Cloning of Canine Galactokinase (\u3cem\u3eGALK1\u3c/em\u3e) and Evaluation as a Candidate Gene for Hereditary Cataracts in Labrador Retrievers

We identified a pedigree of Labrador retrievers (LR) that develop hereditary cataracts between 6 and 18 months of age. In humans, galactokinase deficiency is an autosomal recessive disorder characterized by juvenile onset of cataracts.1 In order to evaluate GALK1 as a candidate gene, we cloned and sequenced the canine GALK1 gene and tested a single nucleotide polymorphism (SNP) in the gene for segregation with cataracts in the LR pedigree

Identification of PADI2 as a potential breast cancer biomarker and therapeutic target.

BACKGROUND: We have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects. METHODS: RNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes. RESULTS: We show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 x 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45alpha, and Ki67. CONCLUSION: Together, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy

Willpower Satisficing

Satisficing Consequentialism is often rejected as hopeless. Perhaps its greatest problem is that it risks condoning the gratuitous prevention of goodness above the baseline of what qualifies as “good enough”. I propose a radical new willpower-based version of the view that avoids this problem, and that better fits with the motivation of avoiding an excessively demanding conception of morality. I further demonstrate how, by drawing on the resources of an independent theory of blameworthiness, we may obtain a principled specification of what counts as “good enough”

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Should we de-moralize philosophical ethics?

Some philosophers, such as Roger Crisp and Alastair Norcross, have recently argued that the traditional moral categories of wrongness, permissibility and obligation should be avoided when doing ethical theory. I argue that even if morality does not itself provide reasons for action, the moral categories nevertheless have a central role to play in ethical theory: they allow us to make crucial judgements about how to feel about, and react to, agents who behave in anti-social ways, and they help motivate us to act altruistically.<br/

The rights and wrongs of consequentialism

I argue that the strongest form of consequentialism is one which rejects the claim that we are morally obliged to bring about the best available consequences, but which continues to assert that what there is most reason to do is bring about the best available consequences. Such an approach promises to avoid common objections to consequentialism, such as demandingness objections. Nevertheless, the onus is on the defender of this approach either to offer her own account of what moral obligations we do face, or to explain why offering such a theory is ill-advised. I consider, and reject, one attempt at the second sort of strategy, put forward by Alastair Norcross, who defends a ‘scalar’ consequentialism which eschews the moral concepts of right, wrong and obligation, and limits itself to claims about what is better and worse. I go on to raise some considerations which suggest that no systematic consequentialist theory of our moral obligations will be plausible, and propose instead that consequentialism should have a more informal and indirect role in shaping what we take our moral obligations to be

Demandingness objections in ethics

It is common for moral philosophers to reject a moral theory on the basis that its verdicts are unreasonably demanding—it requires too much of us to be a correct account of our moral obligations. Even though such objections frequently strike us as convincing, they give rise to two challenges: Are demandingness objections really independent of other objections to moral theories? Do standard demandingness objections not presuppose that costs borne by the comfortably off are more important than costs borne by the poor? These challenges have led some writers to question whether there really can be convincing demandingness objections, notwithstanding their strong initial appeal. David Sobel has argued that standard demandingness objections are ‘impotent’, Liam Murphy that they can be ‘dissolved’. In this paper, I aim to vindicate the possibility of demandingness objections by addressing these two challenges

Impartial reasons, moral demands

Consequentialism is often charged with demandingness objections which arise in response to the theory's commitment to impartiality. It might be thought that the only way that consequentialists can avoid such demandingness objections is by dropping their commitment to impartialism. However, I outline and defend a framework within which all reasons for action are impartially grounded, yet which can avoid demandingness objections. I defend this framework against what might appear to be a strong objection, namely the claim that anyone who accepts the theory will be practically irrational

Consequentialism and moral demands

The aim of this thesis is to outline a form of consequentialism which denies the deeply unintuitive claim that we have a moral obligation to bring about the best consequences we can. Consequentialism should not be understood primarily as a theory of morality narrowly conceived as focusing on obligation, but instead as a theory of the goodness and choiceworthiness of our actions and practices, and of what there is most reason to do. I begin from the well-rehearsed objection to consequentialism that it is unreasonably demanding, arguing that this constitutes a good objection to the theory in its traditional form, but showing that my favoured form of consequentialism- one which limits itself to claims about value and reasons- is not susceptible to it. I discuss criticisms of consequentialism from influential work in the second half of the twentieth century, showing how the strongest objections outlined therein apply only to consequentialism as a theory of moral obligation, and not to consequentialism as a theory of value. Finally, I outline what a consequentialist should say positively about moral demands, explaining the limited role which the theory should have in shaping our moral obligations. I conclude that consequentialists should not be preoccupied with developing a distinctively consequentialist theory of moral demands