Consignment Inventory Optimization at Ethicon, a Johnson & Johnson franchise

The global economic slowdown and the current low growth period has forced companies to reduce their costs wherever they could. As one of the world's largest pharmaceutical, consumer product and medical device manufacturer, Johnson & Johnson follows a strategy that allows them to maintain reasonable prices while facing higher costs. Storage cost and Inventory management are some of them. This paper will focus on consignment stock and has two aims : the first one is to create a tool that will give stock visibility at a client level (to see where the inefficiencies are) and the second on is to optimize the inventory levels at the customer's facilities. The tool and the analysis of this paper have shown that there are many opportunities in different EMEA countries such as in Italy where a potential consignment stock (for Ethicon Endo-Surgery products) reduction of XX.X% can be made by optimizing stock management.Master [120] en Ingénieur de gestion, Université catholique de Louvain, 201

Homéostasie mécanique des épithéliums (rôle de la dynamique du cytosquelette et des jonctions adhérentes)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

NEW INSIGHTS INTO THE REGULATION OF E-CADHERIN DISTRIBUTION BY ENDOCYTOSIS

Homeostasis of adherens junctions is achieved through complex regulatory mechanisms. The junctions are highly dynamic in contact establishment, in remodeling events during development, and during processes involving a loss of adhesion like epithelial mesenchyme transition. It appeared recently that they are also dynamically renewed in mature, steady-state adhesions. Indeed, maintenance of a steady state must be integrated into a tight control of force equilibrium between a cell and its neighbors. Therefore, it appears that E-cadherin dynamics allows to respond constantly to various biochemical and mechanical stimuli and to regulate the movement and shape of junctions in active remodeling processes. E-cadherin dynamics is mediated through several mechanisms (diffusion, trafficking) in function of the biological system. In mature junctions, membrane E-cadherin is quickly renewed by endocytosis in many cell types. E-cadherin endocytosis shows a complex regulation, depending on small G proteins, ubiquitination, cleavage events, actomyosin cytoskeleton, and other trans molecules in adherens junctions. It is modulated by growth factor stimulations and physical factors. Consequently, E-cadherin endocytosis tightly controls a number of functional processes: cell movements, junction maintenance, cell sorting, and polarity. Misregulated E-cadherin endocytosis is involved in many diseases, from cancerous processes to organogenesis defects

MULTI-RESOLUTION BASED SPATIALLY ADAPTIVE MULTI-ORDER TOTAL VARIATION FOR IMAGE RESTORATION

We propose a novel total variation based image restoration method that combines first and second order total variation functionals in a structurally adaptive manner. Specifically, as opposed to recent practical combined order methods, which choose the relative weight between the functionals of different derivative orders as a global scalar parameter, we construct a functional that uses a spatially varying relative weight between functionals of different orders so as to adapt to the local image structure. Further, as opposed to known combined order methods which leave the relative weight as a user parameter, the proposed method automatically computes the relative weight using a novel multi-resolution based formulation. The proposed spatially adaptive combined order TV (SAMTV) performs better than the state of art total generalized variation (TGV) method in experiments

Endocytosis is required for E-cadherin redistribution at mature adherens junctions

E-cadherin plays a key role at adherens junctions between epithelial cells, but the mechanisms controlling its assembly, maintenance, and dissociation from junctions remain poorly understood. In particular, it is not known to what extent the number of E-cadherins engaged at junctions is regulated by endocytosis, or by dissociation of adhesive bonds and redistribution within the membrane from a pool of diffusive cadherins. To determine whether cadherin levels at mature junctions are regulated by endocytosis or dissociation and membrane diffusion, the dynamics of E-cadherin were quantitatively analyzed by a new approach combining 2-photon fluorescence recovery after photobleaching (FRAP) and fast 3D wide-field fluorescence microscopy. Image analysis of fluorescence recovery indicates that most E-cadherin did not diffuse in the membrane along mature junctions, but followed a first order turn-over process that was rate-limited by endocytosis. In confluent cultures of MCF7 or MDCK cells, stably expressed EGFP-E-cadherin was rapidly recycled with spatially uniform kinetics (50 s in MCF7 and 4 min in MDCK). In addition, when endocytosis was pharmacologically blocked by dynasore or MiTMAB, no fluorescence recovery was observed, suggesting that no endocytosis-independent membrane redistribution was occurring. Our data show that membrane redistribution of E-cadherin molecules engaged in mature junctions requires endocytosis and subsequent exocytosis, and lead to the notion that E-cadherins engaged at junctions do not directly revert to free membrane diffusion. Our results point to the possibility that a direct mechanical coupling between endocytosis efficiency and cadherin-mediated forces at junctions could help to regulate intercellular adhesion and locally stabilize epithelia

E-cadherin turnover rates vary in space and fluctuate in time.

