TDP-43 impairs sleep in Drosophila through Ataxin-2-dependent metabolic disturbance.

Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila. Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2-regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.

Neurofibromin 1 regulates early developmental sleep in Drosophila.

Sleep disturbances are common in neurodevelopmental disorders, but knowledge of molecular factors that govern sleep in young animals is lacking. Evidence across species, including Drosophila, suggests that juvenile sleep has distinct functions and regulatory mechanisms in comparison to sleep in maturity. In flies, manipulation of most known adult sleep regulatory genes is not associated with sleep phenotypes during early developmental (larval) stages. Here, we examine the role of the neurodevelopmental disorder-associated gene Neurofibromin 1 (Nf1) in sleep during numerous developmental periods. Mutations in Neurofibromin 1 (Nf1) are associated with sleep and circadian disorders in humans and adult flies. We find in flies that Nf1 acts to regulate sleep across the lifespan, beginning during larval stages. Nf1 is required in neurons for this function, as is signaling via the Alk pathway. These findings identify Nf1 as one of a small number of genes positioned to regulate sleep across developmental periods.

Impact of Privacy Messaging on COVID-19 Exposure Notification App Downloads: Evidence From a Randomized Experiment.

Introduction: Digital contact-tracing smartphone apps have the potential to slow the spread of disease but are not widely used. We tested whether messages describing how a COVID-19 digital contact-tracing app protects users' privacy led to increased or decreased intentions to download the app by either calming privacy concerns or increasing their saliency. Design: Randomized controlled trial. Setting/participants: We recruited adult smartphone owners in the U.S. (oversampled for younger adults aged 18-34 years) in November 2020 through an online panel. Intervention: Survey software randomly assigned 860 participants to 1 of 2 parallel messaging conditions (n=430 privacy assured, n=430 no privacy described). Main outcome measures: 4-point scale of intention to use the app "if public health officials released a COVID Exposure Notification app in their state" that averaged likelihood to (1) download and install the app on their phone; (2) keep the app active on their phone; and (3) keep Bluetooth active on their phone (needed for the app to work). Results: After removing incompletes, those who failed the manipulation checks, or those who had already downloaded a COVID-19 digital contact-tracing app, we analyzed 671 participants (n=330 privacy, n=341 no privacy) in 2021. There was no relationship between privacy condition and download intention (meanprivacy=2.69, meannoprivacy=2.69, b=0.01, 95% CI= -0.13, 0.15, p=0.922) but also no evidence that describing the app's security increased context-dependent privacy concerns (measured 3 ways). Instead, we found increased endorsement of data security in the privacy condition using a scale of beliefs about the app keeping privacy secure (meanprivacy=2.74, meannoprivacy=2.58, b=0.16, 95% CI=0.04, 0.28, p=0.009, small effect ω2=0.009). Conclusions: This study provides some evidence that people developing contact-tracing messaging campaigns do not need to worry that describing a digital contact-tracing app's privacy protections will backfire. Future mixed methods testing of messages about who has access to information-and for how long-may uncover new communication strategies to increase public trust in contact-tracing apps. Trial registration: This study is registered with AsPredicted#51826.