We previously reported that cortical expression levels of chaperones and proteases involved in the mitochondrial unfolded protein response (mtUPR) are upregulated in frank familial and sporadic Alzheimer's disease (AD), suggesting sustained activation of this protective proteostasis pathway. However, whether mtUPR activation is evident earlier in disease and the functional consequences of this sustained response are unknown. To measure mtUPR activation during the progression of AD, we performed quantitative PCR (qPCR) and western blotting for several mtUPR markers in frozen temporal cortex samples from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild AD (n=8/group). To study sustained mtUPR activation in vitro, we mimicked mitochondrial proteostatic stress by transfecting differentiated human hNT neurons with a mutant form of ornithine transcarbamylase (OTC), which activates the mtUPR. Cultures were: 1) probed for mtUPR gene expression using qPCR, 2) co-treated with MitoTracker and LysoTracker dyes to analyze subcellular mitochondrial dynamics, or 3) evaluated for cell survival. Transcripts encoding the mtUPR chaperone Hsp60 and protease Yme1l1 were upregulated by 50–60% in MCI and AD compared to NCI (p < 0.01), whereas protein levels for the mtUPR chaperone Dnaja3/Hsp40 and protease ClpP were also upregulated by 50–60% in MCI and AD (p < 0.01). In vitro studies revealed that mutant OTC-transfected hNT neurons displayed an upregulation of mtUPR genes (e.g., Hsp60, Dnaja3) and then, paradoxically, underwent cell death compared to wild type OTC-transfected neurons (p< 0.01, via LIVE/DEAD assay). Further analysis revealed that cell death was preceded by increased mitochondrial fission, mitophagy, and caspase 2 activation. Sustained activation of the normally protective mtUPR may trigger a unique neuronal cell death effector pathway during the early stages of AD.
Alterations in synaptic protein stoichiometry may contribute to neocortical synaptic dysfunction in Alzheimer disease (AD). Whether perturbations in synaptic protein expression occur during the earliest stages of cognitive decline remain unclear. We examined protein levels of synaptophysin (SYP), synaptotagmin (SYT), and drebrin (DRB) in 5 neocortical regions (anterior cingulate, superior frontal, superior temporal, inferior parietal, and visual) of people clinically diagnosed with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD, or severe AD. Normalized SYP levels were decreased approximately 35% in the superior temporal and inferior parietal cortex in severe AD compared with NCI. SYT levels were unchanged across clinical diagnosis in the cortical regions. Levels of DRB, a dendritic spine plasticity marker, were reduced approximately 40% to 60% in all cortical regions in AD compared with NCI. DRB protein was also reduced approximately 35% in the superior temporal cortex of MCI subjects, and DRB and SYP levels in the superior temporal cortex correlated with Mini-Mental State Examination and Braak scores. In contrast, DRB levels in the superior frontal cortex increased approximately 30% in MCI subjects. The differential changes in DRB expression in the frontal and temporal cortex in MCI suggest a disparity of dendritic plasticity within these regions that may contribute to the early impairment of temporal cortical functions subserving memory and language compared with the relative preservation of frontal cortical executive function during the initial stages of cognitive decline.
We explored the social and gaming attributes of interactive casual gaming on mobile phones. To do so, we developed a game called MoMENTus, a multiplayer mobile brain teaser game, and deployed it to 43 participants, divided into various multiplayer and team configurations, over the course of one week. Participants generally liked the interactive and mobile aspects of our casual game, while the team concept was unexpectedly less compelling. Our results suggest that mobile multiplayer casual gaming is a promising new direction, with game play fostering a feeling of community among players. Team play was found to be counter to the casual nature of the game, but competition acted as an effective motivator. Additionally, since mobile phones are "always-on-person," casual mobile gaming was successful in filling interstitial time. Findings address aspects of multiplayer mobile casual gaming, such as the role of competition, manner in which these games are played, and the impact of the type of content on such games. Implications for the design of interactive casual games for mobile phones are discussed.
Microblogs have become an increasingly important source of information, both in the U.S. (Twitter) and in China (Weibo). However, the brevity of microblog updates, combined with increasing access of microblog content through search rather than through direct network connections, makes it challenging to assess the credibility of news relayed in this manner [34]. This paper reports on experimental and survey data that compare the impact of several features of microblog updates (author’s gender, name style, profile image, location, and degree of network overlap with the reader) on credibility perceptions among U.S. and Chinese audiences. We reveal the complex mechanism of credibility perceptions, identify several key differences in how users from each country critically consume microblog content, and discuss how to incorporate these findings into the design of improved user interfaces for accessing microblogs in different cultural settings.
To examine associations between nurse work environment, serum biomarkers, and patient outcomes in a large hospital.A work environment questionnaire was administered in 2017 to the total sample of nurses in a Midwestern hospital. A subsample of nurses (n = 83) provided blood samples. Correlation analyses examined associations between work environment ratings, biomarkers (dehydroepiandrosterone-sulphate [DHEA-S] and interleukin-6 [IL-6]), and unit-level patient outcomes.Work stress was negatively correlated with DHEA-S (r = -0.23) and positively correlated with IL-6 (r = 0.31; P < 0.05). Psychological safety (r = 0.22) and competence development (r = 0.25) were both positively correlated with DHEA-S (P < 0.05). DHEA-S was negatively correlated with central line-associated bloodstream infections (rho = -0.61; P < 0.05).Work environment-associated physiological mechanisms might adversely impact patient safety, in addition to nurse health.
Dysfunction of basocortical cholinergic projection neurons of the nucleus basalis (NB) correlates with cognitive deficits in Alzheimer disease (AD). Nucleus basalis neurons receive cholinergic inputs and express nicotinic acetylcholine receptors (nAChRs) and muscarinic AChRs (mAChRs), which may regulate NB neuron activity in AD. Although alterations in these AChRs occur in the AD cortex, there is little information detailing whether defects in nAChR and mAChR gene expression occur in cholinergic NB neurons during disease progression.To determine whether nAChR and mAChR gene expression is altered in cholinergic NB neurons during the progression of AD.Individual NB neurons from subjects diagnosed ante mortem as having no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild to moderate AD were analyzed by single-cell AChR expression profiling via custom-designed microarrays.Academic research.Participants were members of the Rush Religious Orders Study cohort.Real-time quantitative polymerase chain reaction was performed to validate microarray findings.Cholinergic NB neurons displayed a statistically significant up-regulation of alpha7 nAChR messenger RNA expression in subjects with mild to moderate AD compared with those with NCI and MCI (P<.001). No differences were found for other nAChR and mAChR subtypes across the cohort. Expression levels of alpha7 nAChRs were inversely associated with Global Cognitive Score and with Mini-Mental State Examination performance.Up-regulation of alpha7 nAChRs may signal a compensatory response to maintain basocortical cholinergic activity during AD progression. Alternatively, putative competitive interactions of this receptor with beta-amyloid may provide a pathogenic mechanism for NB dysfunction. Increasing NB alpha7 nAChR expression may serve as a marker for the progression of AD.
As users of social networking websites expand their network of friends, they are often flooded with newsfeed posts and status updates, most of which they consider to be "unimportant" and not newsworthy. In order to better understand how people judge the importance of their newsfeed, we conducted a study in which Facebook users were asked to rate the importance of their newsfeed posts as well as their friends. We learned classifiers of newsfeed and friend importance to identify predictive sets of features related to social media properties, the message text, and shared background information. For classifying friend importance, the best performing model achieved 85% accuracy and 25% error reduction. By leveraging this model for classifying newsfeed posts, the best newsfeed classifier achieved 64% accuracy and 27% error reduction.
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