Le wip concurrent : une proposition de file d'attente du point de vue du produit pour caractériser le temps de cycle

International audienceNous nous intéressons à des modèles de théorie des files d'attente pour caractériser les temps de cycle (délais de fabrication à différentes étapes de production) de produits dans des productions complexes. Des modèles de théorie de file d'attente sont régulièrement utilisés dans l'industrie pour cela, mais en dehors de leurs hypothèses de modélisation. Nous montrons tout d'abord dans cet article l'incidence d'une utilisation de ces modèles hors hypothèses sur la qualité de l'estimation du temps de cycle. Nous proposons alors un nouveau type de représentation des files d'attente, du point de vue des produits et sans hypothèses sur les équipements. Nous montrons sur un cas d'étude réel d'équipements complexes de microélectronique comment cette nouvelle représentation des files d'attente permet, en plus d'une première caractérisation du temps de cycle, d'extraire des informations fondamentales de n'importe quel groupe d'équipements traitant un même flux de produits. Enfin, nous discutons des étapes à venir pour intégrer cette représentation dans des outils de simulation ainsi que dans des modèles totalement génériques de files d'attente

A study of variability induced by events dependency in microelectronic production

-Complex manufacturing systems are subject to high levels of variability that decrease productivity, increase cycle times and severely impact the systems tractability. As accurate modelling of the sources of variability is a cornerstone to intelligent decision making, we investigate the consequences of the assumption of independent and identically distributed variables that is often made when modelling sources of variability such as down-times, arrivals, or process-times. We first explain the experiment setting that allows, through simulations and statistical tests, to measure the variability potential stored in a specific sequence of data. We show from industrial data that dependent behaviors might actually be the rule with potentially considerable consequences in terms of cycle time. As complex industries require strong levers to allow their tractability, this work underlines the need for a richer and more accurate modelling of real systems. Keywords-variability; cycle time; dependent events; simulation; complex manufacturing; industry 4.0 I. Accurate modelling of variability and the independence assumption Industry 4.0 is said to be the next industrial revolution. The proper use of real-time information in complex manufacturing systems is expected to allow more customization of products in highly flexible production factories. Semiconductor High Mix Low Volume (HMLV) manufacturing facilities (called fabs) are one example of candidates for this transition towards "smart industries". However, because of the high levels of variability, the environment of a HMLV fab is highly stochastic and difficult to manage. The uncontrolled variability limits the predictability of the system and thus the ability to meet delivery requirements in terms of volumes, cycle times and due dates. Typically, the HMLV STMicroelectronics Crolles 300 fab regularly experiences significant mix changes that result in unanticipated bottlenecks, leading to firefighting to meet commitment to customers. The overarching goal of our strategy is to improve the forecasting of future occurrences of bottlenecks and cycle time issues in order to anticipate them through allocation of the correct attention and resources. Our current finite capacity projection engine can effectively forecast bottlenecks, but it does not include reliable cycle time estimates. In order to enhance our projections, better forecast cycle time losses (queuing times), improve the tractability of our system and reduce our cycle times, we now need accurate dynamic cycle time predictions. As increased cycle-time is the main reason workflow variability is studied (both by the scientific community and practitioners, see e.g. [1] and [2]), what follows concentrates on cycle times. Moreover, the "variability" we account for should be understood as the potential to create higher cycle times, even though "variability" may be understood in a broader meaning. This choice is made for the sake of clarity, but the methodology we propose and the discussion we lead can be applied to any other measurable indicator. Sources of variability have been intensely investigated in both the literature and the industry, and tool down-times, arrivals variability as well as process-time variability are recognized as the major sources of variability in that sense that they create higher cycle times (see [3] for a review and discussion). As a consequence, these factors are widely integrated into queuing formulas and simulation models with the objective to better model the complex reality of manufacturing facilities. One commonly accepted assumption in the development of these models is that the variables (MTBF, MTTR, processing times, time between arrivals, etc.) are independent and identically distributed (i.i.d.) random variables. However, these assumptions might be the reason for models inaccuracies as [4] points out in a literature review on queuing theory. Several authors have studied the potential effects of dependencies, such as [5] who studied the potential effects of dependencies between arrivals and process-times or [6] who investigated dependent process times, [4] also gives further references for studies on dependencies effects. In a previous work [3], we pinpointed a few elements from industrial data that questioned the viability of this assumption in complex manufacturing systems. Figure 1: Number of arrivals per week from real data (A) and generated by removing dependencies (B)Comment: International Conference on Industrial Engineering and Systems Management, Oct 2017, Saarebr{\"u}cke, German

Synthesis of Two New Group 13 Benzoato-Chloro Complexes: A Structural Study of Gallium and Indium Chelating Carboxylates

Two new heteroleptic chelated-benzoato gallium (III) and indium (III) complexes have been prepared and structurally characterized. The molecular structures of [GaCl2(4-Mepy)2(O2CPh)]4-Mepy (1) and [InCl(4-Mepy)2(O2CPh)2]4-Mepy (2) have been determined by single-crystal x-ray diffraction. The gallium compound (1) is a distorted octahedron with cis-chloride ligands co-planar with the chelating benzoate and the 4-methylpyridines trans to each other. This is the first example of a Ga(III) structure with a chelating benzoate. The indium compound (2) is a distorted pentagonal bipyramid with two chelating benzoates, one 4-methylpyridine in the plane and a chloride trans to the other 4-methylpyridine. The indium bis-benzoate is an unusual example of a seven-coordinate structure with classical ligands. Both complexes, which due to the chelates, could also be described as pseudo-trigonal bipyramidal, include a three-bladed motif with three roughly parallel aromatic rings that along with a solvent of crystallization and electron-withdrawing chloride ligand(s) stabilize the solid-state structures

