Biology subjects

Williams, K. S.

Publications and source records attributed to Williams, K. S..

3 recordsLinked to original sources

bioRxiv2019

Repression of LKB1 by miR-17~92 sensitizes MYC-dependent lymphoma to biguanide treatment

Cancer cells display metabolic plasticity to survive metabolic and energetic stresses in the tumor microenvironment, prompting the need for tools to target tumor metabolism. Cellular adaptation to energetic stress is coordinated in part by signaling through the Liver Kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Reducing LKB1-AMPK signaling exposes metabolic vulnerabilities in tumor cells with potential for therapeutic targeting. Here we describe that miRNA-mediated silencing of LKB1 (mediated by the oncogenic miRNA cluster miR-17[~]92) confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and novel (IM156) biguanides, we demonstrate that Myc+ lymphoma cells with elevated miR-17[~]92 expression display increased sensitivity to biguanide treatment both in cell viability assays in vitro and tumor growth assays in vivo. This increased biguanide sensitivity is driven by miR-17-dependent silencing of LKB1, which results in reduced AMPK activation in response to bioenergetic stress. Mechanistically, biguanide treatment inhibits TCA cycle metabolism and mitochondrial respiration in miR-17[~]92-expressing tumor cells, targeting their metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17[~]92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17[~]92 expression as a potential biomarker for biguanide sensitivity in hematological malignancies and solid tumors. One Sentence SummarymiR-17[~]92 expression in Myc+ tumors sensitizes cancer cells to biguanide treatment by disrupting bioenergetic stability in lymphoma cells.

cancer biology↗

bioRxiv2019

Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment

HIV-Associated Neurocognitive Disorders (HAND) affect over half of HIV-infected individuals worldwide, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive. We developed a human-induced pluripotent stem cell (HiPSC) based model; whereby, we independently differentiate HiPSCs into neurons, astrocytes, and microglia and systematically combine to generate a tri-culture with or without HIV-infection and ART. scRNAseq analysis on tri-cultures including HIV-infected microglia revealed inflammatory signatures in the microglia and EIF2 signaling in all three cell types. Remarkably, EFZ alone induced a similar response to infection. Treatment with the antiretroviral compound Efavirenz (EFZ) mostly resolved these signatures; However, EFZ increased RhoGDI and CD40 signaling in the HIV-infected microglia. This activation was associated with a persistent increase in TNFa expression. This work establishes a tri-culture that recapitulates key features of HIV infection in the CNS and provides a new model to examine the effects of HIV infection and its treatment with antiretrovirals.

pathology↗

bioRxiv2019

Low-intensity environmental education can enhance perceptions of culturally taboo wildlife

1.Traditional cultural beliefs influence perceptions of animals, and in some cases can result in persecution of wildlife. Stigmas against species associated with witchcraft, for example, can act as a barrier to the uptake of more cost effective, sustainable, and environmentally sound practices such as reducing crop damage by controlling rodent agricultural pests by relying on indigenous predators rather than pesticides. One way of enhancing perceptions of wildlife to increase participation in such ecologically-based rodent management (EBRM) schemes, is the development of environmental education initiatives. Low intensity programmes are cost-effective and can produce positive attitudinal shifts, but their impact has not been assessed for species strongly associated with witchcraft. We set out to test whether a single presentation on the natural history of owls (order Strigiformes) could improve perceptions of these species, and increase willingness to participate in an EBRM scheme that involved the installation of owl boxes to increase owl populations and reduce rodent populations and crop damage in agricultural fields. We used a questionnaire survey to assess perceptions of owls at four schools in two villages in South Africa. Our initial survey sampled perceptions of respondents before listening to the presentation. A follow-up survey conducted three months later sampled the perceptions of respondents that had listened to the presentation as well as perceptions of a control group that did not listen to the presentation. We found that associations between owls and witchcraft was a common theme driving negative perceptions of owls. Respondents that watched the presentation had more positive perceptions of owls than respondents that had not watched the presentation, and they were more likely to be willing to put up owl boxes near their home. Despite this shift, negative perceptions of owls still dominated responses due to cultural associations with the occult. These findings indicate that even low-intensity programmes can be effective at enhancing perceptions of wildlife associated with witchcraft. We suggest that environmental education programmes featuring culturally taboo species should adopt a culturally sensitive and locally tailored approach, focus on the benefits these species provide, and may be more effective when delivered with greater intensity.

scientific communication and education↗