Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15

IL-15 and NKG2D promote autoimmunity and celiac disease by arming cytotoxic T lymphocytes (CTLs) to cause tissue destruction. However, the downstream signaling events underlying these functional properties remain unclear. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central molecule in NKG2D-mediated cytolysis in CTLs. Furthermore, we report that NKG2D induces, upon recognition of MIC+ target cells, the release of arachidonic acid (AA) by CTLs to promote tissue inflammation in association with target killing. Interestingly, IL-15, which licenses NKG2D-mediated lymphokine killer activity in CTLs, cooperates with NKG2D to induce cPLA2 activation and AA release. Finally, cPLA2 activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA2 activation in CTLs. These results reveal an unrecognized link between NKG2D and tissue inflammation, which may underlie the emerging role of NKG2D in various immunopathological conditions and define new therapeutic targets

Electrophysiological measurement of information flow during visual search

Abstract The temporal relationship between different stages of cognitive processing is long debated. This debate is ongoing, primarily because it is often difficult to measure the time course of multiple cognitive processes simultaneously. We employed a manipulation that allowed us to isolate ERP components related to perceptual processing, working memory, and response preparation, and then examined the temporal relationship between these components while observers performed a visual search task. We found that, when response speed and accuracy were equally stressed, our index of perceptual processing ended before both the transfer of information into working memory and response preparation began. However, when we stressed speed over accuracy, response preparation began before the completion of perceptual processing or transfer of information into working memory on trials with the fastest reaction times. These findings show that individuals can control the flow of information transmission between stages, either waiting for perceptual processing to be completed before preparing a response or configuring these stages to overlap in time. Descriptors: Attention, ERPs, Visual processes, N2pc, LRP, Speed accuracy trade-off One of the oldest debates in psychology centers on the temporal relationship between cognitive operations. For example, it has been hypothesized that responding appropriately to an object that we encounter requires information to be processed in a sequence of discrete stages in which one stage must finish before the next can begin (Donders, 1868 The goal of the current study was to determine whether evidence for continuous information flow can be observed during visual search and, if so, to specify precisely which cognitive operations can be configured to overlap with one another in time using ERPs. The ERP technique is uniquely suited to address these questions because discrete ERP components have been shown to measure discrete aspects of cognition and are temporally precise, indexing the earliest and latest time points at which the underlying cognitive processes are operative To overcome this problem and enable the ability to directly compare components related to discrete processing stages, we examined the time course of two components that can be distinguished by their lateralized distributions, the perceptual attentionrelated N2pc and the response-related lateralized readiness potential (LRP), alongside a nonlateralized measure of the transfer of information into working memory, the P3b. The goal was to directly examine the temporal relationship between these components in order to provide a window into the temporal unfolding of cognitive processes from perceptual processing through response preparation in a typical visual search task The N2pc is lateralized on the scalp relative to the locus of spatial attention, and previous research in visual search tasks has demonstrated that the onset of the N2pc can be used to track when perceptual-level attention is deployed to an object. Critically, during search the N2pc is directly followed by the onset of a lateralized positivity (the Pd), which signals the termination of perceptua

Replacing sedentary time with physical activity or sleep: effects on cancer-related cognitive impairment in breast cancer survivors

Abstract Background Evidence suggests reallocating daily sedentary time to physical activity or sleep confers important health benefits in cancer survivors. Despite emerging research suggesting physical activity as a treatment for cancer-related cognitive impairment (CRCI), little is known about the interactive effects of behaviors across the 24-h period. The present purpose was to examine the cognitive effects of reallocating sedentary time to light-intensity physical activity, moderate-to-vigorous physical activity (MVPA), or sleep in breast cancer survivors. Methods Breast cancer survivors (N = 271, Mage = 57.81 ± 9.50 years) completed iPad-based questionnaires and cognitive tasks assessing demographics, health history, executive function, and processing speed (Task-Switch, Trail Making). Participants wore an accelerometer for seven consecutive days to measure their sedentary, physical activity, and sleep behaviors. Single effects (each behavior individually) and partition (controlling for other behaviors) models were used to examine associations among behaviors and cognitive performance. Isotemporal substitution models were used to test the cognitive effects of substituting 30 min of sedentary time with 30 min of light-intensity activity, MVPA, and sleep. Results MVPA was associated with faster Task-switch reaction time in the partition models (stay: B = − 35.31, p = 0.02; switch: B = − 48.24, p = 0.004). Replacing 30 min of sedentary time with 30 min of MVPA yielded faster reaction times on Task-Switch stay (B = − 29.37, p = 0.04) and switch (B = − 39.49, p = 0.02) trials. In Trails A single effects models, sedentary behavior was associated with faster completion (B = − 0.97, p = 0.03) and light-intensity activity with slower completion (B = 1.25, p = 0.006). No single effects were observed relative to Trails B completion (all p > 0.05). Only the effect of MVPA was significant in the partition models (Trails A: B = − 3.55, p = 0.03; Trails B: B = − 4.46, p = 0.049). Replacing sedentary time with light-intensity activity was associated with slower Trails A (B = 1.55 p = 0.002) and Trails B (B = 1.69, p = 0.02) completion. Replacing light activity with MVPA yielded faster Trails A (B = − 4.35, p = 0.02) and Trails B (B = − 5.23, p = 0.03) completion. Conclusions Findings support previous research suggesting MVPA may be needed to improve cognitive function in breast cancer survivors. Trails findings underscore the need to dissect sedentary contexts to better understand the impact of daily behavioral patterns on CRCI. Additional research investigating the cognitive impacts of behaviors across the 24-h period is warranted. Trial registration This study is registered with United States ClinicalTrials.gov (NCT02523677; 8/14/2015)

Effects of Teriparatide, Alendronate, or Both in Women with Postmenopausal Osteoporosis

Context: Teriparatide increases both bone formation and bone resorption

Additional file 1: of Replacing sedentary time with physical activity or sleep: effects on cancer-related cognitive impairment in breast cancer survivors

Supplementary File (Additional Questionnaires). (PDF 78 kb

Effects of Teriparatide Treatment and Discontinuation in Postmenopausal Women and Eugonadal Men with Osteoporosis

Context: In postmenopausal women, bone mineral density (BMD) declines after teriparatide therapy is stopped. The pattern of BMD loss after teriparatide therapy is stopped in men is less clear