Neutrophil Chemotaxis in Multiple Chemoattractant Gradients

Chemotaxis, the phenomenon in which cells move in response to extracellular chemical gradients, plays a prominent role in the mammalian immune response. During this process, a number of chemical signals, called chemoattractants, are produced at or proximal to sites of infection and diffuse into the surrounding tissue. Immune cells sense these chemoattractants and move in the direction where their concentration is greatest, thereby locating the source of attractants and their associated targets. Leading the assault against new infections is a specialized class of leukocytes (white blood cells) known as neutrophils, which normally circulate in the bloodstream. Upon activation, these cells emigrate out of the vasculature and navigate through interstitial tissues toward target sites. There they phagocytose bacteria and release a number of proteases and reactive oxygen intermediates with antimicrobial activity. Neutrophils recruited by infected tissue in vivo are likely confronted by complex chemical environments consisting of a number of different chemoattractant species. These signals may include end target chemicals produced in the vicinity of the infectious agents, and endogenous chemicals released by local host tissues during the inflammatory response. To successfully locate their pathogenic targets within these chemically diverse and heterogeneous settings, activated neutrophils must be capable of distinguishing between the different signals and employing some sort of logic to prioritize among them. This ability to simultaneously process and interpret mulitple signals is thought to be essential for efficient navigation of the cells to target areas. In particular, aberrant cell signaling and defects in this functionality are known to contribute to medical conditions such as chronic inflammation, asthma and rheumatoid arthritis. To elucidate the biomolecular mechanisms underlying the neutrophil response to different chemoattractants, a number of efforts have been made toward understanding how cells respond to different combinations of chemicals. Most notably, recent investigations have shown that in the presence of both end target and endogenous chemoattractant variants, the cells migrate preferentially toward the former type, even in very low relative concentrations of the latter. Interestingly, however, when the cells are exposed to two different endogenous chemical species, they exhibit a combinatorial response in which distant sources are favored over proximal sources. Some additional results also suggest that cells located between two endogenous chemoattractant sources will respond to the vectorial sum of the combined gradients. In the long run, this peculiar behavior could result in oscillatory cell trajectories between the two sources. To further explore the significance of these and other observations, particularly in the context of physiological conditions, we introduce in this work a simplified phenomenological model of neutrophil chemotaxis. In particular, this model incorporates a trait commonly known as directional persistence - the tendency for migrating neutrophils to continue moving in the same direction (much like momentum) - while also accounting for the dose-response characteristics of cells to different chemical species. Simulations based on this model suggest that the efficiency of cell migration in complex chemical environments depends significantly on the degree of directional persistence. In particular, with appropriate values for this parameter, cells can improve their odds of locating end targets by drifting through a network of attractant sources in a loosely-guided fashion. This corroborates the prediction that neutrophils randomly migrate from one chemoattractant source to the next while searching for their end targets. These cells may thus use persistence as a general mechanism to avoid being trapped near sources of endogenous chemoattractants - the mathematical analogue of local maxima in a global optimization problem. Moreover, this general foraging strategy may apply to other biological processes involving multiple signals and long-range navigation.

Enhanced Direct and Indirect Genetic Algorithm Approaches for a Mall Layout and Tenant Selection Problem

During our earlier research, it was recognised that in order to be successful with an indirect genetic algorithm approach using a decoder, the decoder has to strike a balance between being an optimiser in its own right and finding feasible solutions. Previously this balance was achieved manually. Here we extend this by presenting an automated approach where the genetic algorithm itself, simultaneously to solving the problem, sets weights to balance the components out. Subsequently we were able to solve a complex and non-linear scheduling problem better than with a standard direct genetic algorithm implementation.

'Enhanced Direct and Indirect Genetic Algorithm Approaches for a Mall Layout and Tenant Selection Problem'

During our earlier research, it was recognised that in order to be successful with an indirect genetic algorithm approach using a decoder, the decoder has to strike a balance between being an optimiser in its own right and finding feasible solutions. Previously this balance was achieved manually. Here we extend this by presenting an automated approach where the genetic algorithm itself, simultaneously to solving the problem, sets weights to balance the components out. Subsequently we were able to solve a complex and non-linear scheduling problem better than with a standard direct genetic algorithm implementation.

Exact solutions to the short sea shipping distribution problem

Short sea shipping has several advantages over other means of transportation, recognized by EU members. The maritime transportation could be dealt like a combination of two well-known problems: the container stowage problem and routing planning problem. The integration of these two well-known problems results in a new problem CSSRP (Container stowage and ship routing problem) that is also an hard combinatorial optimization problem. The aim of this work is to solve the CSSRP using a mixed integer programming model. It is proved that regardless the complexity of this problem, optimal solutions could be achieved in a reduced computational time. For testing the mathematical model some problems based on real data were generated and a sensibility analysis was performed.

