The endocycle represents an alternative cell cycle that is activated in various developmental processes, including placental formation, Drosophila oogenesis, and leaf development. In endocycling cells, mitotic cell cycle exit is followed by successive doublings of the DNA content, resulting in polyploidy. The timing of endocycle onset is crucial for correct development, because polyploidization is linked with cessation of cell division and initiation of terminal differentiation. The anaphase-promoting complex/cyclosome (APC/C) activator genes CDH1, FZR, and CCS52 are known to promote endocycle onset in human, Drosophila, and Medicago species cells, respectively; however, the genetic pathways governing development-dependent APC/C CDH1/FZR/CCS52 activity remain unknown. We report that the atypical E2F transcription factor E2Fe/DEL1 controls the expression of the CDH1/FZR orthologous CCS52A2 gene from Arabidopsis thaliana. E2Fe/DEL1 misregulation resulted in untimely CCS52A2 transcription, affecting the timing of endocycle onset. Correspondingly, ectopic CCS52A2 expression drove cells into the endocycle prematurely. Dynamic simulation illustrated that E2Fe/DEL1 accounted for the onset of the endocycle by regulating the temporal expression of CCS52A2 during the cell cycle in a development-dependent manner. Analogously, the atypical mammalian E2F7 protein was associated with the promoter of the APC/C-activating CDH1 gene, indicating that the transcriptional control of APC/C activator genes by atypical E2Fs might be evolutionarily conserved.D uring the mitotic cell cycle, DNA that is duplicated during the S phase is divided at the M phase, so that each daughter cell produced has a genomic DNA content equal to that of its parents. In contrast, during the endoreduplication cycle, no cytokinesis occurs between rounds of DNA replication, resulting in successive doublings of the DNA ploidy level. This process occurs in a wide variety of cell types in arthropods and mammals and is particularly prominent in dicotyledonous plants (1), especially in species with a small genome and a short life cycle, in which repetitive DNA replication might support growth under conditions that require rapid development (2, 3).Mitotic cell cycle progression and endoreduplication are linked events. Premature or delayed exit from the cell division program results in an increased or decreased DNA ploidy, respectively (4-10). Therefore, the onset of endoreduplication must be controlled precisely. At the molecular level, endoreduplication is likely achieved through elimination of the components needed to progress through mitosis (11). Predominant roles in this process are played by the anaphase-promoting complex/cyclosome (APC/C) activator genes, such as CDH1, FZR, and CCS52A, which have been found to promote endocycle onset and progression in human, Drososphila melanogaster, and Medicago truncatula cells, respectively (12-17). The mechanisms controlling the transcriptional activity of these genes remain unclear, however.Over the years, it has beco...
A recent application field of bifurcation theory is in modelling the cell cycle. We refer in particular to the work of J.J. Tyson and B. Novak where the fundamental idea is that the cell cycle is an alternation between two stable steady states of a system of kinetic equations. We study and extend the basic model of Tyson and Novak using the Matlab numerical bifurcation software MatCont, in a two-parameter setting and highlight several new features. We show that the limit point curves in the two-variable model behave in an ungeneric way under variation of the natural parameters and that the hysteresis loop in the model is not the usual loop caused by the existence of a codimension-2 cusp point. We continue orbits homoclinic-to-saddle-node (HSN) in the three-variable model and find that these orbits die in a non-central orbit homoclinic-to-saddle-node under a natural parameter variation. As an extension we introduce a model in which cell division appears as a continuous-in-time limit cycle. We perform a continuation of this limit cycle under a natural parameter variation and show that it loses stability in a limit point of cycles bifurcation. Alternatively, we study the cell cycle as a boundary value problem as proposed by Tyson and Novak. This leads to an interpretation of the cell as a slow-fast system and we derive several conclusions on the relation between the growth rate of the cells and the cell size at division, and on the controllability of the process.
Introduction Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1 in development for the induction and maintenance of clinical remission in patients with ulcerative colitis (UC). This study aimed to assess the long-term pharmacokinetics (PK) of ontamalimab in patients with UC, and the effects of concomitant medications on PK parameters. Methods A 12-week induction study (TURANDOT; NCT01620255) was performed to assess the PK, efficacy and safety of ontamalimab (7.5, 22.5, 75 and 225 mg subcutaneous [s.c.] every four weeks [Q4W]) in patients with UC. Individuals who completed the induction study were eligible for enrollment in an open-label extension (OLE) study (TURANDOT II; NCT01771809) to assess the long-term PK, efficacy and safety of ontamalimab (75 or 225 mg s.c. Q4W up to week 72). Population PK analyses were performed using nonlinear mixed-effects modelling. Exposure-response analyses were performed to assess the relationships between minimum concentration (Cmin,ss) of ontamalimab and clinical response, clinical remission and mucosal healing. The effect of concomitant treatments (used for ≥20% of treatment duration) on PK parameters was also evaluated. Results The PK population included 130 (39.8%) women and 197 (60.2%) men, of median age of 40 years. A 1-compartment model with linear elimination adequately described the PK of ontamalimab. Population estimates of apparent clearance (CL/F) and volume of distribution (V/F) were 0.00917 L/h (0.22 L/day) and 7.44 L, respectively. Albumin had a significant effect on the variability of CL/F. Individuals with albumin levels of 30 g/L and 47 g/L are expected to have CL/F values 44% higher and 23% lower, respectively, than a typical patient with an albumin level of 39 g/L. Anti-inflammatory agents affected CL/F, such that CL/F is expected to be 14% higher in patients receiving than not receiving these agents. Other medications including immunosuppressants, steroids and treatments for peptic ulcers and gastroesophageal reflux disease had no effect on CL/F. Weight was the only covariate that significantly affected V/F. The half-life of ontamalimab was 23.4 days. Concentrations of ontamalimab over 72 weeks in the OLE study were consistent with those observed in the 12-week induction study. Ontamalimab Cmin,ss was related to efficacy, such that at week 16 (week 28 in total including induction), patients with higher Cmin,ss values were more likely to have clinical response, clinical remission and mucosal healing than those with lower Cmin,ss. Conclusion The exposure to ontamalimab was sustained following prolonged treatment in patients with UC for up to 72 weeks. Higher ontamalimab exposure was associated with a higher probability of clinical response.
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