Ribosome-Associated Vesicles promote activity-dependent local translation.

Local protein synthesis in axons and dendrites underpins synaptic plasticity. However, the composition of the protein synthesis machinery in distal neuronal processes and the mechanisms for its activity-driven deployment to local translation sites remain unclear. Here, we employed cryo-electron tomography, volume electron microscopy, and live-cell imaging to identify Ribosome-Associated Vesicles (RAVs) as a dynamic platform for moving ribosomes to distal processes. Stimulation via chemically-induced long-term potentiation causes RAV accumulation in distal sites to drive local translation. We also demonstrate activity-driven changes in RAV generation and dynamics in vivo, identifying tubular ER shaping proteins in RAV biogenesis. Together, our work identifies a mechanism for ribosomal delivery to distal sites in neurons to promote activity-dependent local translation.

Fundamental roles for inter-organelle communication in aging.

Advances in public health have nearly doubled life expectancy over the last century, but this demographic shift has also changed the landscape of human illness. Today, chronic and age-dependent diseases dominate the leading causes of morbidity and mortality worldwide. Targeting the underlying molecular, genetic and cell biological drivers of the aging process itself appears to be an increasingly viable strategy for developing therapeutics against these diseases of aging. Towards this end, one of the most exciting developments in cell biology over the last decade is the explosion of research into organelle contact sites and related mechanisms of inter-organelle communication. Identification of the molecular mediators of inter-organelle tethering and signaling is now allowing the field to investigate the consequences of aberrant organelle interactions, which frequently seem to correlate with age-onset pathophysiology. This review introduces the major cellular roles for inter-organelle interactions, including the regulation of organelle morphology, the transfer of ions, lipids and other metabolites, and the formation of hubs for nutrient and stress signaling. We explore how these interactions are disrupted in aging and present findings that modulation of inter-organelle communication is a promising avenue for promoting longevity. Through this review, we propose that the maintenance of inter-organelle interactions is a pillar of healthy aging. Learning how to target the cellular mechanisms for sensing and controlling inter-organelle communication is a key next hurdle for geroscience.

Ventilation by mask before and after the administration of neuromuscular blockade: a pragmatic non-inferiority trial.

BACKGROUND: Test ventilating prior to administration of neuromuscular blockade (NMB) in order to avoid a cannot intubate-cannot ventilate situation is a classic anesthesia teaching. The primary aim of our study was to show that facemask ventilation (FMV) after NMB was not inferior to FMV prior to NMB with respect to exhaled gas volumes before and after their administration. METHODS: This study was approved by the University of Washington Human Subjects Division (Seattle, Washington, USA). Written informed consent was obtained from all patients. Measurements of tidal volume (Vte) as well as other respiratory parameters during FMV were made for 60 s after induction of anesthesia and again after NMB. Difficult, impossible, inadequate, and dead-space only mask ventilation was graded using published definitions. Difficult intubation was defined as >2 attempts at intubation. The primary outcome was non-inferiority in Vte during both study periods defined as a mean difference of <50 mL. Multivariate analysis was performed to assess for interaction between operator experience, patient risk factors for difficult mask ventilation, exhaled volumes, and use of airway adjuncts. RESULTS: Two-hundred and ten patients were studied. Overall, FMV improved after NMBD. The mean (SD) Vte in mL/breath increased from 399 (169) to 428 (166) (mean dif. 30 mL, p = 0.001) and the minute ventilation in L/min from 5.6 (2.5) to 6.3 (2.5) (mean dif. 0.6, p < 0.001). No patient who was difficult to ventilate after induction became impossible after NMB. DISCUSSION: In patients at risk for or judged to be a difficult FMV by clinical grading scales, tidal volumes improved after administration of NMBDs. None of these patients exhibited a decline in ventilation or became impossible to ventilate after NMBDs. Several limitations are noted, including the use of hand-delivered breaths and inability to account for time-related changes in ventilation conditions independent of NMBDs. CONCLUSION: We conclude that FMV is no worse after NMB than before and is likely to improve airway conditions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02237443 . Registered August 28, 2014.

A manual small molecule screen approaching high-throughput using zebrafish embryos.