The suppliers selection problem: a case study

The effective supplier evaluation and purchasing processes are of vital importance to business organizations, making the suppliers selection problem a fundamental key issue to their success. We consider a complex supplier selection problem with multiple products where minimum package quantities, minimum order values related to delivery costs, and discounted pricing schemes are taken into account. Our main contribution is to present a mixed integer linear programming (MILP) model for this supplier selection problem. The model is used to solve several examples including three real case studies from an electronic equipment assembly company.

Nested Rollout Policy Adaptation for optimizing vehicle selection in complex VRPs

The goal of Vehicle Routing Problems (VRP) and their variations is to transport a set of orders with the minimum number of vehicles at least cost. Most approaches are designed to solve specific problem variations independently, whereas in real world applications, different constraints are handled concurrently. This research extends solutions obtained for the traveling salesman problem with time windows to a much wider class of route planning problems in logistics. The work describes a novel approach that:  supports a heterogeneous fleet of vehicles  dynamically reduces the number of vehicles  respects individual capacity restrictions  satisfies pickup and delivery constraints  takes Hamiltonian paths (rather than cycles) The proposed approach uses Monte-Carlo Tree Search and in particular Nested Rollout Policy Adaptation. For the evaluation of the work, real data from the industry was obtained and tested and the results are reported.

Tabu search for the cyclic bandwidth problem

International audience

Boosting the performance of metaheuristics for the MinLA problem using a more discriminating evaluation function

International audience

Climbing Combinatorial Fitness Landscapes

International audience

Model predictive control applied to a supply chain management problem

Supply chains are ubiquitous in any commercial delivery systems. The exchange of goods and services, from different supply points to distinct destinations scattered along a given geographical area, requires the management of stocks and vehicles fleets in order to minimize costs while maintaining good quality services. Even if the operating conditions remain constant over a given time horizon, managing a supply chain is a very complex task. Its complexity increases exponentially with both the number of network nodes and the dynamical operational changes. Moreover, the management system must be adaptive in order to easily cope with several disturbances such as machinery and vehicles breakdowns or changes in demand. This work proposes the use of a model predictive control paradigm in order to tackle the above referred issues. The obtained simulation results suggest that this strategy promotes an easy tasks rescheduling in case of disturbances or anticipated changes in operating conditions. © Springer International Publishing Switzerland 2017

Iterated responsive threshold search for the quadratic multiple knapsack problem

International audience

Lot production size problem and simulation of urban transport

OBJECTIVES AND STUDY METHOD: There are two subjects in this thesis: “Lot production size for a parallel machine scheduling problem with auxiliary equipment” and “Bus holding for a simulated traffic network”. Although these two themes seem unrelated, the main idea is the optimization of complex systems. The “Lot production size for a parallel machine scheduling problem with auxiliary equipment” deals with a manufacturing setting where sets of pieces form finished products. The aim is to maximize the profit of the finished products. Each piece may be processed in more than one mold. Molds must be mounted on machines with their corresponding installation setup times. The key point of our methodology is to solve the single period lot-sizing decisions for the finished products together with the piece-mold and the mold-machine assignments, relaxing the constraint that a single mold may not be used in two machines at the same time. For the “Bus holding for a simulated traffic network” we deal with One of the most annoying problems in urban bus operations is bus bunching, which happens when two or more buses arrive at a stop nose to tail. Bus bunching reflects an unreliable service that affects transit operations by increasing passenger-waiting times. This work proposes a linear mathematical programming model that establishes bus holding times at certain stops along a transit corridor to avoid bus bunching. Our approach needs real-time input, so we simulate a transit corridor and apply our mathematical model to the data generated. Thus, the inherent variability of a transit system is considered by the simulation, while the optimization model takes into account the key variables and constraints of the bus operation. CONTRIBUTIONS AND CONCLUSIONS: For the “Lot production size for a parallel machine scheduling problem with auxiliary equipment” the relaxation we propose able to find solutions more efficiently, moreover our experimental results show that most of the solutions verify that molds are non-overlapping even if they are installed on several machines. We propose an exact integer linear programming, a Relax&Fix heuristic, and a multistart greedy algorithm to solve this problem. Experimental results on instances based on real-world data show the efficiency of our approaches. The mathematical model and the algorithm for the lot production size problem, showed in this research, can be used for production planners to help in the scheduling of the manufacturing. For the “Bus holding for a simulated traffic network” most of the literature considers quadratic models that minimize passenger-waiting times, but they are harder to solve and therefore difficult to operate by real-time systems. On the other hand, our methodology reduces passenger-waiting times efficiently given our linear programming model, with the characteristic of applying control intervals just every 5 minutes.

