The dynamic traveling repairman problem

Includes bibliographical references (p. 30-32).Partially supported by the National Science Foundation. ECS-8717970Dimitris Bertsimas, Garrett van Ryzin

A stochastic and dynamic vehicle routing problem in the Euclidean plane

"February 1990."Includes bibliographical references (p. 29-31).Research supported by the National Science Foundation. DDM-9014751 Research supported by a grant from Draper Laboratory.Dimitris J. Bertsimas, Garrett van Ryzin

A stochastic and dynamic vehicle routing problem in the Euclidean plane

"February 1990."Includes bibliographical references (p. 29-31).Research supported by the National Science Foundation. DDM-9014751 Research supported by a grant from Draper Laboratory.Dimitris J. Bertsimas, Garrett van Ryzin

Traveling Salesman Problem

The idea behind TSP was conceived by Austrian mathematician Karl Menger in mid 1930s who invited the research community to consider a problem from the everyday life from a mathematical point of view. A traveling salesman has to visit exactly once each one of a list of m cities and then return to the home city. He knows the cost of traveling from any city i to any other city j. Thus, which is the tour of least possible cost the salesman can take? In this book the problem of finding algorithmic technique leading to good/optimal solutions for TSP (or for some other strictly related problems) is considered. TSP is a very attractive problem for the research community because it arises as a natural subproblem in many applications concerning the every day life. Indeed, each application, in which an optimal ordering of a number of items has to be chosen in a way that the total cost of a solution is determined by adding up the costs arising from two successively items, can be modelled as a TSP instance. Thus, studying TSP can never be considered as an abstract research with no real importance

The Carbon Assimilation Network in Escherichia coli Is Densely Connected and Largely Sign-Determined by Directions of Metabolic Fluxes

Gene regulatory networks consist of direct interactions but also include indirect interactions mediated by metabolites and signaling molecules. We describe how these indirect interactions can be derived from a model of the underlying biochemical reaction network, using weak time-scale assumptions in combination with sensitivity criteria from metabolic control analysis. We apply this approach to a model of the carbon assimilation network in Escherichia coli. Our results show that the derived gene regulatory network is densely connected, contrary to what is usually assumed. Moreover, the network is largely sign-determined, meaning that the signs of the indirect interactions are fixed by the flux directions of biochemical reactions, independently of specific parameter values and rate laws. An inversion of the fluxes following a change in growth conditions may affect the signs of the indirect interactions though. This leads to a feedback structure that is at the same time robust to changes in the kinetic properties of enzymes and that has the flexibility to accommodate radical changes in the environment

Predicción de la resistencia a antibióticos, intrínseca y adquirida, en Pseudomonas aeruginosa

