"Antiscepticism and Easy Justification" - Ch 5 of Seemings and Epistemic Justification

In this chapter I investigate epistemological consequences of the fact that seeming-based justification is elusive, in the sense that the subject can lose this justification simply by reflecting on her seemings. I argue that since seeming-based justification is elusive, the antisceptical bite of phenomenal conservatism is importantly limited. I also contend that since seeming-based justification has this feature, phenomenal conservatism isn’t actually afflicted by easy justification problems

Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation

Objective Mitochondrial disturbances of energy-generating systems in childhood are a heterogeneous group of disorders. The aim of this multi-site survey was to characterise the natural course of a novel mitochondrial disease with ATP synthase deficiency and mutation in the TMEM70 gene. Methods Retrospective clinical data and metabolic profiles were collected and evaluated in 25 patients (14 boys, 11 girls) from seven European countries with a c. 317-2A -> G mutation in the TMEM70 gene. Results Severe muscular hypotonia (in 92% of newborns), apnoic spells (92%), hypertrophic cardiomyopathy (HCMP; 76%) and profound lactic acidosis (lactate 5-36 mmol/l; 92%) with hyperammonaemia (100-520 mu mol/l; 86%) were present from birth. Ten patients died within the first 6 weeks of life. Most patients surviving the neonatal period had persisting muscular hypotonia and developed psychomotor delay. HCMP was non-progressive and even disappeared in some children. Hypospadia was present in 54% of the boys and cryptorchidism in 67%. Increased excretion of lactate and 3-methylglutaconic acid (3-MGC) was observed in all patients. In four surviving patients, life-threatening hyperammonaemia occurred during childhood, triggered by acute gastroenteritis and prolonged fasting. Conclusions ATP synthase deficiency with mutation in TMEM70 should be considered in the diagnosis and management of critically ill neonates with early neonatal onset of muscular hypotonia, HCMP and hypospadias in boys accompanied by lactic acidosis, hyperammonaemia and 3-MGC-uria. However, phenotype severity may vary significantly. The disease occurs frequently in the Roma population and molecular-genetic analysis of the TMEM70 gene is sufficient for diagnosis without need of muscle biopsy in affected children

Immigration Enforcement and Fairness to Would-Be Immigrants

This chapter argues that governments have a duty to take reasonably effective and humane steps to minimize the occurrence of unauthorized migration and stay. While the effects of unauthorized migration on a country’s citizens and institutions have been vigorously debated, the literature has largely ignored duties of fairness to would-be immigrants. It is argued here that failing to take reasonable steps to prevent unauthorized migration and stay is deeply unfair to would-be immigrants who are not in a position to bypass visa regulations. Importantly, the argument here is orthogonal to the debate as to how much and what kinds of immigration ought to be allowed

Skepticism Motivated: On the Skeptical Import of Motivated Reasoning

Empirical work on motivated reasoning suggests that our judgments are influenced to a surprising extent by our wants, desires and preferences (Kahan 2016; Lord, Ross, and Lepper 1979; Molden and Higgins 2012; Taber and Lodge 2006). How should we evaluate the epistemic status of beliefs formed through motivated reasoning? For example, are such beliefs epistemically justified? Are they candidates for knowledge? In liberal democracies, these questions are increasingly controversial as well as politically timely (Beebe et al. 2018; Lynch forthcoming, 2018; Slothuus and de Vreese 2010). And yet, the epistemological significance of motivated reasoning has been almost entirely ignored by those working in mainstream epistemology. We aim to rectify this oversight. Using politically motivated reasoning as a case study, we show how motivated reasoning gives rise to three distinct kinds of skeptical challenges. We conclude by showing how the skeptical import of motivated reasoning has some important ramifications for how we should think about the demands of intellectual humility

Lysine Residue at Position 22 of the AID Protein Regulates Its Class Switch Activity

