Classical Cepheid Pulsation Models. III. The Predictable Scenario

Within the current uncertainties in the treatment of the coupling between pulsation and convection, limiting amplitude, nonlinear, convective models appear the only viable approach for providing theoretical predictions about the intrinsic properties of radial pulsators. In this paper we present the results of a comprehensive set of Cepheid models computed within such theoretical framework for selected assumptions on their original chemical composition.Comment: 24 pages, 1 latex file containing 6 tables, 10 postscript figures, accepted for publication on Ap

High resolution DNA barcode library for European butterflies reveals continental patterns of mitochondrial genetic diversity

The study of global biodiversity will greatly benefit from access to comprehensive DNA barcode libraries at continental scale, but such datasets are still very rare. Here, we assemble the first high-resolution reference library for European butterflies that provides 97% taxon coverage (459 species) and 22,306 COI sequences. We estimate that we captured 62% of the total haplotype diversity and show that most species possess a few very common haplotypes and many rare ones. Specimens in the dataset have an average 95.3% probability of being correctly identified. Mitochondrial diversity displayed elevated haplotype richness in southern European refugia, establishing the generality of this key biogeographic pattern for an entire taxonomic group. Fifteen percent of the species are involved in barcode sharing, but two thirds of these cases may reflect the need for further taxonomic research. This dataset provides a unique resource for conservation and for studying evolutionary processes, cryptic species, phylogeography, and ecology.Peer reviewe

Targeting the Mitotic Checkpoint to Kill Tumor Cells

One of the most common hallmarks of cancer cells is aneuploidy or an abnormal number of chromosomes. This abnormal chromosome content is a consequence of chromosome missegregation during mitosis, a defect that is seen more frequently in tumor cell divisions as in normal cell divisions. In fact, a large fraction of human tumors display a chromosome instable phenotype, meaning that they very frequently missegregate chromosomes. This can cause variegated aneuploidy within the tumor tissue. It has been argued that this hallmark of cancer could be exploited in anti-cancer therapies. Here we test this hypothesis by inactivation of the mitotic checkpoint through RNAi-mediated depletion of an essential checkpoint component, Mps1. The mitotic checkpoint delays segregation of chromosomes during mitosis until all chromosomes are properly attached to the mitotic spindle. Its inactivation will therefore lead to increased segregation errors. Indeed, we show that this can lead to increased cell death in tumor cells. We demonstrate that increased cell death is associated with a dramatic increase in segregation errors. This suggests that inhibition of the mitotic checkpoint might represent a useful anti-cancer strategy

Diminished circadian and ultradian rhythms in pathological brain tissue in human in vivo

Chronobiological rhythms, such as the circadian rhythm, have long been linked to neurological disorders, but it is currently unknown how pathological processes affect the expression of biological rhythms in the brain. Here, we use the unique opportunity of long-term, continuous intracranially recorded EEG from 38 patients (totalling 6338 hours) to delineate circadian and ultradian rhythms in different brain regions. We show that functional circadian and ultradian rhythms are diminished in pathological tissue, independent of regional variations. We further demonstrate that these diminished rhythms are persistent in time, regardless of load or occurrence of pathological events. These findings provide the first evidence that brain pathology is functionally associated with persistently diminished chronobiological rhythms in vivo in humans, independent of regional variations or pathological events. Future work interacting with, and restoring, these modulatory chronobiological rhythms may allow for novel therapies

Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci

The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider positional conservation across mammalian genomes as an indicator of functional commonality. We identify 665 conserved lncRNA promoters in mouse and human genomes that are preserved in genomic position relative to orthologous coding genes. The identified positionally conserved lncRNA genes are primarily associated with developmental transcription factor loci with which they are co-expressed in a tissue-specific manner. Strikingly, over half of all positionally conserved RNAs in this set are linked to distinct chromatin organization structures, overlapping the binding sites for the CTCF chromatin organizer and located at chromatin loop anchor points and borders of topologically associating domains (TADs). These topological anchor point (tap)RNAs possess conserved sequence domains that are enriched in potential recognition motifs for Zinc Finger proteins. Characterization of these non-coding RNAs and their associated coding genes shows that they are functionally connected: they regulate each other ′s expression and influence the metastatic phenotype of cancer cells in vitro in a similar fashion. Thus, interrogation of positionally conserved lncRNAs identifies a new subset of tapRNAs with shared functional properties. These results provide a large dataset of lncRNAs that conform to the ″extended gene″ model, in which conserved developmental genes are genomically and functionally linked to regulatory lncRNA loci across mammalian evolution

Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide-MHC

Recent work has demonstrated that nonstimulatory endogenous peptides can enhance T cell recognition of antigen, but MHCI- and MHCII-restricted systems have generated very different results. MHCII-restricted TCRs need to interact with the nonstimulatory peptide–MHC (pMHC), showing peptide specificity for activation enhancers or coagonists. In contrast, the MHCI-restricted cells studied to date show no such peptide specificity for coagonists, suggesting that CD8 binding to noncognate MHCI is more important. Here we show how this dichotomy can be resolved by varying CD8 and TCR binding to agonist and coagonists coupled with computer simulations, and we identify two distinct mechanisms by which CD8 influences the peptide specificity of coagonism. Mechanism 1 identifies the requirement of CD8 binding to noncognate ligand and suggests a direct relationship between the magnitude of coagonism and CD8 affinity for coagonist pMHCI. Mechanism 2 describes how the affinity of CD8 for agonist pMHCI changes the requirement for specific coagonist peptides. MHCs that bind CD8 strongly were tolerant of all or most peptides as coagonists, but weaker CD8-binding MHCs required stronger TCR binding to coagonist, limiting the potential coagonist peptides. These findings in MHCI systems also explain peptide-specific coagonism in MHCII-restricted cells, as CD4–MHCII interaction is generally weaker than CD8–MHCI.National Institutes of Health (U.S.). Pioneer Awar

Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide–MHC

Recent work has demonstrated that nonstimulatory endogenous peptides can enhance T cell recognition of antigen, but MHCI- and MHCII-restricted systems have generated very different results. MHCII-restricted TCRs need to interact with the nonstimulatory peptide–MHC (pMHC), showing peptide specificity for activation enhancers or coagonists. In contrast, the MHCI-restricted cells studied to date show no such peptide specificity for coagonists, suggesting that CD8 binding to noncognate MHCI is more important. Here we show how this dichotomy can be resolved by varying CD8 and TCR binding to agonist and coagonists coupled with computer simulations, and we identify two distinct mechanisms by which CD8 influences the peptide specificity of coagonism. Mechanism 1 identifies the requirement of CD8 binding to noncognate ligand and suggests a direct relationship between the magnitude of coagonism and CD8 affinity for coagonist pMHCI. Mechanism 2 describes how the affinity of CD8 for agonist pMHCI changes the requirement for specific coagonist peptides. MHCs that bind CD8 strongly were tolerant of all or most peptides as coagonists, but weaker CD8-binding MHCs required stronger TCR binding to coagonist, limiting the potential coagonist peptides. These findings in MHCI systems also explain peptide-specific coagonism in MHCII-restricted cells, as CD4–MHCII interaction is generally weaker than CD8–MHCI.National Institutes of Health (U.S.). Pioneer Awar

Teleology and Realism in Leibniz's Philosophy of Science

This paper argues for an interpretation of Leibniz’s claim that physics requires both mechanical and teleological principles as a view regarding the interpretation of physical theories. Granting that Leibniz’s fundamental ontology remains non-physical, or mentalistic, it argues that teleological principles nevertheless ground a realist commitment about mechanical descriptions of phenomena. The empirical results of the new sciences, according to Leibniz, have genuine truth conditions: there is a fact of the matter about the regularities observed in experience. Taking this stance, however, requires bringing non-empirical reasons to bear upon mechanical causal claims. This paper first evaluates extant interpretations of Leibniz’s thesis that there are two realms in physics as describing parallel, self-sufficient sets of laws. It then examines Leibniz’s use of teleological principles to interpret scientific results in the context of his interventions in debates in seventeenth-century kinematic theory, and in the teaching of Copernicanism. Leibniz’s use of the principle of continuity and the principle of simplicity, for instance, reveal an underlying commitment to the truth-aptness, or approximate truth-aptness, of the new natural sciences. The paper concludes with a brief remark on the relation between metaphysics, theology, and physics in Leibniz

On tacit knowledge for philosophy of education

This article offers a detailed reading Gascoigne and Thornton’s book Tacit Knowledge (2013), which aims to account for the tacitness of tacit knowledge (TK) while preserving its status as knowledge proper. I take issue with their characterization and rejection of the existential-phenomenological Background—which they presuppose even as they dismiss—and their claim that TK can be articulated “from within”—which betrays a residual Cartesianism, the result of their elision of conceptuality and propositionality. Knowledgeable acts instantiate capacities which we might know we have and of which we can be aware, but which are not propositionally structured at their “core”. Nevertheless, propositionality is necessary to what Robert Brandom calls, in Making It Explicit (1994) and Articulating Reasons (2000), “explicitation”, which notion also presupposes a tacit dimension, which is, simply, the embodied person (the knower), without which no conception of knowledge can get any purchase. On my view, there is no knowledgeable act that can be understood as such separately from the notion of skilled corporeal performance. The account I offer cannot make sense of so-called “knowledge-based” education, as opposed to systems and styles which supposedly privilege “contentless” skills over and above “knowledge”, because on the phenomenological and inferentialist lines I endorse, neither the concepts “knowledge” nor “skill” has any purchase or meaning without the other