CDK-Mediated Regulation of Cell Functions via c-Jun Phosphorylation and AP-1 Activation

Cyclin-dependent kinases (CDKs) and their targets have been primarily associated with regulation of cell-cycle progression. Here we identify c-Jun, a transcription factor involved in the regulation of a broad spectrum of cellular functions, as a newly recognized CDK substrate. Using immune cells from mouse and human, and several complementary in vitro and in vivo approaches including dominant negative protein expression, pharmacologic inhibitors, kinase assays and CDK4 deficient cells, we demonstrate the ability of CDK4 to phosphorylate c-Jun. Additionally, the activity of AP-1, a ubiquitous transcription factor containing phosphorylated c-Jun as a subunit, was inhibited by abrogating CDK4. Surprisingly, the regulation of c-Jun phosphorylation by CDK4 occurred in non-dividing cells, indicating that this pathway is utilized for cell functions that are independent of proliferation. Our studies identify a new substrate for CDK4 and suggest a mechanism by which CDKs can regulate multiple cellular activation functions, not all of which are directly associated with cell cycle progression. These findings point to additional roles of CDKs in cell signaling and reveal potential implications for therapeutic manipulations of this kinase pathway

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Paint Failure Studies at Fort Churchill

Peer reviewed: NoNRC publication: Ye

Installations de conditionnement d'air

Quelques-uns des syst\ue8mes communs de conditionnement de l' air sont d\ue9crits en donnant une importance \ue0 leurs possibilit\ue9s et leurs limitations. Le degr\ue9 auquel les sp\ue9 cifications pour le b\ue2timent et ses conditions int\ue9rieures affectent le co\ufbt et la complexit\ue9 du syst\ue8me est discut\ue9.Also available in English: Air conditioning systemsPeer reviewed: NoNRC publication: Ye

Churchill Grain Elevator Settlement Tests

Peer reviewed: NoNRC publication: Ye

Air conditioning processes

The basic processes involved in treating air for comfort air conditioning are discussed. An understanding of these processes is expected to provide an appreciation of the general capabilities and limitations of different processes and to recognize the implications of the conditions specified in a particular building.Aussi disponible en fran\ue7ais : Phases du conditionnement de l'airPeer reviewed: NoNRC publication: Ye

Pressures and Stresses in Sealed Double Glazing Units

A simple method was devised for calculating the pressure differences that occur on sealed double glazing units due to the combined effect of changes in temperature and barometric pressure, and wind loads. The behaviour has been shown to depend on a simple factor related to the size and shape of the unit, the glass thickness, and the thickness of the air space.On a trouv\ue9 une m\ue9thode simple de calcul des diff\ue9rences de pression, se pr\ue9sentant dans les unit\ue9s \ue0 double vitrage scell\ue9, caus\ue9es par l'effet combin\ue9 des changements de temp\ue9 rature et de la pression barom\ue9trique, et les surcharges du vent. D'apr\ue8s les essais en laboratoire, leur comportement d\ue9pend d'un seul facteur li\ue9 aux dimensions et \ue0 la forme de l'unit\ue9, \ue0 l'\ue9paisseur du verre, et \ue0 l'espace d'air.Peer reviewed: NoNRC publication: Ye

Arctic Heat Pump Installation

Peer reviewed: NoNRC publication: Ye