Zeno and Stoic Consistency

It seems that the Stoics were prepared to say two things : 1) It will in fact pay to be virtuous provided that you want to be happy; and 2) the good man will seek virtue for its own sake. Some of the apparent difficulties in reconciling these propositions may be resolved by examining the notion of seeking virtue for its own sake. What then do the Stoics say that virtue is? Any Cynic could advocate a consistent life, for the description is purely formal. But one consistent life might be set against another, and Zeno\u27s appeal to natural consistency prevents this, as well as showing exactly why virtue pays. The question could, of course, have been tackled in another way. Is there in fact more than one kind of consistent life? Zeno would certainly have agreed that there is not, but though he thought that in all but the wise inconsistency leads to conflict and misery, he did not ask such a necessary question as: Is an injury to someone else also an injury to myself? Why did he not? In part because by separating the goal (happiness) from the end (virtue) he underestimated the importance of eudaemonism in preaching a moral system to the unconverted. Or if he did not underestimate it, he kept implying that he did and that one should

Plotinus and the Value of the Human Person

Plotinus\u27 views on man and his value must be closely related to his views of the One. His first principle is radically different from that of the Platonists, Aristotelians, and Stoics who precede him. In many respects, as in all other areas of his thought, his conception is a synthesis of what went before, but it cannot be overemphasized that it is a new conception, a dynamic first principle whose character as efficient cause is to be viewed in terms of Eros and of will as much as of mind and knowledge. That being so, and man being a microcosm, one should expect to find - and we do find - a different conception of man, and, compared with Plato and Aristotle, a new intrinsic importance assigned to him. Man in Plotinus is created perfectible and valuable, but he may not live up to himself; if he does not do so, it is own fault and neither man nor gods should be held responsible. Above all, for Plotinus no saviour god is required to get us out of the troubles in which we immerse ourselves through crime and folly

Notes on Aristotle De Anima 3.5

Of all the Aristotelian doctrines perhaps the most difficult is that concerning the Active and Passive Intellects which we find in the short fifth chapter of the third book of the De Anima. Interpretations of this chapter have been almost as numerous as interpreters, and it would be naive to expect at this stage to be definitive. Nevertheless it seems that progress has been delayed in many cases by a too casual approach to what Aristotle says in the chapter itself - and this at least admits of some improvement

An EBSD study of the deformation of service-aged 316 austenitic steel

Electron backscatter diffraction (EBSD) has been used to examine the plastic deformation of an ex-service 316 austenitic stainless steel at 297K and 823K (24 °C and 550 °C)at strain rates 3.5x10-3 to 4 x 10-7 s-1. The distribution of local misorientations was found to depend on the imposed plastic strain following a lognormal distribution at true strains 0.1. At 823 K (550 °C), the distribution of misorientations depended on the applied strain rate. The evolution of lattice misorientations with increasing plastic strain up to 0.23 was quantified using the metrics kernel average misorientation, average intragrain misorientation, and low angle misorientation fraction. For strain rate down to 10-5 s-1 all metrics were insensitive to deformation temperature, mode (tension vs. compression) and orientation of the measurement plane. The strain sensitivity of the different metrics was found to depend on the misorientation ranges considered in their calculation. A simple new metric, proportion of undeformed grains, is proposed for assessing strain in both aged and unaged material. Lattice misorientations build up with strain faster in aged steel than in un-aged material and most of the metrics were sensitive to the effects of thermal aging. Ignoring aging effects leads to significant overestimation of the strains around welds. The EBSD results were compared with nanohardness measurements and good agreement established between the two techniques of assessing plastic strain in aged 316 steel

Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor

Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes

Differential preservation of endogenous human and microbial DNA in dental calculus and dentin

Dental calculus (calcified dental plaque) is prevalent in archaeological skeletal collections and is a rich source of oral microbiome and host-derived ancient biomolecules. Recently, it has been proposed that dental calculus may provide a more robust environment for DNA preservation than other skeletal remains, but this has not been systematically tested. In this study, shotgun-sequenced data from paired dental calculus and dentin samples from 48 globally distributed individuals are compared using a metagenomic approach. Overall, we find DNA from dental calculus is consistently more abundant and less contaminated than DNA from dentin. The majority of DNA in dental calculus is microbial and originates from the oral microbiome; however, a small but consistent proportion of DNA (mean 0.08 ± 0.08%, range 0.007–0.47%) derives from the host genome. Host DNA content within dentin is variable (mean 13.70 ± 18.62%, range 0.003–70.14%), and for a subset of dentin samples (15.21%), oral bacteria contribute \u3e 20% of total DNA. Human DNA in dental calculus is highly fragmented, and is consistently shorter than both microbial DNA in dental calculus and human DNA in paired dentin samples. Finally, we find that microbial DNA fragmentation patterns are associated with guanine-cytosine (GC) content, but not aspects of cellular structure

Optimal combinations of broadly neutralizing antibodies for prevention and treatment of HIV-1 clade C infection.

CAPRISA, 2016.Abstract available in PDF file

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology