The paradox of the long term: human evolution and entanglement★

Over recent decades, many archaeologists have eschewed evolutionary theories, and in doing so they have turned away from the identification of long-term trends that are of great relevance to present-day matters of concern. In particular, there is clear evidence for an overall long-term increase in the amount of human-made material and associated human-thing entanglements, an increase tied up with environmental impact and global inequalities. The directionality of these long-term changes is clear and yet evolutionary theory largely shuns notions of overall directional change. This paradox and its implications are the subject of this article, with the suggestion made that, for human evolution at least, notions of directionality and path dependence need to be embraced, with concomitant changes in human evolutionary theory, and with implications for responses to environmental change. Adding to earlier accounts of entanglement, emphases are placed on the self-amplifying processes that lead to change and on irreversibility in the place of teleology.     

Lipopolysaccharides of the motile aeromonads; core oligosaccharide analysis as an aid to taxonomic classification

Twelve motile Aeromonas strains have been examined with respect to the hexose and heptose monosaccharide residures present in the core region of their cell wall lipopolysaccharides. These strains were divided into three distinctly separate groups on the basis of the various combinations of hexose and heptose residues. The assignment of a strain to any one of the three groups furnishes a distribution which is substantially the same as that recently reported in a computerbased numerical analysis. All strains tested which were previoulsy named A. liquefaciens fall into the same group.     

Obtaining maximum muscle excitation for normalizing shoulder electromyography in dynamic contractions

Muscle specific maximal voluntary isometric contractions (MVIC) are commonly used to elicit reference amplitudes to normalize electromyographic signals (EMG). It has been questioned whether this is appropriate for normalizing EMG from dynamic contractions. This study compares EMG amplitude when shoulder muscle activity from dynamic contractions is normalized to isometric and isokinetic maximal excitation as well as a hybrid approach currently used in our laboratory. Anterior, middle and posterior deltoid, upper and lower trapezius, pectoralis major, latissimus dorsi and infraspinatus were monitored during (1) manually resisted MVICs, and (2) maximum voluntary dynamic concentric contractions (MVDC) on an isokinetic dynamometer. Dynamic contractions were performed (a) at 30°/s about the longitudinal, frontal and sagittal axes of the shoulder, and (b) during manual bi-rotation of a tilted wheel at 120°/s. EMG from the wheel task was normalized to the maximum excitation from (i) the muscle specific MVIC, (ii) from any MVIC (MVIC_ALL), (iii) for any MVDC, (iv) from any exertion (maximum experimental excitation, MEE). Mean EMG from the wheel task was up to 45% greater when normalized to muscle specific isometric contractions (method i) than when normalized to MEE (method iv). Seventy-five percent of MEE’s occurred during MVDCs. This study presents an 20 useful and effective process for obtaining the greatest excitation from the shoulder muscles when normalizing dynamic efforts.     

Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker

Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic.     

A sphingosine 1-phosphate receptor 2 selective allosteric agonist

Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound.     

CD4+ T cells acting independently of antibody contribute to protective immunity to Plasmodium chabaudi infection after apical membrane antigen 1 immunization

Apical membrane Ag 1 (AMA1) is a leading malaria vaccine candidate. Homologues of AMA1 can induce protection in mice and monkeys, but the mechanism of immunity is not understood. Mice immunized with a refolded, recombinant, Plasmodium chabaudi AMA1 fragment (AMA1B) can withstand subsequent challenge with P. chabaudi adami. Here we show that CD4+ T cell depletion, but not gammadelta T cell depletion, can cause a significant drop in antiparasite immunity in either immunized normal or immunized B cell KO mice. In normal mice, this loss of immunity is not accompanied by a decline in Ab levels. These observations indicate a role for AMA1-specific Ab-independent T cell-mediated immunity. However, the loss of immunity in normal CD4+ T cell-depleted mice is temporary. Furthermore, immunized B cell KO mice cannot survive infection, demonstrating the absolute importance of B cells, and presumably Ab, in AMA1-induced immunity. CD4+ T cells specific for a cryptic conserved epitope on AMA1 can adoptively transfer protection to athymic (nu/nu) mice, the level of which is enhanced by cotransfer of rabbit anti-AMA1-specific antisera. Recipients of rabbit antisera alone do not survive. Some protected recipients of T cells plus antisera do not develop their own AMA 1-specific Ab response, suggesting that AMA 1-specific CMI alone can protect mice. These data are the first to demonstrate the specificity of any protective CMI response in malaria and have important implications for developing a malaria vaccine.