A Look into Moral Luck

The term “moral luck” is used to describe any instance of where a moral agent is appropriately praised or blamed for an event or its outcomes despite having no control over the preceding causes of either the event or its consequences. The possibility of moral luck would be rejected by thinkers such as Immanuel Kant. According to Kant, to be a good person all that is required is that one have a “good will.” Per the Kantian moral framework, “The good will is not good because of what it effects or accomplishes or because of its adequacy to achieve some proposed end; it is good only because of its willing, i.e., it is good of itself” (Kant 1785, pg. 11). Simply put, regardless of the consequence of any action, if a moral agent acts in a way that comes from a good intention, they will be morally vindicated. There is no such thing as moral luck because one’s blameworthiness or praiseworthiness will always be in one’s control. Influential political philosopher and author of the 1979 publication titled “Moral Luck,” Thomas Nagel pushes back against the idea that moral luck cannot exist. His reason for believing this comes from our complicated reactions to what is known as the “control principle,” which posits that moral agents cannot be held accountable for events whose antecedent factors are outside of their control. Nagel believes that when we apply the control principle to our understanding of how ethics works on a human level, we will always see a paradox arise. Per Nagel it seems to be the case that everything arises from factors, both “antecedent and posterior,” human beings can just simply never have control over. This lack of control allows us to make our moral reactions to people’s actions only mere “aesthetic” claims, not deeper claims of moral blameworthiness or praise. Philosopher and author of Justice, Luck, and Knowledge Susan Hurley delves deeper into the question of moral luck by connecting to debates on determinism. She identifies the role responsibility must play in identifying and explaining moral luck and explains why Nagel’s defense of moral luck is accurate, but not entirely so, due to what she calls conceptions of thick luck and thin luck. The topic of moral luck forces us to ask several questions, with the most pertinent being whether the actions we perform that turn out to be morally permissible or morally wrong are truly in our control. In this paper I aim to argue against skepticism about moral luck by putting together the conversation on moral luck from the beginning, starting with Thomas Nagel and finishing with Susan Hurley. I will show how Hurley’s account of moral luck aims to make significant improvements to how Nagel originally presents the topic

Rhesus lymphocryptovirus latent membrane protein 2A activates β-catenin signaling and inhibits differentiation in epithelial cells

AbstractRhesus lymphocryptovirus (LCV) is a γ-herpesvirus closely related to Epstein–Barr virus (EBV). The rhesus latent membrane protein 2A (LMP2A) is highly homologous to EBV LMP2A. EBV LMP2A activates the phosphatidylinositol 3-kinase (PI3K) and β-catenin signaling pathways in epithelial cells and affects differentiation. In the present study, the biochemical and biological properties of rhesus LMP2A in epithelial cells were investigated. The expression of rhesus LMP2A in epithelial cells induced Akt activation, GSK3β inactivation and accumulation of β-catenin in the cytoplasm and nucleus. The nuclear translocation, but not accumulation of β-catenin was dependent on Akt activation. Rhesus LMP2A also impaired epithelial cell differentiation; however, this process was not dependent upon Akt activation. A mutant rhesus LMP2A lacking six transmembrane domains functioned similarly to wild-type rhesus LMP2A indicating that the full number of transmembrane domains is not required for effects on β-catenin or cell differentiation. These results underscore the similarity of LCV to EBV and the suitability of the macaque as an animal model for studying EBV pathogenesis

Use of a systems model of drug-induced liver injury (DILIsym®) to elucidate the mechanistic differences between acetaminophen and its less-toxic isomer, AMAP, in mice

AbstractAcetaminophen (APAP) has been used as a probe drug to investigate drug-induced liver injury (DILI). In mice, 3′-hydroxyacetanilide (AMAP), a less-toxic isomer of APAP, has also been studied as a negative control. Various mechanisms for the divergence in toxicological response between the two isomers have been proposed. This work utilized a mechanistic, mathematical model of DILI to test the plausibility of four mechanistic hypotheses. Simulation results were compared to an array of measured endpoints in mice treated with APAP or AMAP. The four hypotheses included: (1) quantitative differences in drug metabolism profiles as a result of different affinities for the relevant enzymes; (2) differences in the amount of reactive metabolites produced due to cytochrome P450 (CYP450) inhibition by the AMAP reactive metabolites; (3) differences in the rate of conjugation between the reactive metabolites and proteins; (4) differences in the downstream effects or potencies of the reactive metabolites on vital components within hepatocytes. The simulations did not support hypotheses 3 or 4 as the most likely hypotheses underlying the difference in hepatoxic potential of APAP and AMAP. Rather, the simulations supported hypotheses 1 and 2 (less reactive metabolite produced per mole of AMAP relative to APAP). Within the simulations, the difference in reactive metabolite formation was equally likely to have occurred from differential affinities for the relevant drug metabolism enzymes or from direct CYP450 inhibition by the AMAP reactive metabolite. The demonstrated method of using simulation tools to probe the importance of possible contributors to toxicological observations is generally applicable across species

