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The final step in Notch signaling activation is the transmembrane cleavage of Notch receptor by γ secretase. Thus far, genetic and biochemical evidence indicates that four subunits are essential for γ secretase activity in vivo: presenilin (the catalytic core), APH-1 , PEN-2 , and APH-2 /nicastrin. Although some γ secretase activity has been detected in APH-2 /nicastrin-deficient mammalian cell lines, the lack of biological relevance for this activity has left the quaternary γ secretase model unchallenged. Here, we provide the first example of in vivo Notch signal transduction without APH-2 /nicastrin. The surprising dispensability of APH-2 /nicastrin is observed in Caenorhabditis elegans germline stem cells (GSCs) and contrasts with its essential role in previously described C. elegans Notch signaling events. Depletion of GLP-1 /Notch, presenilin, APH-1 , or PEN-2 causes a striking loss of GSCs. In contrast, aph-2 /nicastrin mutants maintain GSCs and exhibit robust and localized expression of the downstream Notch target sygl-1. Interestingly, APH-2 /nicastrin is normally expressed in GSCs and becomes essential under conditions of compromised Notch function. Further insight is provided by reconstituting the C. elegans γ secretase complex in yeast, where we find that APH-2 /nicastrin increases but is not essential for γ secretase activity. Together, our results are most consistent with a revised model of γ secretase in which the APH-2 /nicastrin subunit has a modulatory, rather than obligatory role. We propose that a trimeric presenilin-APH-1-PEN-2 γ secretase complex can provide a low level of γ secretase activity, and that cellular context determines whether or not APH-2 /nicastrin is essential for effective Notch signal transduction. [ABSTRACT FROM AUTHOR]

Background: Inclementweather and home environment can act as barriers to physical activity. However, it is unclear if they reduce the activity of persons participating in activity-promoting programs. Methods: Data from a 6-monthworkplace financial incentives program were used to establish the association between meteorologic (temperature, rain, snow, and wind) and geographic factors (urban/nonurban home location and distance between home and work) and moderate to vigorous physical activity (MVPA). Multivariable models were built to estimate mean weekly minutes of MVPA adjusting for demographic factors, clinical factors, and impulsivity. Results: The 292 participants had a mean age of 38 (SD = 11) years. Eighty-three percent were female and 62% were white. Twentynine percent lived within 3miles of work, and 35% lived in urban areas. Participants who lived more than 3miles from work averaged 75 [95% confidence interval (CI), 65-84] minutes of weekly MVPA compared with 105 (95% CI, 88-122) minutes for those who lived within 3 miles of work. Urban participants averaged 70 (95% CI, 57-83) minutes of MVPA compared with 91 (95% CI, 80-102) minutes for nonurban participants. Colder temperatures were associated with decreased MVPA, and impulsivity modified the effect. Conclusions: Colder temperatures, greater distance from work, and an urban residence are associated with fewer minutes of MVPA. [ABSTRACT FROM AUTHOR]

Objective: Diet and exercise (D+E) for knee osteoarthritis (OA) is effective and cost‐effective. However, cost‐effectiveness does not imply affordability; the impact of knee OA–specific D+E programs on insurer budgets is unknown. Methods: We estimated changes in undiscounted medical expenditures (2016 US dollars) with and without a D+E program. We accounted for both additional program outlays and potential savings from reduced use of other knee OA treatments and from reduced incidence of comorbidities. We adopted the perspective of a representative commercial insurance plan covering 200 000 individuals aged 25 to 64 years and a representative Medicare Advantage plan covering 200 000 Medicare‐eligible individuals aged 65 years and older. We used the Osteoarthritis Policy Model, a validated microsimulation model of knee OA, to model D+E efficacy (measured by pain and weight reduction), adherence, and price based on the Intensive Diet and Exercise for Arthritis (IDEA) trial. In sensitivity analyses, we varied time horizon, D+E efficacy, and D+E price. Results: Over 3 years, the D+E program increased spending by $752 200 ($0.10 per member per month [PMPM]) in the commercial plan and by $6.0 million ($0.84 PMPM) in the Medicare plan. Over 3 years, the D+E program reduced opioid use by 6% and 5% and reduced total knee replacements by 5% and 4% in the commercial and Medicare plans, respectively. Expenses were higher in the Medicare plan because it had more patients with knee OA than the commercial plan. Conclusion: Although there is no established threshold to define affordability, a D+E program for knee OA would likely produce expenditures comparable with outlays for other health‐promotion interventions. [ABSTRACT FROM AUTHOR]

