Background The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer’s Disease (AD). Unfortunately, many current Trem2R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2R47H NSS (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products. Methods Trem2R47H NSS mice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain’s response to plaques. Results Trem2R47H NSS mice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in Trem2R47H NSS mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2R47H NSS (5xFAD/Trem2R47H NSS) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity for Trem2R47H NSS suppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/Trem2R47H NSS mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month old Trem2R47H NSS mice also display LTP deficits and postsynaptic loss. Conclusions The Trem2R47H NSS mouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.
Warfighter safety can be significantly increased by offloading critical reconnaissance and surveillance missions to robotic assets. The subtleties of these tasks require significant operator involvement-usually carried out locally to the robot's deployment. Human soldiers use gestures to communicate movements and commands when engaged in this type of task. While considerable work has been done with robots visually observing humans to interpret their gestures, we propose a simpler, more field-appropriate system that allows robot operators to use their natural movements and gestures (via inertial measurement units [IMUs]) to teleoperate a robot while reducing the physical, as well as the cognitive, load on the soldier. This paper describes an operator control interface implemented on a smartphone, in contrast to the proprietary robot controllers typically used. The controller utilizes the device's IMUs, or attitude sensors, to bypass the touchscreen while accepting user input via gestures; this addresses a primary concern for gloved users in dirty environments where touchscreens lack reliability. We also propose that it provides a less visually-intense alternative for control, freeing up the soldier's cognitive load toward other functions. We present details of the attitude-based control software, as well as the design heuristics resulting from its iterative build-test-rebuild development. Additionally, results from a set of user studies are presented, showing that as a controller, this technique performs as well, or better than, other screenbased control systems, even when ignoring its advantages to gloved users. Twenty-five users were recruited to assess usability of these attitude-aware controls, testing their suitability for both driving and camera manipulation tasks. Participants drove a small tracked robot on an indoor course using the attitude-aware controller and a virtual [touchscreen] joystick, while metrics regarding performance, mental workload, and user satisfaction were collected. Results indicate that the tilt controller is preferred by 64% of users and performs equally as well, if not better to the alternative, on most performance metrics. These results support the development of a smartphone-based control option for military robotics, with a focus on more physical, attitude-based input methods that overcome deficiencies of current touch-based systems, namely lack of physical feedback, high attention demands, and unreliability in field environments.
Smartphones have put video communications, computation, and proprioceptive sensing (e.g. accelerometers and gyros) into the hands of hundreds of millions of consumers. These small, microelectromechanical systems can be used in many applications, including remote control. This study proposes using smartphones with proprioception as handheld robot controllers and aims to determine feasibility of accelerometers as control inputs for tele-operation while defining heuristics for use. Initial results indicate accelerometers are suitable for tele-operation commands, but identify specific design characteristics meriting further investigation.
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