The Role of LCV and EBV Latent Membrane Protein 2A in Epithelial Cells

Epstein-Barr Virus (EBV) is a ubiquitous human herpesvirus that is associated with malignancies of both lymphoid and epithelial origin including Burkitt's lymphoma and nasopharyngeal carcinoma (NPC) among others. The focus of this study was to investigate both EBV and rhesus EBV (LCV) latent membrane protein 2A (LMP2A) signaling and biological functions in epithelial cells and their contribution to EBV-mediated carcinogenesis. Rhesus LCV LMP2A (Rh-LMP2A) has an overall sequence homology of 62% to EBV LMP2A. The 12 transmembrane domains and the N-terminal cytoplasmic domain containing an immunoreceptor tyrosine-based activation motif (ITAM) and PY motifs are conserved in Rh-LMP2A. In this study, Rh-LMP2A expression in human foreskin keratinocytes (HFK) activated Akt and inactivated GSK3[beta]. This led to the subsequent accumulation and nuclear translocation of [beta]-catenin which was found to be Akt dependent. Rh-LMP2A also inhibited epithelial cell differentiation. A mutant form of Rh-LMP2A lacking the last six transmembrane domains was able to function similarly to full-length Rh-LMP2A. Since EBV LMP2A is consistently expressed in metastatic NPC, the potential role of LMP2A in metastasis was investigated. EBV LMP2A expression in HFK cells led to increased expression and activity of several matrix metalloproteinases (MMPs), which are involved in basement membrane and extracellular matrix degradation. The activity of MMP-7 and MMP-13 was dependent on Akt activation, whereas MMP-2 activity was dependent on MAPK activation. These results identify a mechanism by which EBV LMP2A could contribute to NPC metastasis. Through the activation of the PI3K/Akt and [beta]-catenin pathways that impact cell proliferation and survival in addition to upregulating MMP expression and activity, LMP2A likely contributes to carcinogenesis and metastasis. Lastly, the similarity of rhesus LCV to EBV further validates the rhesus macaque model for the study of EBV pathogenesis

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be employed to construct physiologically-based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been employed to study cytotoxicity and perturbation of biological processes by drugs and hepatically-generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model was used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction

Pure silica nanoparticles for liposome/lipase system encapsulation: Application in biodiesel production

In this work we report the synthesis of organic inorganic solid with spherical morphology where enzyme, as active compounds, is encapsulated. The organic phase of nanospheres is composed of l-phosphatidylcholine, as liposome, and lipase from Rhizomucor miehei, as enzyme. The organic phase is covered with porous inorganic silica shell that could stabilize the internal liposomal phase and, consequently, isolate and protect the bioactive molecules. The liposome and silica amount used during the immobilization procedure have been optimized in order to obtain active and stable heterogeneous biocatalyst. Hybrid-nanospheres containing the enzyme were used to catalyze the transesterification reaction of triolein with methanol to methyl esters, typical biodiesel mixture compounds. The encapsulated enzyme retains its activity after 5 reaction cycles. The total productivity of the best catalyst obtained is higher than that of the free enzyme.The authors, A.C. and U.D., thank the Spanish MICINN (Consolider Ingenio 2010-MULTICAT (CSD2009-00050) and MAT2011-29020-C02-01) for their financial support.Macario, A.; Verri, F.; Díaz Morales, UM.; Corma Canós, A.; Giordano, G. (2013). Pure silica nanoparticles for liposome/lipase system encapsulation: Application in biodiesel production. Catalysis Today. 204:148-155. doi:10.1016/j.cattod.2012.07.014S14815520

Additions to Philippine slender skinks of the Brachymeles bonitae complex (Reptilia: Squamata: Scincidae) IV: Resurrection and redescription of Brachymeles burksi

