Entrainment of the Mammalian Cell Cycle by the Circadian Clock: Modeling Two Coupled Cellular Rhythms

The cell division cycle and the circadian clock represent two major cellular rhythms. These two periodic processes are coupled in multiple ways, given that several molecular components of the cell cycle network are controlled in a circadian manner. For example, in the network of cyclin-dependent kinases (Cdks) that governs progression along the successive phases of the cell cycle, the synthesis of the kinase Wee1, which inhibits the G2/M transition, is enhanced by the complex CLOCK-BMAL1 that plays a central role in the circadian clock network. Another component of the latter network, REV-ERBα, inhibits the synthesis of the Cdk inhibitor p21. Moreover, the synthesis of the oncogene c-Myc, which promotes G1 cyclin synthesis, is repressed by CLOCK-BMAL1. Using detailed computational models for the two networks we investigate the conditions in which the mammalian cell cycle can be entrained by the circadian clock. We show that the cell cycle can be brought to oscillate at a period of 24 h or 48 h when its autonomous period prior to coupling is in an appropriate range. The model indicates that the combination of multiple modes of coupling does not necessarily facilitate entrainment of the cell cycle by the circadian clock. Entrainment can also occur as a result of circadian variations in the level of a growth factor controlling entry into G1. Outside the range of entrainment, the coupling to the circadian clock may lead to disconnected oscillations in the cell cycle and the circadian system, or to complex oscillatory dynamics of the cell cycle in the form of endoreplication, complex periodic oscillations or chaos. The model predicts that the transition from entrainment to 24 h or 48 h might occur when the strength of coupling to the circadian clock or the level of growth factor decrease below critical values

Mechanisms of seawater acclimation in a primitive, anadromous fish, the green sturgeon

Relatively little is known about salinity acclimation in the primitive groups of fishes. To test whether physiological preparative changes occur and to investigate the mechanisms of salinity acclimation, anadromous green sturgeon, Acipenser medirostris (Chondrostei) of three different ages (100, 170, and 533 dph) were acclimated for 7 weeks to three different salinities (<3, 10, and 33 ppt). Gill, kidney, pyloric caeca, and spiral intestine tissues were assayed for Na+, K+-ATPase activity; and gills were analyzed for mitochondria-rich cell (MRC) size, abundance, localization and Na+, K+-ATPase content. Kidneys were analyzed for Na+, K+-ATPase localization and the gastro-intestinal tract (GIT) was assessed for changes in ion and base content. Na+, K+-ATPase activities increased in the gills and decreased in the kidneys with increasing salinity. Gill MRCs increased in size and decreased in relative abundance with fish size/age. Gill MRC Na+, K+-ATPase content (e.g., ion-pumping capacity) was proportional to MRC size, indicating greater abilities to regulate ions with size/age. Developmental/ontogenetic changes were seen in the rapid increases in gill MRC size and lamellar length between 100 and 170 dph. Na+, K+-ATPase activities increased fourfold in the pyloric caeca in 33 ppt, presumably due to increased salt and water absorption as indicated by GIT fluids, solids, and ion concentrations. In contrast to teleosts, a greater proportion of base (HCO3− and 2CO32−) was found in intestinal precipitates than fluids. Green sturgeon osmo- and ionoregulate with similar mechanisms to more-derived teleosts, indicating the importance of these mechanisms during the evolution of fishes, although salinity acclimation may be more dependent on body size

Impact of obstetrics and gynecology resident workload and protected time interventions on well being

