An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.     

Theoretical mechanics: crowd synchrony on the Millennium Bridge

Soon after the crowd streamed on to London's Millennium Bridge on the day it opened, the bridge started to sway from side to side: many pedestrians fell spontaneously into step with the bridge's vibrations, inadvertently amplifying them. Here we model this unexpected and now notorious phenomenon--which was not due to the bridge's innovative design as was first thought--by adapting ideas originally developed to describe the collective synchronization of biological oscillators such as neurons and fireflies. Our approach should help engineers to estimate the damping needed to stabilize other exceptionally crowded footbridges against synchronous lateral excitation by pedestrians.     

The Uses of Reason in Times of Technical Mediation

The art of living idiom suits well a practice-oriented approach in ethics of technology. But what remains or becomes of the functioning and use of reason in ethics? In reaction to the comments by Huijer this reply elaborates in more detail how Foucault’s art of living can be adapted for a critical contemporary ethics of technology. And the aesthetic-political rationality in Foucault’s ethics is compared with Wellner’s suggestions of holding on to the notion of code but with a new meaning. Foucault’s fourfold scheme of subjectivation and a distinction of “below and above reason” structure the argument.     

Platelet–bacterial interactions

Many bacteria are capable of interacting with platelets and inducing platelet aggregation. This interaction may be a direct interaction between a bacterial surface protein and a platelet receptor or may be an indirect interaction where plasma proteins bind to the bacterial surface and subsequently bind to a platelet receptor. However, these interactions usually do not trigger platelet activation as a secondary co-signal is also required. This is usually due to specific antibody bound to the bacteria interacting with FcγRIIa on the platelet surface. Secreted bacterial products such as gingipains and lipopolysaccharide may also be capable of triggering platelet activation.     

Timing is everything: the regulation of type III secretion

Type Three Secretion Systems (T3SSs) are essential virulence determinants of many Gram-negative bacteria. The T3SS is an injection device that can transfer bacterial virulence proteins directly into host cells. The apparatus is made up of a basal body that spans both bacterial membranes and an extracellular needle that possesses a channel that is thought to act as a conduit for protein secretion. Contact with a host-cell membrane triggers the insertion of a pore into the target membrane, and effectors are translocated through this pore into the host cell. To assemble a functional T3SS, specific substrates must be targeted to the apparatus in the correct order. Recently, there have been many developments in our structural and functional understanding of the proteins involved in the regulation of secretion. Here we review the current understanding of protein components of the system thought to be involved in switching between different stages of secretion.     

Effect of soil microtopography on seed bank distribution in the shrub-steppe

The relationship between soil surface cryptogamic crusts and seed banks was investigated in the shrubsteppe in the Lower Columbia Basin. Seventy-four percent of the seeds in a disturbed bunchgrass community were found in crevices bordering cryptogamic crust polygons. In a sagebrush/bunchgrass community, 89% of the seeds were found in crevices. In a disturbed bunchgrass community, Bromus tectorum seeds were found in both the seed bank and aboveground vegetation communities. Bromus tectorum seeds were located in the seed bank of a sagebrush/bunchgrass community, although it had a minor presence in the aboveground community. Seeds of Artemisia tridentata Nutt. were not found in either the bunchgrass or sagebrush/bunchgrass communities. The high number of seeds found in crevices bordering the cryptogamic crust suggests that crevices play a role in determining the small-scale distributional pattern of shrub-steppe plants at the Fitzner-Eberhardt Arid Lands Ecology Reserve.     

Historical variations in δ 13 C leaf of herbarium specimens in the southwestern U.S.

The uncontrolled, global increase in atmospheric CO 2 concentration (ca 80 ppmv) and decline in δ 13 C air (ca 1.5%) since industrialization provide experimental boundary conditions by which to assess physiological response of vegetation. To examine consequences of these global atmospheric changes in the southwestern U.S., 350 specimens of Atriplex confertifolia, A. canescens, Ephedra viridis, Pinus edulis, P. flexilis, Juniperus scopulorum, and Quercus turbinella of precisely known age spanning the last 150 years were acquired from 9 herbaria. Cellulose analysis of δ 13 C plant and estimation of isotopic discrimination (Δ) permitted calculation of water-use efficiency (A/g). The δ 13 C plant chronologies of C 4 Atriplex spp. show some promise as a reliable proxy for δ 13 C air because their mean trends approximate the known δ 13 C air chronology. However, the high variability would necessitate multiple samples at any time period to accurately represent the mean. The generally increasing A/g trends of the 5 C 3 species are particularly pronounced for P. edulis and, after the 1950s, for J. scopulorum, but less evident for P. flexilis, E. viridis, and Q. turbinella, evidencing possible differences in species response to rising CO 2 concentrations. The trends are statistically noisy, however, possibly due to complex microclimates, extreme seasonality, and great interannual variability typical of the southwestern U.S. Herbarium specimens, at least in the Southwest, may be less useful for precise detection of direct CO 2 effects on plant physiology than tree rings, where the variability can be constrained to a single individual over time.