Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α

Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al

Arterial oxygen desaturation during moderate hypoxia hinders sensorimotor performance.

IntroductionModerate hypoxia may impact cognitive and sensorimotor performance prior to self-recognized impairments. Therefore, rapid and objective assessment tools to identify people at risk of impaired function during moderate hypoxia is needed.PurposeTest the hypothesis that reductions in arterial oxygen saturation during moderate normobaric hypoxia (FiO2 = 14%) decreases gamified sensorimotor performance as measured by alterations of motor acuity.MethodsFollowing three consecutive days of practice, thirty healthy adults (25 ± 5 y, 10 females) completed three bouts of the tablet-based gamified assessment (Statespace Labs, Inc.) of motor acuity at Baseline and 60 and 90 min after exposure to 13.8 ± 0.2% (hypoxia) and 20.1 ± 0.4% (normoxia) oxygen. The gamified assessment involved moving the tablet to aim and shoot at targets. Both conditions were completed on the same day and were administered in a single-blind, block randomized manner. Performance metrics included shot time and shot variability. Arterial oxyhemoglobin saturation estimated via forehead pulse oximetry (SpO2). Data were analyzed using linear mixed effects models.ResultsCompared to normoxia (99±1%), SpO2 was lower (pConclusionDecreases in SpO2 during moderate hypoxic exposure hinders sensorimotor performance via decreased motor acuity, i.e., greater variability (less precision) with no change in speed with differing decreases in SpO2. Thus, personnel who are exposed to moderate hypoxia and have greater decreases in SpO2 exhibit lower motor acuity, i.e., less precise movements even though decision time and movement speed are unaffected

Data_Sheet_1_Assessment of human expertise and movement kinematics in first-person shooter games.pdf

In contrast to traditional professional sports, there are few standardized metrics in professional esports (competitive multiplayer video games) for assessing a player's skill and ability. We assessed the performance of professional-level players in Aim LabTM, a first-person shooter training and assessment game, with two target-shooting tasks. These tasks differed primarily in target size: the task with large targets provided an incentive to be fast but imprecise and the task with large targets provided an incentive to be precise but slow. Each player's motor acuity was measured by characterizing the speed-accuracy trade-off in shot behavior: shot time (elapsed time for a player to shoot at a target) and shot spatial error (distance from center of a target). We also characterized the fine-grained kinematics of players' mouse movements. Our findings demonstrate that: 1) movement kinematics depended on task demands; 2) individual differences in motor acuity were significantly correlated with kinematics; and 3) performance, combined across the two target sizes, was poorly characterized by Fitts Law. Our approach to measuring motor acuity has widespread applications not only in esports assessment and training, but also in basic (motor psychophysics) and clinical (gamified rehabilitation) research.</p

Gridshot output variables at 60 and 90 min during normoxia and hypoxia.

Gray bars represents normoxia trials and red bars represent hypoxia trials. Data presented as means with individual responses (n = 21). P-values presented from F-tests for main effects and interaction from two-way repeated measures ANCOVA with baseline values serving as the covariate. (A) Composite score: Average composite score per round. (B) Shot precision: Average distance from target center. (C) Average hits: Average hits per round. (D) Average misses: Average misses per round. (E) Hit rate: Percentage of hits to total shots. (F) Hits per second: Average number of hits in one second. (G) Median time to hit: Average median time between two consecutive hits. (H) Shots per second: Average number of shots made per second.</p

Multitracker output variables at 60 and 90 min during normoxia and hypoxia.

Gray bars represents normoxia trials and red bars represent hypoxia trials. Data presented as means with individual responses (n = 21). P-values presented from F-tests for main effects and interaction from two-way repeated measures ANCOVA with baseline values serving as the covariate. (A) Composite score: Average composite score per round. (B) Mean difficulty: Average difficulty during a round. (C) Median time to hit: Average median time between two consecutive hits. (D) Average Correct Trials: Average number of correct trials per round. (E) Average Incorrect Trials: Average number of incorrect trials per round. (F) Proportion of Correct Trials: Average percentage of correct trials within a round.</p

Multitracker linear mixed effects model estimate tables for each performance metric.

Multitracker linear mixed effects model estimate tables for each performance metric.</p

Capacity linear mixed effects model estimate tables for each performance metric.

Capacity linear mixed effects model estimate tables for each performance metric.</p

Gridshot linear mixed effects model estimate tables for each performance metric.

Gridshot linear mixed effects model estimate tables for each performance metric.</p

Adaptive Reflexshot linear mixed effects model estimates for the motor acuity performance metrics.

Adaptive Reflexshot linear mixed effects model estimates for the motor acuity performance metrics.</p

Study timeline.

Session 1 included consenting, screening, and familiarization. Familiarization of the gamified sensorimotor task consisted of a demonstration of the task followed by 3 sets of the gamified sensorimotor task. Following Session 1, participants completed two practice sessions per day of the gamified sensorimotor task for the three consecutive days prior to returning to the lab for the experimental session. Each practice session consisted of playing 3 sets of the gamified sensorimotor task, and participants were asked to complete one practice session in the morning and the other in the afternoon/evening with at least four hours between practice sessions. Session 2 included baseline measures of body mass, heart rate, oxygen saturation, and the baseline assessment (comprising 3 sets of the task). After completing the baseline assessment, participants sat in a chair in the environmental chamber and were allowed to watch a documentary of their choosing between assessments. The environmental chamber was then set to a hypoxic (FiO2 = 14%) or normoxic (FiO2 = 21%) environment (counterbalanced across participants). Participants were blinded to order of exposure. Participants completed an assessment (3 sets of the task) after 60 min of exposure to either hypoxia or normoxia and again after 90 min of continuous exposure, to see if longer exposure impacts cognitive performance. Following the 90 min assessment, participants were given a 5 min bathroom break and then reentered the chamber. The FiO2 in the environmental chamber was changed to the opposite environmental condition. Again, participants completed an assessment after 60 min of exposure to the experimental conditions and again after 90 min of exposure. Data were upload to a server and participants were free to leave the lab after deinstrumentation.</p