causes a hypermutator phenotype. Analysis of over 600 episodes of human S. aureus colonisation and infection confirmed laboratory findings and showed that mutL SSR hypermutability behaves like a phase-variable evolutionary capacitor that unlocks subsequent adaptive SSR variations. We also experimentally demonstrate that SSRs facilitate foreign DNA uptake (hsdR restriction endonuclease) and lead to gentamicin-resistant small colony variants that are known to cause persistent infections (menF menadione biosynthesis). Furthermore, the phenomenon is widespread, with 27 of 29 diverse human microbiome samples harbouring S. aureus with distinct SSR subpopulations, indicative of niche-specific adaptations. Thus, SSRs are potent reservoirs of previously unrecognized S. aureus genetic heterogeneity that confer rapid adaptive capacity, including in antigens targeted by past vaccine trials. A deeper understanding of SSR evolutionary trajectories has the potential to improve treatments and to anticipate S. aureus responses to new therapies.

microbiology↗

bioRxiv2024

Targeted inhibition of Bcl-xL following radiation reduces tumourigenesis in preclinical models of H3K27M-altered diffuse midline glioma

BackgroundDiffuse midline gliomas (DMGs) with histone H3K27M mutations represent a devastating paediatric brain cancer characterized by abysmal prognosis and limited treatment options. The only approved treatment is radiotherapy (RT), but most of the tumours relapse with fatal consequences. In this study, we sought to investigate whether irradiation leads to senescence induction and explore the efficacy of senolytics against DMG. MethodsWe have characterised the senescent phenotype of five genetically heterogeneous H3K27M-altered human DMG cell lines, combining cellular and/or molecular approaches. The sensitivity of senescent cells to Bcl-xL inhibition has been demonstrated in dose/response curves in vitro and in a PDX model of DMG. ResultsHere, we show that ionizing radiation induces senescence and SASP responses in both TP53 mutant and wild-type H3K27M-altered human DMG cell lines. We identify Navitoclax as a potent senolytic agent that selectively targets senescent DMG cells into apoptosis by inhibiting Bcl-xL. Related compounds, such as a proteolysis-targeting chimera (PROTAC)-mediated Bcl-xL degradation and a galacto-conjugated form of Navitoclax also show an effective senolytic activity in senescent cancer cells. Finally, we show that a combination therapy of irradiation and Navitoclax results in reduced tumor burden and increased mouse survival in an orthotopic xenograft DMG model. ConclusionThese results offer a rationale for further clinical development of senolytic therapies as part of multimodal treatment approaches for DMG patients/ Key PointsO_LIIonising irradiation induces senescence in human DMG cells independently of the p53 status. C_LIO_LIBcl-xL inhibition results in apoptosis of human DMG senescent cells in synergy with irradiation. C_LIO_LICombination of irradiation and BcL-xL inhibition reduces tumourigenesis in a PDX model of DMG. C_LI Importance of the StudyH3K27M-altered DMG are devastating paediatric tumours with an abysmal prognosis. The only approved treatment is radiotherapy but this is palliative and tumours almost always relapse with fatal consequences for the patients. In this study, we show that radiotherapy results in senescence induction in five genomically heterogeneous human DMG cell lines. We identify that drugs targeting the anti-apoptotic protein Bcl-xL show a strong senolytic activity in conjunction with radiotherapy both in vitro in DMG cells and in vivo in a PDX model of H3K27M-altered DMG. Treatment with Bcl-xL inhibitor Navitoclax, or related compounds targeting Bcl-xL protein degradation or containing a galactose conjugated form of Navitoclax results in DMG cancer cell apoptosis. As several of these inhibitors are currently being tested in ongoing clinical trials against other diseases, our data support the use of Bcl-xL inhibition mediated senolytics as an adjuvant therapy to radiotherapy to potentially improve outcomes in this challenging disease setting.

cancer biology↗

bioRxiv2018

Coordination of trait responses to above and belowground resource limitation in cultivated sunflower (Helianthus annuus L.)

O_LIIn the face of resource limitations, plants show plasticity in multiple trait categories, including biomass allocation, morphology and anatomy, yet inevitably also grow less. The extent to which passive mass-scaling plays a role in trait responses that contribute to increased potential for resource acquisition are poorly understood. Here we assessed the role of mass-scaling on the direction, magnitude and coordination of trait plasticity to light and/or nutrient limitation in cultivated sunflower (Helianthus annuus). C_LIO_LIWe grew seedlings of ten sunflower genotypes for three weeks in a factorial of light (50% shade) and nutrient (10% supply) limitation in the greenhouse and measured a suite of allocational, morphological and anatomical traits for leaves, stems, fine roots, and tap roots. C_LIO_LIUnder resource limitation, plants were smaller and more biomass was allocated to the organ capturing the most limiting resource, as expected. Traits varied in the magnitude of plasticity and the extent to which the observed response was passive (scaled with plant mass) and/or had an additional active component. None of the allocational responses were primarily passive. Plastic changes to specific leaf area and specific root length were primarily active, and adjusted towards more acquisitive trait values under light and nutrient limitation, respectively. For many traits, the observed response was a mixture of active and passive components, and for some traits the active adjustment was antagonistic to the direction of passive adjustment, e.g. stem height, and tap root and stem theoretical hydraulic conductance. Passive scaling with size played a major role in the coordinated response to light, but correcting for mass clarified that the active responses to both limitations were more similar in magnitude, although still resource and organ specific. C_LIO_LIOur results demonstrate that both passive plasticity and active plasticity can contribute to increased uptake capacity for limiting resources in a manner that is resource, organ and trait specific. Indeed, passive adjustments (scaling with mass) of traits due to resource stress extends well beyond just mass allocation traits. For a full understanding of plants response to environmental stress both passive and active plasticity needs to be taken into account. C_LI

plant biology↗