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.

A Pyramidal Genetic Algorithm for Multiple-Choice Problems

This paper combines the idea of a hierarchical distributed genetic algorithm with different inter-agent partnering strategies. Cascading clusters of sub-populations are built from bottom up, with higher-level sub-populations optimising larger parts of the problem. Hence, higher-level sub-populations search a larger search space with a lower resolution whilst lower-level sub-populations search a smaller search space with a higher resolution. The effects of different partner selection schemes amongst the agents on solution quality are examined for two multiple-choice optimisation problems. It is shown that partnering strategies that exploit problem-specific knowledge are superior and can counter inappropriate (sub-) fitness measurements.

Leptospirosis in northern Tanzania: exploring the role of rodents and ruminant livestock in a neglected public health problem

Leptospirosis is an important but neglected zoonotic disease that is often overlooked in Africa. Although comprehensive data on the incidence of human disease are lacking, robust evidence of infection has been demonstrated in people and animals from all regions of the continent. However, to date, there are few examples of direct epidemiological linkages between human disease and animal infection. In East Africa, awareness of the importance of human leptospirosis as a cause of non-malarial febrile illness is growing. In northern Tanzania, acute leptospirosis has been diagnosed in 9% of patients with severe febrile illness compared to only 2% with malaria. However, little is known about the relative importance of different potential animal hosts as sources of human infection in this area. This project was established to investigate the roles of rodents and ruminant livestock, important hosts of Leptospira in other settings, in the epidemiology of leptospirosis in northern Tanzania. A cross-sectional survey of rodents living in and around human settlements was performed alongside an abattoir survey of ruminant livestock. Unusual patterns of animal infection were detected by real-time PCR detection. Renal Leptospira infection was absent from rodents but was detected in cattle from several geographic areas. Infection was demonstrated for the first time in small ruminants sub-Saharan Africa. Two major Leptospira species and a novel Leptospira genotype were detected in livestock. L. borgpetersenii was seen only in cattle but L. kirschneri infection was detected in multiple livestock species (cattle, sheep and goats), suggesting that at least two distinct patterns of Leptospira infection occur in livestock in northern Tanzania. Analysis of samples from acute leptospirosis in febrile human patients could not detect Leptospira DNA by real-time PCR but identified social and behavioural factors that may limit the utility of acute-phase diagnostic tests in this community. Analysis of serological data revealed considerable overlap between serogroups detected in cattle and human leptospirosis cases. Human disease was most commonly attributed to the serogroups Mini and Australis, which were also predominant reactive serogroups in cattle. Collectively, the results of this study led to the hypothesis that livestock are an important reservoir of Leptospira infection for people in northern Tanzania. These results also challenge our understanding of the relationship between Leptospira and common invasive rodent species, which do not appear to maintain infection in this setting. Livestock Leptospira infection has substantial potential to affect the well-being of people in East Africa, through direct transmission of infection or through indirect effects on food production and economic security. Further research is needed to quantify the impact of livestock leptospirosis in Africa and to develop effective interventions for the control of human and animal disease.

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.

Contributions to gait recognition using multiple views

Esta tesis se centra en la identificación de personas a través de la forma de caminar. El problema del reconocimiento del paso ha sido tratado mediante diferentes enfoques, en los dominios 2D y 3D, y usando una o varias vistas. Sin embargo, la dependencia con respecto al punto de vista, y por tanto de la trayectoria del sujeto al caminar sigue siendo aún un problema abierto. Se propone hacer frente al problema de la dependencia con respecto a la trayectoria por medio de reconstrucciones 3D de sujetos caminando. El uso de reconstrucciones varias ventajas que cabe destacar. En primer lugar, permite explotar una mayor cantidad de información en contraste con los métodos que extraen los descriptores de la marcha a partir de imágenes, en el dominio 2D. En segundo lugar, las reconstrucciones 3D pueden ser alineadas a lo largo de la marcha como si el sujeto hubiera caminado en una cinta andadora, proporcionando así una forma de analizar el paso independientemente de la trayectoria seguida. Este trabajo propone tres enfoques para resolver el problema de la dependencia a la vista: 1. Mediante la utilización de reconstrucciones volumétricas alineadas. 2. Mediante el uso de reconstrucciones volumétricas no alineadas. 3. Sin usar reconstrucciones. Se proponen además tres tipos de descriptores. El primero se centra en describir el paso mediante análisis morfológico de los volúmenes 3D alineados. El segundo hace uso del concepto de entropa de la información para describir la dinámica del paso humano. El tercero persigue capturar la dinámica de una forma invariante a rotación, lo cual lo hace especialmente interesante para ser aplicado tanto en trayectorias curvas como rectas, incluyendo cambios de dirección. Estos enfoques han sido probados sobre dos bases de datos públicas. Ambas están especialmente diseñadas para tratar el problema de la dependencia con respecto al punto de vista, y por tanto de la dependencia con respecto a la trayectoria. Los resultados experimentales muestran que para el enfoque basado en reconstrucciones volumétricas alineadas, el descriptor del paso basado en entropa consigue los mejores resultados, en comparación con métodos estrechamente relacionados del Estado del Arte actual. No obstante, el descriptor invariante a rotación consigue una tasa de reconocimiento que supera a los métodos actuales sin requerir la etapa previa de alineamiento de las reconstrucciones 3D.