Tested response time to alterations. Metric rhythm and harmonic rhythm of 13-note tonal sequences were either matched or mismatched. Metric rhythm (3/4 or 4/4 meter) was induced by dynamic accents. Harmonic rhythm was induced by implied chord progressions initiated on the first note and on either every third or every fourth note. Responses were not always faster for matched rhythms or for alterations occurring on the dynamic accent. Responses were consistently faster for sequences presented in 4/4 meter. Musically untrained Ss performed similarly to trained Ss, but were slower and more variable. Accuracy of recall on a music dictation task also favored 4/4 meter rather than matched rhythms. Coding of pitch content may have been facilitated by the structural framework of 4/4 meter rather than by expectancies arising from the match of temporal and pitch organization.

Background: We designed and implemented the Brigham and Women’s Wellness Initiative (B-Well), a single-arm study to examine the feasibility of a workplace program that used individual and team-based financial incentives to increase physical activity among sedentary hospital employees. Methods: We enrolled sedentary, non-clinician employees of a tertiary medical center who self-reported low physical activity. Eligible participants formed or joined teams of three members and wore Fitbit Flex activity monitors for two pre-intervention weeks followed by 24 weeks during which they could earn monetary rewards. Participants were rewarded for increasing their moderate-to-vigorous physical activity (MVPA) by 10% from the previous week or for meeting the Centers for Disease Control and Prevention (CDC) physical activity guidelines (150 min of MVPA per week). Our primary outcome was the proportion of participants meeting weekly MVPA goals and CDC physical activity guidelines. Secondary outcomes included Fitbit-wear adherence and factors associated with meeting CDC guidelines more consistently. Results: B-Well included 292 hospital employees. Participants had a mean age of 38 years (SD 11), 83% were female, 38% were obese, and 62% were non-Hispanic White. Sixty-three percent of participants wore the Fitbit ≥4 days per week for ≥20 weeks. Two-thirds were satisfied with the B-Well program, with 79% indicating that they would participate again. Eighty-six percent met either their personal weekly goal or CDC physical activity guidelines for at least 6 out of 24 weeks, and 52% met their goals or CDC physical activity guidelines for at least 12 weeks. African Americans, non-obese subjects, and those with lower impulsivity scores reached CDC guidelines more consistently. Conclusions: Our data suggest that a financial incentives-based workplace wellness program can increase MVPA among sedentary employees. These results should be reproduced in a randomized controlled trial. Trial registration Clinicaltrials.gov, NCT02850094. Registered July 27, 2016 [retrospectively registered].

Twenty melodic tone sequences varying in harmonic structure were first presented once each to listeners selected from three different levels of previous musical training. Listeners rated each sequence on a 6-point scale of "pleasingness". Next, 5 sequences from the original set of 20 were each repeated 10 times in a row and rated after each repetition. The 5 sequences were assigned to listeners so that across listeners the 20 original sequences were equally represented. Finally, all 20 sequences were again each presented once for rating. At all levels of musical training, listeners showed a monotonic relationship between "pleasingness" and level of harmonic structure, with highest ratings of "pleasingness" associated with the highest level of structure. During repeated exposures, judged "pleasingness" increased at all levels of harmonic structure except the highest level, where a decrease of "pleasingness" with exposure was obtained. The effects of repetition did not, however, extend to the final ratings of the original set of 20 sequences. The data are discussed with reference to the optimal- complexity model of aesthetic judgement; specific attention is directed toward the cognitive processes determining sequence complexity. [ABSTRACT FROM PUBLISHER]