Sleep: How stress keeps you up at night.

Stress disrupts sleep, but the neural mechanisms underlying this relationship remain unclear. Novel findings in mice reveal a hypothalamic circuit that fragments sleep and promotes arousal after stress.

A novel machine learning system for identifying sleep-wake states in mice.

Research into sleep-wake behaviors relies on scoring sleep states, normally done by manual inspection of electroencephalogram (EEG) and electromyogram (EMG) recordings. This is a highly time-consuming process prone to inter-rater variability. When studying relationships between sleep and motor function, analyzing arousal states under a four-state system of active wake (AW), quiet wake (QW), nonrapid-eye-movement (NREM) sleep, and rapid-eye-movement (REM) sleep provides greater precision in behavioral analysis but is a more complex model for classification than the traditional three-state identification (wake, NREM, and REM sleep) usually used in rodent models. Characteristic features between sleep-wake states provide potential for the use of machine learning to automate classification. Here, we devised SleepEns, which uses a novel ensemble architecture, the time-series ensemble. SleepEns achieved 90% accuracy to the source expert, which was statistically similar to the performance of two other human experts. Considering the capacity for classification disagreements that are still physiologically reasonable, SleepEns had an acceptable performance of 99% accuracy, as determined blindly by the source expert. Classifications given by SleepEns also maintained similar sleep-wake characteristics compared to expert classifications, some of which were essential for sleep-wake identification. Hence, our approach achieves results comparable to human ability in a fraction of the time. This new machine-learning ensemble will significantly impact the ability of sleep researcher to detect and study sleep-wake behaviors in mice and potentially in humans.

Longitudinal monitoring of SARS-CoV-2 neutralizing antibody titers and its impact on employee personal wellness decisions

Virus neutralizing antibody (vnAb) titers are the strongest laboratory correlate of protection from SARS-CoV-2. Providing individuals with real-time measures of their vnAb titers is predicted to improve their ability to make personal wellness decisions. Yet, widespread commercial testing of SARS-CoV-2 vnAbs does not currently occur. Here, we examined whether knowing their vnAb titer impacted wellness decision-making among individuals. To this end, starting on January 1, 2021, we offered all employees from two companies free IMMUNO-COV testing and conducted a survey to assess their behaviors and decisions regarding booster vaccination. IMMUNO-COV is a clinically validated, surrogate virus assay that quantitates serum titers of SARS-CoV-2 vnAbs. To help participants gauge their level of protection based on their vnAb titer, we calibrated IMMUNO-COV titers to the World Health Organization (WHO) International Standard (IU/mL), making them comparable to published reports of correlates of protection, and we fit historical IMMUNO-COV vnAb titer values into predictive models of immune protection from COVID-19. As expected, data for the 56 program participants showed variability in vnAb titers post vaccination, rates vnAb decay, and fold-increases in vnAb titers after booster vaccination. Based on the participant survey, the majority (66%) of participants indicated that knowing their vnAb titer impacted their social behaviors and/or their decision on the timing of a booster vaccination. Several participants indicated that knowing their vnAb titer contributed to their peace of mind regarding their high level of protection from COVID-19. Together, these data demonstrate that regular determination of SARS-CoV-2 neutralizing antibody titers can significantly impact decisions regarding social interactions and timing of booster vaccinations.

Boosting of SARS-CoV-2 immunity in nonhuman primates using an oral rhabdoviral vaccine

An orally active vaccine capable of boosting SARS-CoV-2 immune responses in previously infected or vaccinated individuals would help efforts to achieve and sustain herd immunity. Unlike mRNA-loaded lipid nanoparticles and recombinant replication-defective adenoviruses, replicating vesicular stomatitis viruses with SARS-CoV-2 spike glycoproteins (VSV-SARS2) were poorly immunogenic after intramuscular administration in clinical trials. Here, by G protein trans-complementation, we generated VSV-SARS2(+G) virions with expanded target cell tropism. Compared to parental VSV-SARS2, G-supplemented viruses were orally active in virus-naive and vaccine-primed cynomolgus macaques, powerfully boosting SARS-CoV-2 neutralizing antibody titers. Clinical testing of this oral VSV-SARS2(+G) vaccine is planned.

Cellular models for discovering prion disease therapeutics: Progress and challenges.

Prions, which cause fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease, are misfolded and infectious protein aggregates. Currently, there are no treatments available to halt or even delay the progression of prion disease in the brain. The infectious nature of prions has resulted in animal paradigms that accurately recapitulate all aspects of prion disease, and these have proven to be instrumental for testing the efficacy of candidate therapeutics. Nonetheless, infection of cultured cells with prions provides a much more powerful system for identifying molecules capable of interfering with prion propagation. Certain lines of cultured cells can be chronically infected with various types of mouse prions, and these models have been used to unearth candidate anti-prion drugs that are at least partially efficacious when administered to prion-infected rodents. However, these studies have also revealed that not all types of prions are equal, and that drugs active against mouse prions are not necessarily effective against prions from other species. Despite some recent progress, the number of cellular models available for studying non-mouse prions remains limited. In particular, human prions have proven to be particularly challenging to propagate in cultured cells, which has severely hindered the discovery of drugs for Creutzfeldt-Jakob disease. In this review, we summarize the cellular models that are presently available for discovering and testing drugs capable of blocking the propagation of prions and highlight challenges that remain on the path towards developing therapies for prion disease.