Discovery of progenitor cell signatures by time-series synexpression analysis during Drosophila embryonic cell immortalization

The use of time series profiling to identify groups of functionally related genes (synexpression groups) is a powerful approach for the discovery of gene function. Here we apply this strategy during RasV12 immortalization of Drosophila embryonic cells, a phenomenon not well characterized. Using high-resolution transcriptional time-series datasets, we generated a gene network based on temporal expression profile similarities. This analysis revealed that common immortalized cells are related to adult muscle precursors (AMPs), a stem cell-like population contributing to adult muscles and sharing properties with vertebrate satellite cells. Remarkably, the immortalized cells retained the capacity for myogenic differentiation when treated with the steroid hormone ecdysone. Further, we validated in vivo the transcription factor CG9650, the ortholog of mammalian Bcl11a/b, as a regulator of AMP proliferation predicted by our analysis. Our study demonstrates the power of time series synexpression analysis to characterize Drosophila embryonic progenitor lines and identify stem/progenitor cell regulators

Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma

The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer. Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric randomized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy. The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone. Three cycles of chemotherapy consisting of Cisplatin (100 mg/m2) on day 1 followed by a 24-hour i.v. infusion of fluorouracil (1000 mg/m2/day) for 5 days were delivered every 21 days. 2–3 weeks after the end of chemotherapy, local treatment was performed. The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou (GETTEC). A total of 318 patients were enrolled in the study between 1986 and 1992. Overall survival was significantly better (P = 0.03) in the neoadjuvant chemotherapy group than in the control group, with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group. The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance (P = 0.11). Stratification of the results on the type of local treatment, surgery plus radiotherapy or radiotherapy alone, did not reveal any heterogeneity in the effect of chemotherapy. © 2000 Cancer Research Campaign http://www.bjcancer.co

From segment to somite: segmentation to epithelialization analyzed within quantitative frameworks

One of the most visually striking patterns in the early developing embryo is somite segmentation. Somites form as repeated, periodic structures in pairs along nearly the entire caudal vertebrate axis. The morphological process involves short- and long-range signals that drive cell rearrangements and cell shaping to create discrete, epithelialized segments. Key to developing novel strategies to prevent somite birth defects that involve axial bone and skeletal muscle development is understanding how the molecular choreography is coordinated across multiple spatial scales and in a repeating temporal manner. Mathematical models have emerged as useful tools to integrate spatiotemporal data and simulate model mechanisms to provide unique insights into somite pattern formation. In this short review, we present two quantitative frameworks that address the morphogenesis from segment to somite and discuss recent data of segmentation and epithelialization

From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm

The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice

Turn it down a notch

In the developing vertebrate embryo, segmentation initiates through the formation of repeated segments, or somites, on either side of the posterior neural tube along the anterior to posterior axis. The periodicity of somitogenesis is regulated by a molecular oscillator, the segmentation clock, driving cyclic gene expression in the unsegmented paraxial mesoderm, from which somites derive. Three signaling pathways underlie the molecular mechanism of the oscillator: Wnt, FGF, and Notch. In particular, Notch has been demonstrated to be an essential piece in the intricate somitogenesis regulation puzzle. Notch is required to synchronize oscillations between neighboring cells, and is moreover necessary for somite formation and clock gene oscillations. Following ligand activation, the Notch receptor is cleaved to liberate the active intracellular domain (NICD) and during somitogenesis NICD itself is produced and degraded in a cyclical manner, requiring tightly regulated, and coordinated turnover. It was recently shown that the pace of the segmentation clock is exquisitely sensitive to levels/stability of NICD. In this review, we focus on what is known about the mechanisms regulating NICD turnover, crucial to the activity of the pathway in all developmental contexts. To date, the regulation of NICD stability has been attributed to phosphorylation of the PEST domain which serves to recruit the SCF/Sel10/FBXW7 E3 ubiquitin ligase complex involved in NICD turnover. We will describe the pathophysiological relevance of NICD-FBXW7 interaction, whose defects have been linked to leukemia and a variety of solid cancers

Dynamic 3D Cell Rearrangements Guided by a Fibronectin Matrix Underlie Somitogenesis

Somites are transient segments formed in a rostro-caudal progression during vertebrate development. In chick embryos, segmentation of a new pair of somites occurs every 90 minutes and involves a mesenchyme-to-epithelium transition of cells from the presomitic mesoderm. Little is known about the cellular rearrangements involved, and, although it is known that the fibronectin extracellular matrix is required, its actual role remains elusive. Using 3D and 4D imaging of somite formation we discovered that somitogenesis consists of a complex choreography of individual cell movements. Epithelialization starts medially with the formation of a transient epithelium of cuboidal cells, followed by cell elongation and reorganization into a pseudostratified epithelium of spindle-shaped epitheloid cells. Mesenchymal cells are then recruited to this medial epithelium through accretion, a phenomenon that spreads to all sides, except the lateral side of the forming somite, which epithelializes by cell elongation and intercalation. Surprisingly, an important contribution to the somite epithelium also comes from the continuous egression of mesenchymal cells from the core into the epithelium via its apical side. Inhibition of fibronectin matrix assembly first slows down the rate, and then halts somite formation, without affecting pseudopodial activity or cell body movements. Rather, cell elongation, centripetal alignment, N-cadherin polarization and egression are impaired, showing that the fibronectin matrix plays a role in polarizing and guiding the exploratory behavior of somitic cells. To our knowledge, this is the first 4D in vivo recording of a full mesenchyme-to-epithelium transition. This approach brought new insights into this event and highlighted the importance of the extracellular matrix as a guiding cue during morphogenesis