Eudaimonistic Argumentation

Virtue theories have lately enjoyed a modest vogue in the study of argumentation, echoing the success of more far-reaching programmes in ethics and epistemology. Virtue theories of argumentation (VTA) comprise several conceptually distinct projects, including the provision of normative foundations for argument evaluation and a renewed focus on the character of good arguers. Perhaps the boldest of these is the pursuit of the fully satisfying argument, the argument that contributes to human flourishing. This project has an independently developed epistemic analogue: eudaimonistic virtue epistemology. Both projects stress the importance of widening the range of cognitive goals beyond, respectively, cogency and knowledge; both projects emphasize social factors, the right sort of community being indispensable for the cultivation of the intellectual virtues necessary to each project. This paper proposes a unification of the two projects by arguing that the intellectual good life sought by eudaimonistic virtue epistemologists is best realized through the articulation of an account of argumentation that contributes to human flourishing

Role of PTP1B in POMC neurons during chronic high fat diet: Sex differences in regulation of liver lipids and glucose tolerance

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin receptor signalling and may contribute to leptin resistance in diet-induced obesity. Although PTP1B inhibition has been suggested as a potential weight loss therapy, the role of specific neuronal PTP1B signalling in cardiovascular and metabolic regulation and the importance of sex differences in this regulation are still unclear. In this study, we investigated the impact of pro-opiomelanocortin (POMC) neuronal PTP1B deficiency in cardiometabolic regulation in male and female mice fed a high fat diet (HFD). Compared to control mice (PTP1Bflox/flox), male and female mice deficient in POMC neuronal PTP1B (PTP1Bflox/flox/POMC-Cre) had attenuated body weight gain (Male: -18%; Female: -16%) and fat mass (Male: -33%; Female: -29%) in response to HFD. Glucose tolerance was improved by 40% and liver lipid accumulation was reduced by 40% in PTP1Bflox/flox/POMC-Cre males but not in females. Compared to control mice, deficiency of POMC neuronal PTP1B did not alter mean arterial pressure (MAP) in male or female mice (Male: 112±1 vs. 112±1 mmHg in controls; Female: 106±3 vs. 109±3 mmHg in controls). Deficiency of POMC neuronal PTP1B also did not alter MAP response to acute stress in male or female compared to control mice (Male: Δ32±0 vs. Δ29±4 mmHg; Female: Δ22±2 vs. Δ27±4 mmHg). These data demonstrate that POMC-specific PTP1B deficiency improved glucose tolerance and attenuated diet-induced fatty liver only in male mice, attenuated weight gain in males and females, but did not enhance the MAP and HR responses to a HFD or to acute stress

Role of SOCS3 in POMC Neurons in metabolic and cardiovascular regulation.

Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of leptin signaling. We previously showed that the chronic effects of leptin on blood pressure (BP) and glucose regulation are mediated by stimulation of pro-opiomelanocortin (POMC) neurons. In this study, we examined the importance of endogenous SOCS3 in POMC neurons in control of metabolic and cardiovascular function and potential sex differences. Male and female SOCS3flox/flox/POMC-Cre mice in which SOCS3 was selectively deleted in POMC neurons and control SOCS3flox/flox mice were studied during a control diet (CD) or high fat diet (HFD) and during chronic leptin infusion. On CD, male and female SOCS3flox/flox/POMC-Cre mice were lighter in body weight despite similar food intake compared to control mice. Male SOCS3flox/flox/POMC-Cre mice exhibited increased energy expenditure. BP and heart rate were similar in male and female SOCS3flox/flox/POMC-Cre and control mice on CD. On a HFD, male and female SOCS3flox/flox/POMC-Cre mice showed attenuated weight gain. Female SOCS3flox/flox/POMC-Cre mice exhibited greater HFD-induced elevations in baseline BP and BP responses to air jet stress test compared to control mice. Chronic leptin infusion produced similar responses in all groups for food intake, body weight, oxygen consumption, blood glucose, BP and heart rate. Thus, SOCS3 deficiency in POMC neurons influences body weight regulation in CD and HFD and differentially affects BP and energy balance in a sex specific manner, but does not amplify the dietary, glycemic or cardiovascular effects of leptin