Chebanov law and Vakar formula in mathematical models of complex systems

Ecological models written in a mathematical language L(M) or model language, with a given style or methodology can be considered as a text. It is possible to apply statistical linguistic laws and the experimental results demonstrate that the behaviour of a mathematical model is the same of any literary text of any natural language. A text has the following characteristics: (a) the variables, its transformed functions and parameters are the lexic units or LUN of ecological models; (b) the syllables are constituted by a LUN, or a chain of them, separated by operating or ordering LUNs; (c) the flow equations are words; and (d) the distribution of words (LUM and CLUN) according to their lengths is based on a Poisson distribution, the Chebanov's law. It is founded on Vakar's formula, that is calculated likewise the linguistic entropy for L(M). We will apply these ideas over practical examples using MARIOLA model. In this paper it will be studied the problem of the lengths of the simple lexic units composed lexic units and words of text models, expressing these lengths in number of the primitive symbols, and syllables. The use of these linguistic laws renders it possible to indicate the degree of information given by an ecological model.

Development of the Andalusian Registry of Patients Receiving Community Case Management, for the follow-up of people with complex chronic diseases.

Background: Complex chronic diseases are a challenge for the current configuration of Health services. Case management is a service frequently provided for people with chronic conditions and despite its effectiveness in many outcomes, such as mortality or readmissions, uncertainty remains about the most effective form of team organization, structures, and the nature of the interventions. Many processes and outcomes of case management for people with complex chronic conditions cannot be addressed with the information provided by electronic clinical records. Registries are frequently used to deal with this weakness. The aim of this study was to generate a registry-based information system of patients receiving case management to identify their clinical characteristics, their context of care, events identified during their follow-up, interventions developed by case managers, and services used. Methods and design: The study was divided into three phases, covering the detection of information needs, the design and its implementation in the healthcare system, using literature review and expert consensus methods to select variables that would be included in the registry. Objective: To describe the essential characteristics of the provision of ca re lo people who receive case management (structure, process and outcomes), with special emphasis on those with complex chronic diseases. Study population: Patients from any District of Primary Care, who initiate the utilization of case management services, to avoid information bias that may occur when including subjects who have already been received the service, and whose outcomes and characteristics could not be properly collected. Results: A total of 102 variables representing structure, processes and outcomes of case management were selected for their inclusion in the registry after the consensus phase. Total sample was composed of 427 patients, of which 211 (49.4%) were women and 216 (50.6%) were men. The average functional level (Barthel lndex) was 36.18 (SD 29.02), cognitive function (Pfeiffer) showed an average of 4.37 {SD 6.57), Chat1son Comorbidity lndex, obtained a mean of 3.03 (SD 2.7) and Social Support (Duke lndex) was 34.2 % (SD 17.57). More than half of patients include in the Registry, correspond lo immobilized or transitional care for patients discharged from hospital (66.5 %). The patient's educational level was low or very low (50.4%). Caregivers overstrain (Caregiver stress index), obtained an average value of 6.09% (SD 3.53). Only 1.2 % of patients had declared their advanced directives, 58.6 had not defined the tutelage and the vast majority lived at home 98.8 %. Regarding the major events recorded at RANGE Registry, 25.8 % of the selected patients died in the first three months, 8.2 % suffered a hospital admission at least once time, 2.3%, two times, and 1.2% three times, 7.5% suffered a fall, 8.7% had pressure ulcer, 4.7% had problems with medication, and 3.3 % were institutionalized. Stroke is the more prevalent health problem recorded (25.1%), followed by hypertension (11.1%) and COPD (11.1%). Patients registered by NCMs had as main processes diabetes (16.8%) and dementia (11.3 %). The most frequent nursing diagnoses referred to the self-care deficit in various activities of daily living. Regarding to nursing interventions, described by the Nursing Intervention Classification (NIC), dementia management is the most used intervention, followed by mutual goal setting, caregiver and emotional support. Conclusions: The patient profile who receive case management services is a chronic complex patient with severe dependence, cognitive impairment, normal social support, low educational level, health problems such as stroke, hypertension or COPD, diabetes or dementia, and has an informal caregiver. At the first follow up, mortality was 19.2%, and a discrete rate of readmissions and falls.

Strategy for succession in family owned small businesses as a wicked problem to be tamed

Contemporary strategic-planning processes don’t help family businesses cope with some of the big problems they face. Owner managers admit that they are confronted with issues, such as those associated with succession and inter-generational transfer that cannot be resolved merely by gathering additional data, defining issues more clearly, or breaking them down into small problems. Preparing for succession is often put off or ignored, many planning techniques don’t generate fresh ideas and implementing solutions is often fraught with political peril. This paper presents a framework to explore the idea of wicked problems, its relevance to succession planning in family businesses and its implications for practice and policy. A wicked problem has many and varied elements, and is complex as well as challenging. These problems are different to hard but ordinary problems, which people can solve in a finite time period by applying standard techniques. In this paper the authors argue that the wicked problem of family business succession requires a different approach to strategy, founded on social planning processes to engage multiple stakeholders and reconcile family/business interests to foster a joint commitment to possible ways of resolution. This requires academics and practitioners to re-frame traditional business strategic planning processes to achieve more sustainable family business futures.