The diversity of Philippine amphibians and reptiles has increased over the last few decades, in part due to re-evaluation of species formerly believed to be widespread. Many of these investigations of widespread species have uncovered multiple closely related cryptic lineages comprising species complexes, each restricted to individual Pleistocene Aggregate Island Complexes (PAICs). One group in particular for which widespread cryptic diversity has been common is the clade of Philippine skinks of the genus Brachymeles. Recent phylogenetic studies of the formerly recognized widespread species Brachymeles bonitae have indicated that this species is actually a complex distributed across several major PAICs and smaller island groups in the central and northern Philippines, with numerous species that exhibit an array of digit loss and limb reduction patterns. Despite the recent revisions to the B. bonitae species complex, studies suggest that unique cryptic lineages still exist within this group. In this paper, we resurrect the species Brachymeles burksi Taylor 1917, for a lineage of non-pentadactyl, semi-fossorial skink from Mindoro and Marinduque islands. First described in 1917, B. burksi was synonymized with B. bonitae in 1956, and has rarely been reconsidered since. Evaluation of genetic and morphological data (qualitative traits, meristic counts, and mensural measurements), and comparison of recently-obtained specimens to Taylor’s original description support this species’ recognition, as does its insular distribution on isolated islands in the central portions of the archipelago. Morphologically, B. burksi is differentiated from other members of the genus based on a suite of unique phenotypic characteristics, including a small body size, digitless limbs, a high number of presacral vertebrae, the absence of auricular openings, and discrete (non-overlapping) meristic scale counts. The recognition of this central Philippine species further increases the diversity of non-pentadactyl members of the B. bonitae complex, and reinforces the biogeographic uniqueness of the Mindoro faunal region

The human genome: a multifractal analysis

<p>Abstract</p> <p>Background</p> <p>Several studies have shown that genomes can be studied via a multifractal formalism. Recently, we used a multifractal approach to study the genetic information content of the <it>Caenorhabditis elegans </it>genome. Here we investigate the possibility that the human genome shows a similar behavior to that observed in the nematode.</p> <p>Results</p> <p>We report here multifractality in the human genome sequence. This behavior correlates strongly on the presence of Alu elements and to a lesser extent on CpG islands and (G+C) content. In contrast, no or low relationship was found for LINE, MIR, MER, LTRs elements and DNA regions poor in genetic information. Gene function, cluster of orthologous genes, metabolic pathways, and exons tended to increase their frequencies with ranges of multifractality and large gene families were located in genomic regions with varied multifractality. Additionally, a multifractal map and classification for human chromosomes are proposed.</p> <p>Conclusions</p> <p>Based on these findings, we propose a descriptive non-linear model for the structure of the human genome, with some biological implications. This model reveals 1) a multifractal regionalization where many regions coexist that are far from equilibrium and 2) this non-linear organization has significant molecular and medical genetic implications for understanding the role of Alu elements in genome stability and structure of the human genome. Given the role of Alu sequences in gene regulation, genetic diseases, human genetic diversity, adaptation and phylogenetic analyses, these quantifications are especially useful.</p

Actinomyces in Chronic Granulomatous Disease: An Emerging and Unanticipated Pathogen

Background.Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system that causes defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections, mostly by catalase-producing organisms. We report for the first time, to our knowledge, chronic infections with Actinomyces species in 10 patients with CGD. Actinomycosis is a chronic granulomatous condition that commonly manifests as cervicofacial, pulmonary, or abdominal disease, caused by slowly progressive infection with oral and gastrointestinal commensal Actinomyces species. Treatment of actinomycosis is usually simple in immunocompetent individuals, requiring long-term, high-dose intravenous penicillin, but is more complicated in those with CGD because of delayed diagnosis and an increased risk of chronic invasive or debilitating disease. Methods.Actinomyces was identified by culture, staining, 16S ribosomal DNA polymerase chain reaction, and/or a complement fixation test in 10 patients with CGD. Results.All 10 patients presented with a history of fever and elevated inflammatory signs without evident focus. Diagnosis was delayed and clinical course severe and protracted despite high-dose intravenous antibiotic therapy and/or surgery. These results suggest an unrecognized and unanticipated susceptibility to weakly pathogenic Actinomyces species in patients with CGD because these are catalase-negative organisms previously thought to be nonpathogenic in CGD. Conclusions.Actinomycosis should be vigorously sought and promptly treated in patients with CGD presenting with uncommon and prolonged clinical signs of infection. Actinomycosis is a catalase-negative infection important to consider in CG