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 23-10-2020La resistencia a antibióticos ha sido históricamente un escollo para el tratamiento de las infecciones bacterianas, mas en décadas recientes se ha visto recrudecida hasta constituir un grave problema de salud pública, debido a la emergencia y diseminación de bacterias multirresistentes, máxime las Gram-negativas. Estos microorganismos pueden resistir intrínsecamente a los antibióticos; y adquirir resistencia vía transferencia genética horizontal o mediante mutaciones. Entre ellos se encuentra Pseudomonas aeruginosa: se trata de un patógeno oportunista ampliamente distribuido en la Naturaleza, que infecta con frecuencia a pacientes hospitalizados y que posee, intrínsecamente, una baja sensibilidad a muchos antibióticos, aparte de desarrollar habitualmente resistencia vía mutaciones durante las infecciones crónicas. Ergo, los estudios predictivos de resistencia intrínseca y adquirida a antimicrobianos clínicamente relevantes en este patógeno son de crucial importancia. El escrutinio de genotecas de inserción es un método útil en el estudio del resistoma intrínseco bacteriano, pero se desconoce si los resultados que proporciona referentes a un antibiótico pueden extrapolarse al resto de su familia estructural. En esta tesis se ha abordado este interrogante en el caso del resistoma intrínseco a aminoglicósidos de P. aeruginosa, hallando no aplicable dicha extrapolación. Adicionalmente, un análisis ulterior reveló que un mutante de pérdida de función de glnD presentaba hipersensibilidad a dispares antibióticos y virulencia morigerada, lo que posiciona a este gen como una diana prometedora para el diseño de coadyuvantes de antibióticos frente a P. aeruginosa. Por otra parte, a fin de desvelar los mecanismos implicados en la adquisición de resistencia (vía mutación) a distintos antimicrobianos en P. aeruginosa, esta bacteria fue sometida a evolución experimental en presencia de tobramicina, tigeciclina, ceftazidima o ceftazidima-avibactam. Las rutas evolutivas adoptadas por las poblaciones en todas las condiciones exhibieron un notable grado de conservación. A la par, se ahondó en algunos de los factores que constriñen la evolución de la resistencia a tobramicina y tigeciclina. Por un lado, se determinó que la presión de selección condiciona las trayectorias evolutivas hacia dicha resistencia en este patógeno. Aparte, se profundizó en el rol que posee la epistasia entre determinantes de virulencia y de resistencia a los antibióticos en delimitar la evolución de esta última. Los resultados apuntaron a la existencia de contingencia recíproca entre ambos atributos. Al respecto de las evoluciones realizadas en presencia de β-lactámicos, éstos seleccionaron prevalentemente mutaciones que dieron lugar a la sobre-expresión de mexAB-oprM, y grandes deleciones cromosómicas. Estas últimas estaban aparejadas a un trade-off evolutivo (sensibilidad colateral) robusto, que podría explotarse en el tratamiento de ciertas infecciones causadas por P. aeruginosa, incluso las que contienen mutantes resistentes a diferentes drogas. En suma, los resultados que esta tesis comprende arrojan luz sobre algunos de los mecanismos de resistencia intrínseca y adquirida por mutaciones en P. aeruginosa, así como ciertos factores restrictivos de su evolución, cuyo análisis podría mejorar su predicció

A Randomized Controlled Trial Comparing PCIT-Toddler, Circle of Security, and Waitlist Controls to Improve Child and Caregiver Emotion Regulation

Emotion regulation is an important developmental task during toddlerhood that is associated with positive psychosocial outcomes (Zeman et al., 2006). The development of adaptive emotion regulation during early childhood occurs largely within the context of a supportive caregiver-child relationship (Morris et al., 2007). Thus, parent-mediated interventions are a promising medium through which emotion regulation problems in toddlers can be treated. However, few interventions specifically designed to treat behavioral and emotion regulation difficulties are available for children in the toddler age range, and these interventions have yet to establish a solid evidence base supporting their efficacy. To fill this gap in the literature, the current study investigated the efficacy of two parenting interventions designed to improve emotion regulation in toddlers: Parent-Child Interaction Therapy-Toddler (PCIT-T; Girard et al., 2018) and Circle of Security-Parenting (COS-P; Cooper et al., 2009). Using a randomized controlled trial design, 76 parent-child dyads were randomly assigned to PCIT-T, COS-P, or waitlist control groups. Of the 76 dyads, 51 completed both Time 1 and Time 2 assessments. Observational coding and parent-report questionnaires were used to measure child and parent emotion regulation and related constructs at pre-treatment and post-treatment. Two-way mixed ANOVA were conducted to examine effects of group, time, and group-by-time interaction on parent and child emotion regulation. No significant interaction effects were found for any of the analyses. However, significant and large main effects of time were found for observed parent negative talk, observed maternal support-seeking, parent-reported child dysregulation, and parent-reported child externalizing behavior. Results are discussed in light of study limitations and future directions

Understanding evolution to tackle antibiotic resistance in Pseudomonas aeruginosa

