Multiple paths to aquatic specialisation in four species of Central American Anolis lizards

Aquatic anoles present an interesting ecomorphological puzzle. On the one hand, the link between habitat use and morphology is well established as convergent within the Caribbean anole radiation. On the other hand, aquatic anoles do not appear to form an ecomorphological group – rather, it appears that there may be several ways to adapt to aquatic habitats. We explore this issue by examining the ecology, morphology and performance of four species of Central American aquatic anoles belonging to two different lineages. Overall, we find that aquatic anoles overlap in multiple ecological and morphological dimensions. However, we do find some differences in substrate use, claw and limb morphology, and bite force that distinguish Anolis aquaticus from the other three species (A. lionotus, A. oxylophus and A. poecilopus). Our results suggest that A. aquaticus is adapted to climb on boulders, whereas the other species utilise vegetation in streamside habitats.     

Ordinary language philosophy,explanation, and the historical turn in philosophy of science

Taking a cue from remarks Thomas Kuhn makes in 1990 about the historical turn in philosophy of science, I examine the history of history and philosophy of science within parts of the British philosophical context in the 1950s and early 1960s. During this time, ordinary language philosophy's influence was at its peak. I argue that the ordinary language philosophers' methodological recommendation to analyze actual linguistic practice influences several prominent criticisms of the deductive-nomological model of scientific explanation and that these criticisms relate to the historical turn in philosophy of science. To show these connections, I primarily examine the work of Stephen Toulmin, who taught at Oxford from 1949 to 1954, and Michael Scriven, who completed a dissertation on explanation under Gilbert Ryle and R.B. Braithwaite in 1956. I also consider Mary Hesse's appeal to an ordinary language-influenced account of meaning in her account of the role of models and analogies in scientific reasoning, and W.H. Watson's Wittgensteinian philosophy of science, an early influence on Toulmin. I think there are two upshots to my historical sketch. First, it fills out details of the move away from logical positivism to more historical- and practice-focused philosophies of science. Second, questions about linguistic meaning and the proper targets and aims of philosophical analysis are part and parcel of the historical turn, as well as its reception. Looking at the philosophical background during which so-called linguistic philosophers also had a hand in bringing these questions to prominence helps us understand why.     

Norton's material theory of analogy

In his book, The Material Theory of Induction, Norton argues that the quest for a universal formal theory or ‘schema’ for analogical inference should be abandoned. In its place, he offers the “material theory of analogy”: each analogical inference is “powered” by a local fact of analogy rather than by any formal schema. His minimalist model promises a straightforward, fact-based approach to the evaluation and justification of analogical inferences. This paper argues that although the rejection of universal schemas is justified, Norton's positive theory is limited in scope: it works well only for a restricted class of analogical inferences. Both facts and quasi-formal criteria have roles to play in a theory of analogical reasoning.     

Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity

Plague is a pandemic human invasive disease caused by the bacterial agent Yersinia pestis. We here report a comparison of 17 whole genomes of Y. pestis isolates from global sources. We also screened a global collection of 286 Y. pestis isolates for 933 SNPs using Sequenom MassArray SNP typing. We conducted phylogenetic analyses on this sequence variation dataset, assigned isolates to populations based on maximum parsimony and, from these results, made inferences regarding historical transmission routes. Our phylogenetic analysis suggests that Y. pestis evolved in or near China and spread through multiple radiations to Europe, South America, Africa and Southeast Asia, leading to country-specific lineages that can be traced by lineage-specific SNPs. All 626 current isolates from the United States reflect one radiation, and 82 isolates from Madagascar represent a second radiation. Subsequent local microevolution of Y. pestis is marked by sequential, geographically specific SNPs.     

Tetraspanin15 regulates cellular trafficking and activity of the ectodomain sheddase ADAM10

A disintegrin and metalloproteinase10 (ADAM10) has been implicated as a major sheddase responsible for the ectodomain shedding of a number of important surface molecules including the amyloid precursor protein and cadherins. Despite a well-documented role of ADAM10 in health and disease, little is known about the regulation of this protease. To address this issue we conducted a split-ubiquitin yeast two-hybrid screen to identify membrane proteins that interact with ADAM10. The yeast experiments and co-immunoprecipitation studies in mammalian cell lines revealed tetraspanin15 (TSPAN15) to specifically associate with ADAM10. Overexpression of TSPAN15 or RNAi-mediated knockdown of TSPAN15 led to significant changes in the maturation process and surface expression of ADAM10. Expression of an endoplasmic reticulum (ER) retention mutant of TSPAN15 demonstrated an interaction with ADAM10 already in the ER. Pulse-chase experiments confirmed that TSPAN15 accelerates the ER-exit of the ADAM10-TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface. Importantly, TSPAN15 also showed the ability to mediate the regulation of ADAM10 protease activity exemplified by an increased shedding of N-cadherin and the amyloid precursor protein. In conclusion, our data show that TSPAN15 is a central modulator of ADAM10-mediated ectodomain shedding. Therapeutic manipulation of its expression levels may be an additional approach to specifically regulate the activity of the amyloid precursor protein alpha-secretase ADAM10.     

The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis.     

Nanoparticle-based drug delivery: case studies for cancer and cardiovascular applications

Nanoparticles (NPs) comprised of nanoengineered complexes are providing new opportunities for enabling targeted delivery of a range of therapeutics and combinations. A range of functionalities can be included within a nanoparticle complex, including surface chemistry that allows attachment of cell-specific ligands for targeted delivery, surface coatings to increase circulation times for enhanced bioavailability, specific materials on the surface or in the nanoparticle core that enable storage of a therapeutic cargo until the target site is reached, and materials sensitive to local or remote actuation cues that allow controlled delivery of therapeutics to the target cells. However, despite the potential benefits of NPs as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of NP materials, as well as their size and shape. The need to validate each NP for safety and efficacy with each therapeutic compound or combination of therapeutics is an enormous challenge, which forces industry to focus mainly on those nanoparticle materials where data on safety and efficacy already exists, i.e., predominantly polymer NPs. However, the enhanced functionality affordable by inclusion of metallic materials as part of nanoengineered particles provides a wealth of new opportunity for innovation and new, more effective, and safer therapeutics for applications such as cancer and cardiovascular diseases, which require selective targeting of the therapeutic to maximize effectiveness while avoiding adverse effects on non-target tissues.     

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.