Multiple solutions and numerical analysis to the dynamic and stationary models coupling a delayed energy balance model involving latent heat and discontinuous albedo with a deep ocean

We study a climatologically important interaction of two of the main components of the geophysical system by adding an energy balance model for the averaged atmospheric temperature as dynamic boundary condition to a diagnostic ocean model having an additional spatial dimension. In this work, we give deeper insight than previous papers in the literature, mainly with respect to the 1990 pioneering model by Watts and Morantine. We are taking into consideration the latent heat for the two phase ocean as well as a possible delayed term. Non-uniqueness for the initial boundary value problem, uniqueness under a non-degeneracy condition and the existence of multiple stationary solutions are proved here. These multiplicity results suggest that an S-shaped bifurcation diagram should be expected to occur in this class of models generalizing previous energy balance models. The numerical method applied to the model is based on a finite volume scheme with nonlinear weighted essentially non-oscillatory reconstruction and Runge–Kutta total variation diminishing for time integration.

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.

STUDY OF A DIRECT SAMPLING METHOD FOR THE INVERSE MEDIUM SCATTERING PROBLEM

Direct sampling methods are increasingly being used to solve the inverse medium scattering problem to estimate the shape of the scattering object. A simple direct method using one incident wave and multiple measurements was proposed by Ito, Jin and Zou. In this report, we performed some analytic and numerical studies of the direct sampling method. The method was found to be effective in general. However, there are a few exceptions exposed in the investigation. Analytic solutions in different situations were studied to verify the viability of the method while numerical tests were used to validate the effectiveness of the method.

Trajectory design of a multiple flyby mission to asteroids

In designing the trajectory for a multiple flyby mission to asteroids the choice of the targets is the most challenging problem. This dissertation faces this problem in the framework of the recently issued medium-size mission call (M5) from ESA: CASTAway. Starting from the preliminary work done in [6], this thesis develops a methodology for sequencing the potential targets in a multiple flyby mission. In order to reduce the computational time, the complete database of known small bodies is firstly pruned on the base of heuristic considerations. Using the assumption of small manoeuvres, a chief orbit concept could be used. Thus, two heuristic thresholds are defined in order to exclude non-promising targets given a chief orbit. The sequencing process takes chief orbit and promising targets as inputs and gives a set of candidate sequences. The results of such a process are analysed in the CASTAway framework and the best feasible sequence studied in details.

Fast and efficient user pairing and power allocation algorithm for non-orthogonal multiple access in cellular networks

Non-orthogonal multiple access (NOMA) is emerging as a promising multiple access technology for the fifth generation cellular networks to address the fast growing mobile data traffic. It applies superposition coding in transmitters, allowing simultaneous allocation of the same frequency resource to multiple intra-cell users. Successive interference cancellation is used at the receivers to cancel intra-cell interference. User pairing and power allocation (UPPA) is a key design aspect of NOMA. Existing UPPA algorithms are mainly based on exhaustive search method with extensive computation complexity, which can severely affect the NOMA performance. A fast proportional fairness (PF) scheduling based UPPA algorithm is proposed to address the problem. The novel idea is to form user pairs around the users with the highest PF metrics with pre-configured fixed power allocation. Systemlevel simulation results show that the proposed algorithm is significantly faster (seven times faster for the scenario with 20 users) with a negligible throughput loss than the existing exhaustive search algorithm.

Using multiple GPUs to accelerate string searching for digital forensic analysis

String searching within a large corpus of data is an important component of digital forensic (DF) analysis techniques such as file carving. The continuing increase in capacity of consumer storage devices requires corresponding im-provements to the performance of string searching techniques. As string search-ing is a trivially-parallelisable problem, GPGPU approaches are a natural fit – but previous studies have found that local storage presents an insurmountable performance bottleneck. We show that this need not be the case with modern hardware, and demonstrate substantial performance improvements from the use of single and multiple GPUs when searching for strings within a typical forensic disk image.

Clustering of Territorial Areas: A Multicriteria Districting problem

The success of regional development policies depends on the homogeneity of the territorial units. This paper aims to propose a framework for obtaining homogenous territorial clusters based on a Pareto frontier considering multiple criteria related to territories’ endogenous resources, economic profile and socio-cultural features. This framework is developed in two phases. First, the criteria correlated with development at the territorial unit level are determined through statistical and econometric methods. Then, a multi-criteria approach is developed to allocate each territorial unit (parishes) to a territorial agglomerate, according to the Pareto frontier established.

