Biology subjects

Brewer, R.

Publications and source records attributed to Brewer, R..

4 recordsLinked to original sources

bioRxiv2024

Experimental evolution of S. cerevisiae for caffeine tolerance alters multidrug resistance and TOR signaling pathways

Caffeine is a natural compound that inhibits the major cellular signaling regulator TOR, leading to widespread effects including growth inhibition. S. cerevisiae yeast can adapt to tolerate high concentrations of caffeine in coffee and cacao fermentations and in experimental systems. While many factors affecting caffeine tolerance and TOR signaling have been identified, further characterization of their interactions and regulation remain to be studied. We used experimental evolution of S. cerevisiae to study the genetic contributions to caffeine tolerance in yeast, through a collaboration between high school students evolving yeast populations coupled with further research exploration in university labs. We identified multiple evolved yeast populations with mutations in PDR1 and PDR5, which contribute to multidrug resistance, and showed that gain-of-function mutations in multidrug resistance family transcription factors PDR1, PDR3, and YRR1 differentially contribute to caffeine tolerance. We also identified loss-of-function mutations in TOR effectors SIT4, SKY1, and TIP41, and show that these mutations contribute to caffeine tolerance. These findings support the importance of both the multidrug resistance family and TOR signaling in caffeine tolerance, and can inform future exploration of networks affected by caffeine and other TOR inhibitors in model systems and industrial applications.

genetics↗

bioRxiv2023

Autistic kinematics diverge from the power laws that typically govern movement

Extant work reliably demonstrates that autistic individuals move with increased jerk (where jerk concerns change in acceleration). Although it follows that autistic movement may therefore diverge from fundamental power laws that govern movement, this hypothesis has not been directly tested to date. This lack of insight holds back progress in understanding the mechanisms underpinning differences in autism in motor control particularly with respect to movement jerkiness. Here we investigated whether movements executed by autistic adults diverged from the typical power law relationship that links movement speed and curvature. x and y position of the stylus tip was recorded at 133 Hz while 21 autistic and 19 non-autistic age-, intelligence quotient- and sex-matched adults traced, on a tablet device, a range of shapes that varied in angular frequency from 2/33 (spiral-like shapes) to 4 (square-like shapes). The gradient of the relationship between speed and curvature for each angular frequency-defined shape is reliably predicted by a set of mathematical equations often referred to as fundamental power laws thus, to assess deviations from power laws, we compared autistic and non-autistic participants in terms of speed-curvature gradients. To gain insight into potential mechanisms underpinning any differences we also used fast Fourier transform to explore amplitude spectral density across all angular frequencies. Compared to non-autistic adults, autistic adults exhibited significantly steeper speed-curvature gradients. Fast Fourier transform further revealed that non-autistic participants exhibited highly precise modulation of speed oscillations around the target frequency. For example, when drawing an ellipse their speed profile was dominated by speed changes in a band centred around the angular frequency 2 with minimal changes in other bands. Autistic adults, in contrast, exhibited less precise modulation of speed oscillations around the target frequency, a result that is reminiscent of a literature reporting broader auditory filters in autistic individuals. These results evidence, in autistic adults, a deviation from the power laws that typically govern movement and suggest differences in motor cortical control policies and/or biomechanical constraints.

neuroscience↗

bioRxiv2021

Viral replication in human macrophages enhances an inflammatory cascade and interferon driven chronic COVID-19 in humanized mice.

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system1-20. Blocking either viral replication with Remdesivir21-23 or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.

immunology↗

bioRxiv2021

Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication

The disialoganglioside GD2 is consistently overexpressed in neuroblastoma and osteosarcoma, and is variably expressed in other sarcomas, gliomas, neuroendocrine tumors, and epithelial cancers. Anti-GD2 antibodies have improved the survival rates of patients with neuroblastoma only when administered as part of intense chemotherapy-based cytotoxic regimens, which are associated with debilitating late effects including hearing loss, growth retardation, and secondary leukemias. Despite broad expression of GD2 on osteosarcoma, anti-GD2 antibody has not mediated significant antitumor activity in that disease or any other GD2+ cancers. CD47 is a checkpoint molecule overexpressed on tumor cells that inhibits macrophage activity, and CD47 blockade has demonstrated promising clinical activity in early human trials. We investigated whether anti-CD47 antibody could enhance the efficacy of anti-GD2 antibody in neuroblastoma and other GD2+ malignancies. We demonstrate substantial synergy of these two agents, resulting in the recruitment of tumor associated macrophages (TAMs) to mediate robust and durable anti-tumor responses. The responses are driven by GD2-specific factors that reorient the balance of macrophage activity towards phagocytosis of tumor cells, including disruption of a newly described GD2:Siglec-7 axis. These results demonstrate the unique synergy of combining anti-GD2 with anti-CD47, which has the potential to significantly enhance outcomes for children with neuroblastoma and osteosarcoma and will soon be investigated in a first-in-human clinical trial.

immunology↗