A digital twin reproducing gene regulatory network dynamics of early Ciona embryos indicates robust buffers in the network

How gene regulatory networks (GRNs) encode gene expression dynamics and how GRNs evolve are not well understood, although these problems have been studied extensively. We created a digital twin that accurately reproduces expression dynamics of 13 genes that initiate expression in 32-cell ascidian embryos. We first showed that gene expression patterns can be manipulated according to predictions by this digital model. Next, to simulate GRN rewiring, we changed regulatory functions that represented their regulatory mechanisms in the digital twin, and found that in 55 of 100 cases, removal of a single regulator from a conjunctive clause of Boolean functions did not theoretically alter qualitative expression patterns of these genes. In other words, we found that more than half the regulators gave theoretically redundant temporal or spatial information to target genes. We experimentally substantiated that the expression pattern of Nodal was maintained without one of these factors, Zfpm, by changing the upstream regulatory sequence of Nodal. Such robust buffers of regulatory mechanisms may provide a basis of enabling developmental system drift, or rewiring of GRNs without changing expression patterns of downstream genes, during evolution

Characterization of Fasting-Induced p21 Expression and Protection of Intestinal Stem Cells

The cyclin dependent kinase inhibitor, p21, plays a key role in cell cycle. Additionally, the p21 gene, Cdkn1a (hereafter p21) is often used as a marker of cellular stress. To investigate p21 promoter activity under basal conditions and in response to various forms of stress, we generated knock-in imaging reporter mice that express firefly luciferase (FLuc) under the control of the endogenous p21 promoter. I demonstrated that FLuc expression and bioluminescence detection mirrored endogenous p21 protein levels and promoter activity in vivo. Contrary to previously known roles for p53-mediate expression of p21, imaging of reporter cells demonstrated that p53 prevented the ERK/MAPK pathway from activating p21 expression when quiescent cells were stimulated with serum to re-enter the cell cycle. In addition, low light bioluminescence imaging identified p21 expression in specific regions of individual organs that were not previously observed including the paraventricular, arcuate and dorsomedial nuclei of the hypothalamus - regions that detect nutrient levels in the blood stream and regulate metabolism throughout the body. These results suggested a link between p21 expression and metabolic regulation. I found that food deprivation (fasting) potently induced p21 expression in tissues involved in metabolic regulation, including liver, pancreas, and hypothalamic nuclei. The ability of fasting to induce p21 expression was found to be independent of p53, but dependent on the transcription factor FOXO1, which was bound to the p21 promoter region only in fasted mice. Previous work has shown that short-term fasting protects mice from what would normally be lethal doses of etoposide. I hypothesized that p21 may be involved in this protection, as p21 expression increased in response to both fasting and DNA damage. I demonstrated that fasting prior to a high dose of etoposide treatment enhanced survival by protecting small intestinal stem cells, but that p21 was not required for this protection. While high dose etoposide treatment caused complete destruction of the crypt-villus architecture and near complete loss of small intestinal stem cells in free-feeding mice, fasting prior to etoposide treatment enabled stem cell survival and subsequent reconstitution of the small intestinal crypts and villi. Using LacZ reporter mice and lineage tracing, I found that both crypt base columnar (CBC) and +4 stem cells contributed to crypt restoration in the fasted mice. Though etoposide in fed and fasted mice induced similar amounts of DNA double strand breaks (DSBs) immediately following treatment, resolution of DNA DSBs, as measured by loss of γH2AX staining, occurred more quickly in stem cells of fasted mice compared to those of fed mice

PURITY AND GORENSTEIN FILTERED RINGS

In this paper, we discuss on the existence of filtrations of modules having good properties. In particular, we focus on filtered homomorphisms called strict, and show that there exists a filtration which makes a filtered homomorphism a strict filtered homomorphism. Moreover, by using this result, we study purity for filtered modules over a Gorenstein filtered ring

La manutenzione programmata negli impianti di produzione industriale

In questo lavoro di tesi si espongono i lavori eseguiti un progetto di stage e sono i seguenti: le basi della manutenzione programmata,si descrivono le procedure di ristrutturazione del bill of material di ogni macchina di produzione attraverso l'utilizzo di due gestionali aziendali: Axalant e SAP. Infine descrizione dell'implementazione di un software di gestione degli ordini di manutenzione

Effective action approach to dynamical generation of fermion mixing

In this paper we discuss a mechanism for the dynamical generation of flavor mixing, in the framework of the Nambu--Jona Lasinio model. Our approach is illustrated both with the conventional operatorial formalism and with functional integral and ensuing one-loop effective action. The results obtained are briefly discussed.Comment: arXiv admin note: text overlap with arXiv:1312.492

A Zariski Topology for Modules

Given a duo module $M$ over an associative (not necessarily commutative) ring $R,$ a Zariski topology is defined on the spectrum $\mathrm{Spec}^{\mathrm{fp}}(M)$ of {\it fully prime} $R$-submodules of $M$. We investigate, in particular, the interplay between the properties of this space and the algebraic properties of the module under consideration.Comment: 22 pages; submitte

Multi-objective global optimization for hydrologic models

The development of automated (computer-based) calibration methods has focused mainly on the selection of a single-objective measure of the distance between the model-simulated output and the data and the selection of an automatic optimization algorithm to search for the parameter values which minimize that distance. However, practical experience with model calibration suggests that no single-objective function is adequate to measure the ways in which the model fails to match the important characteristics of the observed data. Given that some of the latest hydrologic models simulate several of the watershed output fluxes (e.g. water, energy, chemical constituents, etc.), there is a need for effective and efficient multi-objective calibration procedures capable of exploiting all of the useful information about the physical system contained in the measurement data time series. The MOCOM-UA algorithm, an effective and efficient methodology for solving the multiple-objective global optimization problem, is presented in this paper. The method is an extension of the successful SCE-UA single-objective global optimization algorithm. The features and capabilities of MOCOM-UA are illustrated by means of a simple hydrologic model calibration study

Fetal hemoglobin induction in azacytidine responders enlightens methylation patterns related to blast clearance in higher-risk MDS and CMML

Background: As new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine-treated patients. Although epigenetic mechanisms are assumed, responding patients’ epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance. Results: Serial HbF measurements by high-performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.030). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression-free survival (PFS) (p = 0.032, HR = 0.19, CI 0.24–1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD-complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, rs = − 0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site -53 of HBG2 promoter (p = 0.039, rs = − 0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, rs = 0.482), a known HbF repressor. These changes were associated to blast cell clearance (pHBG2 = 0.011, rs = 0.480/pZBTB7A = 0.026, rs = 0.427) and showed prognostic value for PFS (pZBTB7A = 0.037, HR = 1.14, CI 0.34–3.8). Conclusions: Early HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in-depth azacytidine epigenetic mechanism of action. Graphical abstract: (Figure presented.)</p