Identificazione di nuove strategie per la valutazione della malattia minima residua nel Mieloma Multiplo: la Biopsia Liquida

Il Mieloma Multiplo (MM) è una patologia neoplastica delle cellule B caratterizzata dalla proliferazione di più cloni di plasmacellule portatrici di diverse anomalie genomiche. Il MM presenta tipicamente un’eterogeneità genomica spaziale e intraclonale, che rende l’aspirato midollare "a singolo sito", attualmente utilizzato per la valutazione della malattia residua (MRD) dopo trattamento, non realmente informativo sulla taglia di malattia e sul panorama genomico della malattia. In considerazione della crescente importanza che sta assumendo la valutazione della MRD, i test per monitorarla dovrebbero essere non invasivi, affidabili e in grado di rappresentare le eterogeneità che caratterizzano il MM. Il presente studio ha permesso di dimostrare la possibilità di utilizzare la biopsia liquida, una metodica innovativa e non invasiva, per caratterizzare i pazienti con MM attivo o con MM smoldering ad alto rischio di evoluzione (HR-SMM) e per determinale l’MRD nei pazienti sottoposti a terapia di prima linea, integrando le metodiche attualmente validate. Nei pazienti arruolati nel presente studio è stato possibile identificare la frazione tumorale di DNA libero circolante (cfDNA-TF) nel sangue periferico, ed è stato possibile caratterizzare la malattia da un punto di vista qualitativo, dimostrando un’elevata concordanza del profilo genomico tra DNA libero circolante e DNA midollare (100% nei pazienti con HR-SMM e 86% nei pazienti con MM attivo). L’esecuzione seriata di biopsie liquide in corso di terapia, con un follow-up mediano di 24 mesi, ha mostrato una rapida e netta riduzione della cfDNA-TF xdalle prime fasi di terapia, con una tendenza a mantenersi mediamente sotto la soglia di sensibilità della metodica anche nelle fasi successive, indipendentemente dall’eventuale persistenza di MRD individuabile a livello midollare o mediante PET-CT. Con un follow-up più lungo probabilmente sarà possibile valutare meglio la capacità di questa metodica di affiancare o eventualmente sostituire l’aspirato midollare.

User scheduling for low earth orbit multi-user multiple-input-multiple-output non-terrestrial network systems

In rural and isolated areas without cellular coverage, Satellite Communication (SatCom) is the best candidate to complement terrestrial coverage. However, the main challenge for future generations of wireless networks will be to meet the growing demand for new services while dealing with the scarcity of frequency spectrum. As a result, it is critical to investigate more efficient methods of utilizing the limited bandwidth; and resource sharing is likely the only choice. The research community’s focus has recently shifted towards the interference management and exploitation paradigm to meet the increasing data traffic demands. In the Downlink (DL) and Feedspace (FS), LEO satellites with an on-board antenna array can offer service to numerous User Terminals (UTs) (VSAT or Handhelds) on-ground in FFR schemes by using cutting-edge digital beamforming techniques. Considering this setup, the adoption of an effective user scheduling approach is a critical aspect given the unusually high density of User terminals on the ground as compared to the on-board available satellite antennas. In this context, one possibility is that of exploiting clustering algorithms for scheduling in LEO MU-MIMO systems in which several users within the same group are simultaneously served by the satellite via Space Division Multiplexing (SDM), and then these different user groups are served in different time slots via Time Division Multiplexing (TDM). This thesis addresses this problem by defining a user scheduling problem as an optimization problem and discusses several algorithms to solve it. In particular, focusing on the FS and user service link (i.e., DL) of a single MB-LEO satellite operating below 6 GHz, the user scheduling problem in the Frequency Division Duplex (FDD) mode is addressed. The proposed State-of-the-Art scheduling approaches are based on graph theory. The proposed solution offers high performance in terms of per-user capacity, Sum-rate capacity, SINR, and Spectral Efficiency.

The Clinical Impact Of Cerebellar Grey Matter Pathology In Multiple Sclerosis.

The cerebellum is an important site for cortical demyelination in multiple sclerosis, but the functional significance of this finding is not fully understood. To evaluate the clinical and cognitive impact of cerebellar grey-matter pathology in multiple sclerosis patients. Forty-two relapsing-remitting multiple sclerosis patients and 30 controls underwent clinical assessment including the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale (EDSS) and cerebellar functional system (FS) score, and cognitive evaluation, including the Paced Auditory Serial Addition Test (PASAT) and the Symbol-Digit Modalities Test (SDMT). Magnetic resonance imaging was performed with a 3T scanner and variables of interest were: brain white-matter and cortical lesion load, cerebellar intracortical and leukocortical lesion volumes, and brain cortical and cerebellar white-matter and grey-matter volumes. After multivariate analysis high burden of cerebellar intracortical lesions was the only predictor for the EDSS (p<0.001), cerebellar FS (p = 0.002), arm function (p = 0.049), and for leg function (p<0.001). Patients with high burden of cerebellar leukocortical lesions had lower PASAT scores (p = 0.013), while patients with greater volumes of cerebellar intracortical lesions had worse SDMT scores (p = 0.015). Cerebellar grey-matter pathology is widely present and contributes to clinical dysfunction in relapsing-remitting multiple sclerosis patients, independently of brain grey-matter damage.