Rossian Moral Pluralism: A (Partial) Defense

Rossian moral pluralism’s rejection of a founding moral principle and use of ‘prima facie duties’ as opposed to absolute duties makes it unique from most other major ethical theories. It has been attacked in a myriad of different ways because of this. Brad Hooker has proposed two objections based on these ideas. The first is that moral pluralism is lacking justification because of its rejection of a founding moral principle. The second is that because of this, and its lack of absolute duties, moral pluralism is an indeterminate theory. In this paper I will look at Hooker’s objections as well as two responses that have been proposed as solutions. Having shown these solutions to be insufficient I will then propose a way to look at Ross’ moral pluralism that saves it from Hooker’s objections and clearly lays out Ross’ understanding of how we should deliberate about moral matters

The daily tail assignment problem under operational uncertainty using look-ahead maintenance constraints

Abstract The tail assignment problem is a critical part of the airline planning process that assigns specific aircraft to sequences of flights, called lines-of-flight, to satisfy operational constraints. The aim of this paper is to develop an operationally flexible method, based upon the one-day routes business model, to compute tail assignments that satisfy short-range—within the next three days—aircraft maintenance requirements. While maintenance plans commonly span multiple days, the methods used to compute tail assignments for the given plans can be overly complex and provide little recourse in the event of schedule perturbations. The presented approach addresses operational uncertainty by using solutions from the one-day routes aircraft maintenance routing approach as input. The daily tail assignment problem is solved with an objective to satisfy maintenance requirements explicitly for the current day and implicitly for the subsequent two days. A computational study will be performed to assess the performance of exact and heuristic solution algorithms that modify the input lines-of-flight to reduce maintenance misalignments. The daily tail assignment problem and the developed algorithms are demonstrated to compute solutions that effectively satisfy maintenance requirements when evaluated using input data collected from three different airlines

DNA methylation changes from primary cultures through senescence-bypass in Syrian hamster fetal cells initially exposed to benzo[a]pyrene

Current chemical testing strategies are limited in their ability to detect non-genotoxic carcinogens (NGTxC). Epigenetic anomalies develop during carcinogenesis regardless of whether the molecular initiating event is associated with genotoxic (GTxC) or NGTxC events; therefore, epigenetic markers may be harnessed to develop new approach methodologies that improve the detection of both types of carcinogens. This study used Syrian hamster fetal cells to establish the chronology of carcinogen-induced DNA methylation changes from primary cells until senescence-bypass as an essential carcinogenic step. Cells exposed to solvent control for 7 days were compared to naïve primary cultures, to cells exposed for 7 days to benzo[a]pyrene, and to cells at the subsequent transformation stages: normal colonies, morphologically transformed colonies, senescence, senescence-bypass, and sustained proliferation in vitro. DNA methylation changes identified by reduced representation bisulphite sequencing were minimal at day-7. Profound DNA methylation changes arose during cellular senescence and some of these early differentially methylated regions (DMRs) were preserved through the final sustained proliferation stage. A set of these DMRs (e.g., Pou4f1, Aifm3, B3galnt2, Bhlhe22, Gja8, Klf17, and L1l) were validated by pyrosequencing and their reproducibility was confirmed across multiple clones obtained from a different laboratory. These DNA methylation changes could serve as biomarkers to enhance objectivity and mechanistic understanding of cell transformation and could be used to predict senescence-bypass and chemical carcinogenicity

Endothelial and cardiomyocyte PI3Kβ divergently regulate cardiac remodelling in response to ischaemic injury

AIMS: Cardiac remodeling in the ischemic heart determines prognosis in patients with ischemic heart disease (IHD), while enhancement of angiogenesis and cell survival has shown great potential for IHD despite translational challenges. Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway plays a critical role in promoting angiogenesis and cell survival. However, the effect of PI3Kβ in the ischemic heart is poorly understood. This study investigates the role of endothelial and cardiomyocyte PI3Kβ in post-infarct cardiac remodeling. METHODS AND RESEARCH: PI3Kβ catalytic subunit-p110β level was increased in infarcted murine and human hearts. Using cell type-specific loss-of-function approaches, we reported novel and distinct actions of p110β in endothelial cells versus cardiomyocytes in response to myocardial ischemic injury. Inactivation of endothelial p110β resulted in marked resistance to infarction and adverse cardiac remodeling with decreased mortality, improved systolic function, preserved microvasculature, and enhanced Akt activation. Cultured endothelial cells with p110β knockout or inhibition displayed preferential PI3Kα/Akt/eNOS signaling that consequently promoted protective signaling and angiogenesis. In contrast, mice with cardiomyocyte p110β-deficiency exhibited adverse post-infarct ventricular remodeling with larger infarct size and deteriorated cardiac function, which was due to enhanced susceptibility of cardiomyocytes to ischemia-mediated cell death. Disruption of cardiomyocyte p110β signaling compromised nuclear p110β and phospho-Akt levels leading to perturbed gene expression and elevated pro-cell death protein levels, increasing the susceptibility to cardiomyocyte death. A similar divergent response of PI3Kβ endothelial and cardiomyocyte mutant mice was seen using a model of myocardial ischemia-reperfusion injury. CONCLUSIONS: These data demonstrate novel, differential, and cell-specific functions of PI3Kβ in the ischemic heart. While loss of endothelial PI3Kβ activity produces cardioprotective effects, cardiomyocyte PI3Kβ is protective against myocardial ischemic injury