<p>(A) Distribution of turnover rates (k_off) of E-cadherin-GFP measured by FRAP at diffraction-limited spots at different junctions across a confluent layer of MDCK cells. For each junction (N = 41) the individual fluorescence recovery curve was fit with an exponential relaxation. The solid curve shows a gaussian fit (average rate 4.8 10^-3 s^-1 and standard deviation 2.5 10^–3 s^-1) of the distribution of the 34 non-outlying values. (B) At each single spot, the turnover rate was measured twice (#1 and #2) with a 45 minutes time interval. (C) For each spot, the temporal variation of the turnover rate is assessed by the ratio of the successive measurements k_off#2/ k_off#1 (iterative FRAP, left panel, red circles). This ensemble of ratios was compared to the similar ensemble obtained after a random permutation of the rates within the first set (#1) (rand. perm., blue squares). Rates were also compared within matched pairs of spots belonging to two different AJs of the same cell (right panel): ratios for matched pairs (green diamonds) were compared to mismatched pairs (random permutations of values, black crosses). No significant correlations were found between rates, neither in time when sampled across a 45 minutes interval, or in space within single cells.</p

E-cadherin turnover rates increase with intercellular tension.

<p>(A-a) A perpendicular force was applied on individual junctions by pulling on the apical surface with a glass micro-pipette. The junctions were then clamped at a stable position approximately 0.5 μm away from the initial one. (A-b) Typical overlay image of a cell before (gray) and after traction (red), with the micro-pipette (dashed line) and the force vector (arrow). Scale bar: 10 μm. (B) FRAP was achieved on MDCK cells expressing E-cadherin-GFP, giving for each AJ a pair of rates (k_off) before (red dots) and after (blue squares) traction (N = 12). (C) For each rate pair, the ratio k_{off "after"}/ k_{off "before"} is shown (blue squares), and compared to control experiments without traction (red dots). Turnover rates increased after tension was applied in all (N = 11) but one case (red line in B).</p

E-cadherin endocytosis rates match across individual unperturbed AJs.

<p>Endocytosis rates of E-cadherin were measured using dual-color FRAP on mature heterochromatic AJs between MDCK cells expressing either E-cadherin-GFP or E-cadherin-DsRed (A, arrows in B). Kinetics were recorded simultaneously but resolved separately on each side of a same junction (A insert). Each measurement led to a pair of rates shown as a point in a biparametric logarithmic plot (k_off^DsRed, k_off^GFP) (C). A linear fit gives a rate ratio k_off^GFP/k_off^DsRed = 1.07 (red line, R = 0.88). The distribution of ratios of rate pairs k_off^GFP /k_off^DsRed (insert, red dots) is compared to what is obtained following a random permutation with the set of k_off^DsRed values (blue squares).</p

Redox-Triggered Control of Cell Adhesion and Deadhesion on Poly(lysine)- g -poly(ethylene oxide) Adlayers

International audienceSpontaneous adsorption of poly(lysine)-g-poly(ethyleneglycol) comb-like copolymers (PLL-g-PEG) is a versatile mean to coat substrates with polymer layers that resist cell adhesion. We prepared redox cleavable PLL-g-PEG to switch adhesion on demand. Redox sensitivity was obtained by introducing disulfide linkers between the PLL backbone and PEG strands. This modification was done alone or in combination with an azide-end on the PEG strands that enabled in situ conjugations of adhesion peptides or fluorescent labels (by simple application of commercially available molecules for copper-free click chemistry compatible with cell survival). To balance the functional (adhesion-promoting) vs cell-repellent copolymers, mixed layers of adjusted compositions were obtained by coadsorption from mixed solutions of the cleavable copolymer with non-cleavable and repellant PLL-g-PEG. The deposition of copolymers and quantitative cleavage as triggered by reductive conditions (application of solutions of tris(carboxyethyl)phosphine, dithiothreitol or gluthatione) were characterized by QCM-D, XPS, and fluorescence microscopy. In cell culture conditions, redox-triggered cleavage was obtained by non toxic application of TCEP for a few minutes, enabling either to release cell attachment points (i.e. cleavage of RGD-presenting areas) or to "open" non-specific adherent areas (i.e. transition from PEG-presenting areas to adherent PLL-like coatings)