Zebrafish have become a widely used model organism to investigate the mechanisms that underlie developmental biology and to study human disease pathology due to their considerable degree of genetic conservation with humans. Chemical genetics entails testing the effect that small molecules have on a biological process and is becoming a popular translational research method to identify therapeutic compounds. Zebrafish are specifically appealing to use for chemical genetics because of their ability to produce large clutches of transparent embryos, which are externally fertilized. Furthermore, zebrafish embryos can be easily drug treated by the simple addition of a compound to the embryo media. Using whole-mount in situ hybridization (WISH), mRNA expression can be clearly visualized within zebrafish embryos. Together, using chemical genetics and WISH, the zebrafish becomes a potent whole organism context in which to determine the cellular and physiological effects of small molecules. Innovative advances have been made in technologies that utilize machine-based screening procedures, however for many labs such options are not accessible or remain cost-prohibitive. The protocol described here explains how to execute a manual high-throughput chemical genetic screen that requires basic resources and can be accomplished by a single individual or small team in an efficient period of time. Thus, this protocol provides a feasible strategy that can be implemented by research groups to perform chemical genetics in zebrafish, which can be useful for gaining fundamental insights into developmental processes, disease mechanisms, and to identify novel compounds and signaling pathways that have medically relevant applications.

Passion for work and emotional exhaustion: the mediating role of rumination and recovery.

The purpose of the present research is to present a model pertaining to the mediating roles of rumination and recovery experiences in the relationship between a harmonious and an obsessive passion (Vallerand et al., 2003) for work and workers' emotional exhaustion. Two populations were measured in the present research: namely elite coaches and nurses. Study 1's model posits that obsessive passion positively predicts rumination about one's work when being physically away from work, while harmonious passion negatively predicts ruminative thoughts. In turn, rumination is expected to positively contribute to emotional exhaustion. The results of Study 1 were replicated in Study 2. In addition, in the model of Study 2, obsessive passion was expected to undermine recovery experiences, while harmonious passion was expected to predict recovery experiences. In turn, recovery experiences were expected to protect workers from emotional exhaustion. Results of both studies provided support for the proposed model. The present findings demonstrate that passion for work may lead to some adaptive and maladaptive psychological processes depending on the type of passion that is prevalent.

Passion for an activity and quality of interpersonal relationships: the mediating role of emotions.

Our purpose in this research was to investigate the role of passion (Vallerand et al., 2003) for a given activity in the quality of interpersonal relationships experienced within the context of that activity in 4 studies. Study 1 demonstrated that a harmonious passion was positively associated with the quality of interpersonal relationships within the context of the passionate activity, whereas an obsessive passion was unrelated to it. Furthermore, in line with the broaden-and-build theory (Fredrickson, 2001), results also showed that positive emotions experienced at work fully mediated the relation between harmonious passion and quality of interpersonal relationships. Obsessive passion was not associated with positive emotions. Study 2 replicated the results from Study 1 while controlling for trait extraversion. Also, in Study 2, we examined the negative mediating role of negative emotions between obsessive passion and quality of interpersonal relationships. Finally, Studies 3 and 4 replicated the results of Study 2 with prospective designs and with objective ratings of interpersonal relationships quality. Implications for the dualistic model of passion and the broaden-and-build theory are discussed.

On the costs and benefits of gaming: the role of passion.

The dualistic model of passion defines passion as a strong inclination toward a self-defining activity that a person likes and values and in which he or she invests time and energy. The model proposes two distinct types of passion: harmonious and obsessive passion that predict adaptive and less adaptive outcomes respectively. In the present research, we were interested in assessing both the negative and positive consequences that can result from gaming. Participants (n = 222) were all players involved in massively multiplayer online games. They completed an online survey. Results from a canonical correlation revealed that both harmonious and obsessive passion were positively associated with the experience of positive affect while playing. However, only obsessive passion was also positively related to the experience of negative affect while playing. In addition, only obsessive passion was positively related to problematic behaviors generally associated with excessive gaming, the amount of time spent playing, and negative physical symptoms. Moreover, obsessive passion was negatively related to self-realization and unrelated to life satisfaction. Conversely, harmonious passion was positively associated with both types of psychological well-being. This general pattern of results suggests that obsessive passion for gaming is an important predictor of the negative outcomes of gaming, while harmonious passion seems to account for positive consequences. Future research directions are discussed in light of the dualistic model of passion.