Background: Activation induced deaminase (AID) mediates class switch recombination and somatic hypermutation of immunoglobulin (Ig) genes in germinal centre B cells. In order to regulate its specific activity and as a means to keep offtarget mutations low, several mechanisms have evolved, including binding to specific cofactors, phosphorylation and destabilization of nuclear AID protein. Although ubiquitination at lysine residues of AID is recognized as an essential step in initiating degradation of nuclear AID, any functional relevance of lysine modifications has remained elusive. Methodology/Principal Findings: Here, we report functional implications of lysine modifications of the human AID protein by generating a panel of lysine to arginine mutants of AID and assessment of their catalytic class switch activity. We found that only mutation of Lys22 to Arg resulted in a significant reduction of class switching to IgG1 in transfected primary mouse B cells. This decrease in activity was neither reflected in reduced hypermutation of Ig genes in AID-mutant transfected DT40 B cell lines nor recapitulated in bacterial deamination assays, pointing to involvement of post-translational modification of Lys22 for AID activity in B cells. Conclusions/Significance: Our results imply that lysine modification may represent a novel level of AID regulation and tha

"Phenomenal Conservatism" - Ch 2 of Seemings and Epistemic Justification

In this chapter I introduce and analyse the tenets of phenomenal conservatism, and discuss the problem of the nature of appearances. After that, I review the asserted epistemic merits phenomenal conservatism and the principal arguments adduced in support of it. Finally, I survey objections to phenomenal conservatism and responses by its advocates. Some of these objections will be scrutinised and appraised in the next chapters

Rubber friction: role of the flash temperature

When a rubber block is sliding on a hard rough substrate, the substrate asperities will exert time-dependent deformations of the rubber surface resulting in viscoelastic energy dissipation in the rubber, which gives a contribution to the sliding friction. Most surfaces of solids have roughness on many different length scales, and when calculating the friction force it is necessary to include the viscoelastic deformations on all length scales. The energy dissipation will result in local heating of the rubber. Since the viscoelastic properties of rubber-like materials are extremely strongly temperature dependent, it is necessary to include the local temperature increase in the analysis. At very low sliding velocity the temperature increase is negligible because of heat diffusion, but already for velocities of order 0.01 m/s the local heating may be very important. Here I study the influence of the local heating on the rubber friction, and I show that in a typical case the temperature increase results in a decrease in rubber friction with increasing sliding velocity for v > 0.01 m/s. This may result in stick-slip instabilities, and is of crucial importance in many practical applications, e.g., for the tire-road friction, and in particular for ABS-breaking systems.Comment: 22 pages, 27 figure

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire

Purpose: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). Methods: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. Results: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. Conclusion: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib. Keywords: GSD Ib; Glycogen storage disease type Ib; Neutropenia; SGLT2 inhibitors; SLC37A

"Cognitive Penetrability" - Ch 3 of Seemings and Epistemic Justification

In this chapter I introduce the thesis that perceptual appearances are cognitively penetrable and analyse cases made against phenomenal conservatism hinging on this thesis. In particular, I focus on objections coming from the externalist reliabilist camp and the internalist inferentialist camp. I conclude that cognitive penetrability doesn’t yield lethal or substantive difficulties for phenomenal conservatism

Severe depletion of mitochondrial DNA in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromus- cular disorder in childhood leading to a dramatic loss of muscle strength. Functional investigations with high-reso- lution polarography and enzyme measurements of the res- piratory chain revealed lowered activities in muscle tissue of SMA patients. To gain a better understanding of this low energy supply we analyzed the amount of mitochon- drial DNA (mtDNA) in skeletal muscle of 20 unrelated children with genetically proven SMA and 31 controls. Quantitative Southern blot analysis revealed a severe and homogeneous decrease in the content of muscle mtDNA in relation to nuclear DNA in SMA patients (90.3±7.8%), whereas by immunofluorescence no decrease in the num- ber of mitochondria was detected. In addition, a two- to threefold reduction of the nuclear-encoded complex II (succinate dehydrogenase) activity was detected in SMA muscle tissue. Western blot analysis showed a significant reduction of both mitochondrial- and nuclear-encoded cy- tochrome c oxidase subunits. Our results indicate that mtDNA depletion in SMA is a consequence of severe at- rophy, and has to be differentiated by measurement of complex II from an isolated reduction of mtDNA as found in patients with mitochondriocytopathies and the so- called mtDNA depletion syndrome