Background: Between 22% and 60% of practicing physicians are reported to have experienced burnout, with OB/GYN resident burnout having been reported at 90%. Duty-hour limitations were implemented for patient safety and have been associated with some increase in overall resident quality of life and potential sacrifices in resident education and patient care. Contributors to burnout (and drivers of engagement) include workload and job demands, lack of control and flexibility over personal schedule and workload, poor work-life integration, and numerous check box requirements (filling out surveys, module requirements, duplicates, paperwork). Purpose: To improve well-being and decrease burnout among OB/ GYN residents by implementing workload changes and protected time for wellness. Methods: Effective July 2017, we changed 3 resident workload protocols. 1) For weekend rounding, residents continue to round on all antepartum and gynecology patients at the end of each 24-hour shift, but faculty became responsible for completing all postpartum rounding. 2) Weekday postpartum rounding was redistributed, and the number of patients decreased from \u3e10 to maximum of 6–7 patients per junior resident. 3) No resident service obligations on Sundays with 2 months with no residents on night float. Quarterly wellness mornings began in September 2017, using protected education time for residents. We measured pre/post changes in well-being through a brief well-being check in card (WBCIC) and Mayo Well-Being Index (MWBI). Results: Resident response rates ranged from 10 to 12. WBCIC baseline (September 2017), midintervention (May 2018), and postintervention (December 2018) scores on item “Time spent on wellbeing” improved from 1.6 to 2.1 to 2.3 (scale: 1=pitiful to 4=excellent). The item “The work I do is meaningful to me” began at 4.9, then remained constant at 5.2 (scale: 1=strongly disagree to 7=strongly agree). The MWBI identifies those at risk of adverse outcomes due to poor quality of life, burnout, and suicidal ideation if their score is \u3e5. MWBI scores remained more than 1.2 points below the 5.0 cutoff, ranging from 1.2 to 1.8 during report period with seasonal variation (residents were less well in winter). Wellness mornings were most frequently used for sleep, connecting with family/ friends/other residents, exercise, and personal health appointment. Conclusion: The workload interventions were associated with a positive trend in overall well-being and finding meaning in work, making progress towards our goal of creating a workplace dynamic where burnout is combated and well-being is promoted

Mapping “Brain Terrain” Regions on Mars Using Deep Learning

One of the main objectives of the Mars Exploration Program is to search for evidence of past or current life on the planet. To achieve this, Mars exploration has been focusing on regions that may have liquid or frozen water. A set of critical areas may have seen cycles of ice thawing in the relatively recent past in response to periodic changes in the obliquity of Mars. In this work, we use convolutional neural networks to detect surface regions containing “brain terrain,” a landform on Mars whose similarity in morphology and scale to sorted stone circles on Earth suggests that it may have formed as a consequence of freeze/thaw cycles. We use large images (∼100–1000 megapixels) from the Mars Reconnaissance Orbiter to search for these landforms at resolutions close to a few tens of centimeters per pixel (∼25–50 cm). Over 58,000 images (∼28 TB) were searched (∼5% of the Martian surface), and we found detections in 201 images. To expedite the processing, we leverage a classifier network (prior to segmentation) in the Fourier domain that can take advantage of JPEG compression by leveraging blocks of coefficients from a discrete cosine transform in lieu of decoding the entire image at the full spatial resolution. The hybrid pipeline approach maintains ∼93% accuracy while cutting down on ∼95% of the total processing time compared to running the segmentation network at the full resolution on every image

Using prophylactic antihemorrhagic medications in second-trimester surgical abortions

We aimed to estimate the association of prophylactic antihemorrhagic medication use during dilation and evacuation (D&E) with operative hemorrhage and estimated blood loss (EBL). Records for all pregnant patients between 14 and less than 22 weeks of gestation who had a D&E procedure from January 2012 to December 2019 were retrospectively reviewed. Prophylactic antihemorrhagic medication use was defined as receiving vasoconstrictors, uterotonics, or both before identification of hemorrhage during a D&E procedure. Overall, 147 D&E procedures were completed at a mean of 16.4 (±2.2) weeks of gestation. Prophylactic medications were used in 72.1% (n=106) of D&E procedures. Prophylactic medication use was associated with lower operative hemorrhage (21.7% vs 51.2%, P \u3c .01) and lower EBL (336.9 mL vs 551.3 mL, P \u3c .01)

An automaton model for the cell cycle

We consider an automaton model that progresses spontaneously through the four successive phases of the cell cycle: G1, S (DNA replication), G2 and M (mitosis). Each phase is characterized by a mean duration τ and a variability V. As soon as the prescribed duration of a given phase has passed, the transition to the next phase of the cell cycle occurs. The time at which the transition takes place varies in a random manner according to a distribution of durations of the cell cycle phases. Upon completion of the M phase, the cell divides into two cells, which immediately enter a new cycle in G1. The duration of each phase is reinitialized for the two newborn cells. At each time step in any phase of the cycle, the cell has a certain probability to be marked for exiting the cycle and dying at the nearest G1/S or G2/M transition. To allow for homeostasis, which corresponds to maintenance of the total cell number, we assume that cell death counterbalances cell replication at mitosis. In studying the dynamics of this automaton model, we examine the effect of factors such as the mean durations of the cell cycle phases and their variability, the type of distribution of the durations, the number of cells, the regulation of the cell population size and the independence of steady-state proportions of cells in each phase with respect to initial conditions. We apply the stochastic automaton model for the cell cycle to the progressive desynchronization of cell populations and to their entrainment by the circadian clock. A simple deterministic model leads to the same steady-state proportions of cells in the four phases of the cell cycle