VRP with Time Windows

Abstract This paper presents a survey of the research on the Vehicle Routing Problem with Time Windows (VRPTW), an extension of the Capacitated Vehicle Routing Problem. In the VRPTW, the service at each customer must start within an associated time window and the vehicle must remain at the customer location during service. Soft time windows can be violated at a cost while hard time windows do not allow for a vehicle to arrive at a customer after the latest time to begin service. We first present a multi-commodity network flow formulation with time and capacity constraints for the VRPTW. Approximation methods proposed in the literature to derive upper bounds are then reviewed. Then we explain how lower bounds can be obtained using optimal approaches, namely, Lagrangean relaxation and column generation. Next, we provide branching and cutting strategies that can be embedded within these optimal approaches to produce integer solutions. Special cases and extensions to the VRPTW follow as well as our conclusions. Résumé Cet article synthèse porte sur les récents développements concernant le problème du routage de véhicules sous des contraintes de fenêtres de temps. Dans ce problème, le serviceà un client doit débuterà l'intérieur d'un intervalle de temps. Celui-ci peutêtre, soit relaché au prix d'une certaine pénalité, soit rigide, auquel cas, il n'est pas permis de dépasser la limite supérieure. Nous présentons un modèle de réseau multi-flots avec des contraintes de temps et de capacité. Les méthodes heuristiques permettant de calculer des bornes supérieures sont d'abord présentées. Suivent les modèles d'optimisation basés sur la relaxation lagrangienne et la génération de colonnes pourévaluer des bornes inférieures. Enfin, on présente les stratégies de coupes et de branchements liéesà ces méthodes afin de déterminer des solutions entières. L'article se termine par l'étude de cas particuliers et d'extensions ainsi que nos conclusions

LH-Independent Testosterone Secretion Is Mediated by the Interaction Between GNRH2 and Its Receptor Within Porcine Testes

Unlike classic gonadotropin-releasing hormone 1 (GNRH1), the second mammalian isoform (GNRH2) is an ineffective stimulant of gonadotropin release. Species that produce GNRH2 may not maintain a functional GNRH2 receptor (GNRHR2) due to coding errors. A full-length GNRHR2 gene has been identified in swine, but its role in reproduction requires further elucidation. Our objective was to examine the role of GNRH2 and GNRHR2 in testicular function of boars. We discovered that GNRH2 levels were higher in the testis than in the anterior pituitary gland or hypothalamus, corresponding to greater GNRHR2 abundance in the testis versus the anterior pituitary gland. Moreover, GNRH2 immunostaining was most prevalent within seminiferous tubules, whereas GNRHR2 was detected in high abundance on Leydig cells. GNRH2 pretreatment of testis explant cultures elicited testosterone secretion similar to that of human chorionic gonadotropin stimulation. Treatment of mature boars with GNRH2 elevated testosterone levels similar to those of GNRH1-treated males, despite minimal GNRH2-induced release of luteinizing hormone (LH). When pretreated with a GNRHR1 antagonist (SB-75), subsequent GNRH2 treatment stimulated low levels of testosterone secretion despite a pattern of LH release similar to that in the previous trial, suggesting that SB-75 inhibited testicular GNRHR2s. Given that pigs lack testicular GNRHR1, these data may indicate that GNRH2 and its receptor are involved in autocrine or paracrine regulation of testosterone secretion. Notably, our data are the first to suggest a biological function of a novel GNRH2-GNRHR2 system in the testes of swine

Workforce scheduling and routing problems: literature survey and computational study

In the context of workforce scheduling, there are many scenarios in which personnel must carry out tasks at different locations hence requiring some form of transportation. Examples of these type of scenarios include nurses visiting patients at home, technicians carrying out repairs at customers’ locations and security guards performing rounds at different premises, etc. We refer to these scenarios as workforce scheduling and routing problems (WSRP) as they usually involve the scheduling of personnel combined with some form of routing in order to ensure that employees arrive on time at the locations where tasks need to be performed. The first part of this paper presents a survey which attempts to identify the common features of WSRP scenarios and the solution methods applied when tackling these problems. The second part of the paper presents a study on the computational difficulty of solving these type of problems. For this, five data sets are gathered from the literature and some adaptations are made in order to incorporate the key features that our survey identifies as commonly arising in WSRP scenarios. The computational study provides an insight into the structure of the adapted test instances, an insight into the effect that problem features have when solving the instances using mathematical programming, and some benchmark computation times using the Gurobi solver running on a standard personal computer