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 04-11-2022Antibiotic resistance (AR) constitutes a major public health concern, which has been aggravated in recent decades due to the emergence and spread of multidrug-resistant microorganisms, especially Gram-negative bacteria. Among them, Pseudomonas aeruginosa stands out; it is an opportunistic pathogen, widely distributed in nature, that frequently infects hospitalized patients and presents low susceptibility to many antimicrobials, as well as an overwhelming capacity to develop AR via mutation, mainly during chronic infections. Hence, novel treatment strategies are needed to deal with the infections caused by this bacterium. Collateral sensitivity, whereby acquiring resistance to one drug increases susceptibility to a second drug, is an evolutionary trade-off that may be exploited for treating bacterial infections by the combination or sequential use of drugs' pairs. This application is only possible if those collateral sensitivity phenotypes are conserved within different genetic contexts, environments and situations; robust collateral sensitivity events were searched for during this thesis. We determined that tobramycin, tigecycline and ceftazidime resistance acquisition in P. aeruginosa is associated with a robust fosfomycin collateral sensitivity and ascertained the mechanism responsible for this event. Further, we observed that ciprofloxacin exposure selects distinct mutations in different genetic backgrounds of P. aeruginosa, all of them leading to a robust tobramycin and aztreonam collateral sensitivity, and we proposed tobramycin-ciprofloxacin and ciprofloxacin-aztreonam combinations as promising therapies against infections caused by this bacterium. We also determined that media composition and nutrients’ availability constrain the pathways towards tobramycin, ceftazidime and ceftazidime-avibactam resistance in P. aeruginosa, but fosfomycin collateral sensitivity associated with ceftazidime resistance robustly emerges when P. aeruginosa evolves in different media mimicking those that can be encountered during infection. The compensation of fitness costs associated with the acquisition of AR in the absence of selective pressure could cause a decline of AR, which may also be used for designing therapeutic strategies considering those specific antibiotics whose resistance is robustly unstable in absence of selection. In this thesis, we observed that compensatory evolution of fitness costs associated with ceftazidime resistance in P. aeruginosa leads to a ceftazidime resistance decline in distinct genetic backgrounds, both in antibiotic-free and in sublethal tobramycin environments. The alternation of ceftazidime with drug restriction periods or the switch back to ceftazidime after a ceftazidime-tobramycin alternation may be feasible therapeutic approaches against P. aeruginosa infections. For its part, AR may be transiently induced by some conditions encountered by bacteria during infection, compromising the antibiotic treatments. In this thesis we identified dequalinium chloride, procaine and atropine, which can be present in P. aeruginosa site infections, as inducers of the expression of MexCD-OprJ efflux pump encoding genes, hence transiently increasing ciprofloxacin resistance of this bacterium. Finally, by further studying efflux pumps regulation and considering their ancestral function, we determined that the identification of compounds which are both substrates and inducers of efflux pumps of P. aeruginosa constitutes an effective strategy for finding molecules that reduce the virulence potential of this pathogen. Overall, the results of this thesis allow us to propose novel treatment strategies against P. aeruginosa infections, based on the identification of novel drugs and on the rational use of the antibiotics that we already have, as well as to better understand AR evolutio