Impact of leptin deficiency on male tibia and vertebral body 3D bone architecture independent of changes in body weight

Leptin an adipokine with potent effects on energy balance and body weight plays an important role in defining bone architecture in growing mammals. However, major changes in body weight can also influence morphology of trabecular and cortical bone. Therefore, we examined the impact of leptin deficiency on tibia and vertebral body 3D bone architecture independent of changes in body weight. Furthermore, advances in computational 3D image analysis suggest that average morphological values may mask regional specific differences in trabecular bone thickness. The study utilized leptin-deficient Ob/Ob mice (n = 8) weight-paired to C57BL/6 (C57) control mice (n = 8) which were split into either lean or obese groups for 24 ± 2 weeks. Whole tibias and L3 vertebrae were fixed before high resolution microcomputed tomography (μCT) scanning was performed. Leptin deficiency independent of body weight reduced tibia cortical bone volume, trabecular bone volume/tissue volume, number, and mineral density. Mean tibia trabecular thickness showed no significant differences between all groups; however, significant changes in trabecular thickness were found when analyzed by region. This study demonstrates that leptin deficiency significantly impacts tibia and vertebral body trabecular and cortical bone 3D architecture independent of changes in body weight

Mathematical practice, crowdsourcing, and social machines

The highest level of mathematics has traditionally been seen as a solitary endeavour, to produce a proof for review and acceptance by research peers. Mathematics is now at a remarkable inflexion point, with new technology radically extending the power and limits of individuals. Crowdsourcing pulls together diverse experts to solve problems; symbolic computation tackles huge routine calculations; and computers check proofs too long and complicated for humans to comprehend. Mathematical practice is an emerging interdisciplinary field which draws on philosophy and social science to understand how mathematics is produced. Online mathematical activity provides a novel and rich source of data for empirical investigation of mathematical practice - for example the community question answering system {\it mathoverflow} contains around 40,000 mathematical conversations, and {\it polymath} collaborations provide transcripts of the process of discovering proofs. Our preliminary investigations have demonstrated the importance of "soft" aspects such as analogy and creativity, alongside deduction and proof, in the production of mathematics, and have given us new ways to think about the roles of people and machines in creating new mathematical knowledge. We discuss further investigation of these resources and what it might reveal. Crowdsourced mathematical activity is an example of a "social machine", a new paradigm, identified by Berners-Lee, for viewing a combination of people and computers as a single problem-solving entity, and the subject of major international research endeavours. We outline a future research agenda for mathematics social machines, a combination of people, computers, and mathematical archives to create and apply mathematics, with the potential to change the way people do mathematics, and to transform the reach, pace, and impact of mathematics research.Comment: To appear, Springer LNCS, Proceedings of Conferences on Intelligent Computer Mathematics, CICM 2013, July 2013 Bath, U

Distinct lineages of feline parvovirus associated with epizootic outbreaks in Australia, New Zealand and the United Arab Emirates

Feline panleukopenia (FPL), a frequently fatal disease of cats, is caused by feline parvovirus (FPV) or canine parvovirus (CPV). We investigated simultaneous outbreaks of FPL between 2014 and 2018 in Australia, New Zealand and the United Arab Emirates (UAE) where FPL outbreaks had not been reported for several decades. Case data from 989 cats and clinical samples from additional 113 cats were obtained to determine the cause of the outbreaks and epidemiological factors involved. Most cats with FPL were shelter-housed, 9 to 10 weeks old at diagnosis, unvaccinated, had not completed a primary vaccination series or had received vaccinations noncompliant with current guidelines. Analysis of parvoviral VP2 sequence data confirmed that all FPL cases were caused by FPV and not CPV. Phylogenetic analysis revealed that each of these outbreaks was caused by a distinct FPV, with two virus lineages present in eastern Australia and virus movement between different geographical locations. Viruses from the UAE outbreak formed a lineage of unknown origin. FPV vaccine virus was detected in the New Zealand cases, highlighting the difficulty of distinguishing the co-incidental shedding of vaccine virus in vaccinated cats. Inadequate vaccination coverage in shelter-housed cats was a common factor in all outbreaks, likely precipitating the multiple re-emergence of infection events

Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by impaired clearance of pulmonary bacteria. OBJECTIVES: The effect of COPD on alveolar macrophage (AM) microbicidal responses was investigated. METHODS: Alveolar macrophages (AMs) were obtained from bronchoalveolar lavage from healthy donors or COPD patients and challenged with opsonized serotype 14 Streptococcus pneumoniae. Cells were assessed for apoptosis, bactericidal activity and mitochondrial reactive oxygen species (mROS) production. A transgenic mouse line, in which the CD68 promoter ensures macrophage specific expression of human Mcl-1 (CD68.hMcl-1), was used to model the molecular aspects of COPD. MEASUREMENTS AND MAIN RESULTS: COPD AM had elevated levels of Mcl-1, an anti-apoptotic Bcl-2 family member, with selective reduction of delayed intracellular bacterial killing. CD68.hMcl-1 AM phenocopied the microbicidal defect since transgenic mice demonstrated impaired clearance of pulmonary bacteria and increased neutrophilic inflammation. Murine bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages (MDM) generated mitochondrial reactive oxygen species (mROS) in response to pneumococci, which co-localized with bacteria and phagolysosomes to enhance bacterial killing. The Mcl-1 transgene increased oxygen consumption rates and mROS expression in mock-infected BMDM but reduced caspase-dependent mROS production after pneumococcal challenge. COPD AM also increased basal mROS expression, but failed to increase production after pneumococcal challenge, in keeping with reduced intracellular bacterial killing. The defect in COPD AM intracellular killing was associated with a reduced ratio of mROS /superoxide dismutase 2. CONCLUSIONS: Upregulation of Mcl-1 and chronic adaption to oxidative stress alters mitochondrial metabolism and microbicidal function, reducing the delayed phase of intracellular bacterial clearance in COPD

Precision medicine in cats:novel niemann-pick type C1 diagnosed by whole-genome sequencing

State-of-the-art health care includes genome sequencing of the patient to identify genetic variants that contribute to either the cause of their malady or variants that can be targeted to improve treatment. The goal was to introduce state-of-the-art health care to cats using genomics and a precision medicine approach. To test the feasibility of a precision medicine approach in domestic cats, a single cat that presented to the University of Missouri, Veterinary Health Center with an undiagnosed neurologic disease was whole-genome sequenced. The DNA variants from the cat were compared to the DNA variant database produced by the 99 Lives Cat Genome Sequencing Consortium. Approximately 25× genomic coverage was produced for the cat. A predicted p.H441P missense mutation was identified in NPC1, the gene causing Niemann-Pick type C1 on cat chromosome D3.47456793 caused by an adenine-to-cytosine transversion, c.1322A>C. The cat was homozygous for the variant. The variant was not identified in any other 73 domestic and 9 wild felids in the sequence database or 190 additionally genotyped cats of various breeds. The successful effort suggested precision medicine is feasible for cats and other undiagnosed cats may benefit from a genomic analysis approach. The 99 Lives DNA variant database was sufficient but would benefit from additional cat sequences. Other cats with the mutation may be identified and could be introduced as a new biomedical model for NPC1. A genetic test could eliminate the disease variant from the population

How to think about informal proofs

This document is the Accepted Manuscript version of the following article: Brendan Larvor, ‘How to think about informal proofs’, Synthese, Vol. 187(2): 715-730, first published online 9 September 2011. The final publication is available at Springer via doi:10.1007/s11229-011-0007-5It is argued in this study that (i) progress in the philosophy of mathematical practice requires a general positive account of informal proof; (ii) the best candidate is to think of informal proofs as arguments that depend on their matter as well as their logical form; (iii) articulating the dependency of informal inferences on their content requires a redefinition of logic as the general study of inferential actions; (iv) it is a decisive advantage of this conception of logic that it accommodates the many mathematical proofs that include actions on objects other than propositions; (v) this conception of logic permits the articulation of project-sized tasks for the philosophy of mathematical practice, thereby supplying a partial characterisation of normal research in the fieldPeer reviewedFinal Accepted Versio

Werewolf, there wolf : Variants in hairless associated with hypotrichia and roaning in the lykoi cat breed

Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non‐lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR lysine demethylase and nuclear receptor corepressor) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.Peer reviewe