Long-term Informative Path Planning with Autonomous Soaring

The ability of UAVs to cover large areas efficiently is valuable for information gathering missions. For long-term information gathering, a UAV may extend its endurance by accessing energy sources present in the atmosphere. Thermals are a favourable source of wind energy and thermal soaring is adopted in this thesis to enable long-term information gathering. This thesis proposes energy-constrained path planning algorithms for a gliding UAV to maximise information gain given a mission time that greatly exceeds the UAV's endurance. This thesis is motivated by the problem of probabilistic target-search performed by an energy-constrained UAV, which is tasked to simultaneously search for a lost ground target and explore for thermals to regain energy. This problem is termed informative soaring (IFS) and combines informative path planning (IPP) with energy constraints. IFS is shown to be NP-hard by showing that it has a similar problem structure to the weight-constrained shortest path problem with replenishments. While an optimal solution may not exist in polynomial time, this thesis proposes path planning algorithms based on informed tree search to find high quality plans with low computational cost. This thesis addresses complex probabilistic belief maps and three primary contributions are presented: • First, IFS is formulated as a graph search problem by observing that any feasible long-term plan must alternate between 1) information gathering between thermals and 2) replenishing energy within thermals. This is a first step to reducing the large search state space. • The second contribution is observing that a complex belief map can be viewed as a collection of information clusters and using a divide and conquer approach, cluster tree search (CTS), to efficiently find high-quality plans in the large search state space. In CTS, near-greedy tree search is used to find locally optimal plans and two global planning versions are proposed to combine local plans into a full plan. Monte Carlo simulation studies show that CTS produces similar plans to variations of exhaustive search, but runs five to 20 times faster. The more computationally efficient version, CTSDP, uses dynamic programming (DP) to optimally combine local plans. CTSDP is executed in real time on board a UAV to demonstrate computational feasibility. • The third contribution is an extension of CTS to unknown drifting thermals. A thermal exploration map is created to detect new thermals that will eventually intercept clusters, and therefore be valuable to the mission. Time windows are computed for known thermals and an optimal cluster visit schedule is formed. A tree search algorithm called CTSDrift combines CTS and thermal exploration. Using 2400 Monte Carlo simulations, CTSDrift is evaluated against a Full Knowledge method that has full knowledge of the thermal field and a Greedy method. On average, CTSDrift outperforms Greedy in one-third of trials, and achieves similar performance to Full Knowledge when environmental conditions are favourable

Transdiagnostic Classification of Behavior in Childhood: Profile Analysis and Interrater Stability

There is growing concern among both researchers and practitioners that mainstream psychopathological classification schemes inadequately meet the needs of individuals seeking treatment for mental illness. Recent efforts in childhood psychopathology have sought to derive new diagnostic subgroups that are less susceptible to the heterogeneity and comorbidity issues that have been reported with categories specified in more recent versions of the diagnostic and statistical manual of mental illness. These transdiagnostic subgroups are generated by using unsupervised machine-learning algorithms that separate cases into homogenous groups with information from multiple continuous indicators. This dissertation seeks to expand on this work by exploring natural groups of children and adolescents that emerge from the normative samples of a rating scale designed to measure the following domains: conduct, negative affect, cognitive/attention, social, and academic functioning. This project uniquely contributes to the previous literature by comparing solutions across teacher, parent, and child raters, by including two adaptive domains (social and academic functioning) and by exploring differences in item-level versus subscale-level methods for profile estimation. Profile membership was also contrasted with categorical diagnostic categories. Results indicated solutions that ranged from four to six profiles across samples. Out of 10 separate analyses across rater groups, developmental levels, and indicator types, 10 qualitatively different latent profiles were identified, six of which fell across a broad spectrum of severity ranging from an extreme level of psychopathology to above average functioning. Two profiles characterized by social dysfunction were identified across all rater groups but not all developmental levels. The remaining two profiles were defined by attention/executive dysfunction but were only present in teacher-rater samples. Thus, latent profiles were replicated across samples to a varying degree, indicating a low level of interrater stability overall. Findings further indicated that, while the item-level approach was helpful in identifying key profile symptoms and yielded broadly similar results, the subscale-approach tended to have higher stability during the enumeration phase and was a more reliable indicator of overall psychopathology. Low associations between profiles and specific categorical diagnoses were found. However, subscale profiles characterized by more extreme maladaptive estimated means were associated with a higher degree of overall psychopathology. Profile demographics are discussed, along with implications for latent profile analysis, the classification of mental health in children and adolescents, treatment and intervention, and psychological assessment. Overall, the results of this study support a broad and transdiagnostic view of child and adolescent behavioral and emotional functioning that continues to show a promising ability to address problems endemic to our current nosological paradigm, improve problematic practices in effectiveness research, and increase the precision and size of treatment effects