Nonprice incentives and energy conservation
Omar I. Asensio and Magali A. Delmas
We investigate the effectiveness of nonprice incentives to motivate conservation behavior. We test whether tailored information about environmental and health damages produces behavior change in the residential electricity sector. In a randomized controlled trial with real-time appliance-level energy metering over 8 mo, we find that environment and health-based information strategies outperform monetary savings information to drive energy conservation. Environment and health-based messages, which communicate the environmental and public health externalities of electricity production—such as pounds of pollutants, childhood asthma, and cancer—motivated 8% energy savings versus control. This strategy (pp. E510–E515) was particularly effective on families with children, who achieved 19% energy savings. However, we do not study the persistence of these behavioral changes after the conclusion of the study.
Membranes serve as allosteric activators of phospholipase A2, enabling it to extract, bind, and hydrolyze phospholipid substrates
Varnavas D. Mouchlis, Denis Bucher, J. Andrew McCammon, and Edward A. Dennis
The catalytic mechanisms of interfacial enzymes acting directly on the interfacial surface of the membrane are notoriously difficult to study experimentally with X-ray crystallography and other biophysical methods. This scientific study is, to our knowledge, the first to highlight similarities and differences in the extraction and binding of a phospholipid molecule into the substrate binding pocket of two human phospholipases A2 (PLA2s): the cytosolic Group IVA cPLA2 and the calcium-independent Group VIA iPLA2. Molecular dynamics simulations, guided by deuterium exchange experiments, are used to show that pathways to the active sites of these PLA2s are opened upon allosteric interaction with the membrane to facilitate entry of the substrate lipid (pp. E516–E525). These enzymes are involved in various diseases, and understanding their mechanisms will aid in the discovery of therapeutics.
Bordetella pertussis fim3 gene regulation by BvgA: Phosphorylation controls the formation of inactive vs. active transcription complexes
Alice Boulanger, Kyung Moon, Kimberly B. Decker, Qing Chen, Leslie Knipling, Scott Stibitz, and Deborah M. Hinton
The response regulator BvgA controls virulence gene expression in the human pathogen Bordetella pertussis. Phosphorylated BvgA together with RNA polymerase form transcription complexes that synthesize RNA from the B. pertussis promoter for the fimbrial gene fim3. We show (pp. E526–E535) that nonphosphorylated BvgA and RNA polymerase form stable but inactive complexes. We propose that these complexes may modulate fim3 expression under inducing conditions and facilitate rapid repression of the fim3 promoter under noninducing conditions. The ability of a response regulator to activate and repress depending on environmental conditions represents a different paradigm in two-component system regulation.
BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model
Daniele Perna, Florian A. Karreth, Alistair G. Rust, Pedro A. Perez-Mancera, Mamunur Rashid, Francesco Iorio, Constantine Alifrangis, Mark J. Arends, Marcus W. Bosenberg, Gideon Bollag, David A. Tuveson, and David J. Adams
Using Sleeping Beauty transposon mutagenesis in a melanoma model driven by oncogenic BRAF (B-Raf proto-oncogene, serine/threonine kinase), we identified both known and novel candidate genes that mediate resistance to the BRAF inhibitor PLX4720. We validate ES-cell expressed Ras as a novel promoter of BRAF inhibitor resistance and propose that AKT (v-akt murine thymoma viral oncogene homolog 1)-mediated inactivation of BAD (BCL2-associated agonist of cell death) constitutes a pathway that may contribute to hepatocyte growth factor-mediated therapy resistance. Our work (pp. E536–E545) establishes Sleeping Beauty mutagenesis as a powerful tool for the identification of novel resistance genes and mechanisms in genetically modified mouse models.
Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions
Marc Seifert, Martina Przekopowitz, Sarah Taudien, Anna Lollies, Viola Ronge, Britta Drees, Monika Lindemann, Uwe Hillen, Harald Engler, Bernhard B. Singer, and Ralf Küppers
Human IgM+IgD+CD27+ B lymphocytes represent a large subpopulation of the human B-cell pool, but their generation is debated and their immunological functions are poorly understood. This work (pp. E546–E555) shows that these lymphocytes possess typical memory B-cell expression patterns, enabling them to differentiate rapidly into plasma cells upon restimulation. Moreover, we reveal unique features of these IgM memory B cells, their potential to reenter germinal center reactions, and their specific interaction with immunomodulatory neutrophils in early inflammatory responses. Thus, key characteristics and functions of a major human B-cell subset are elucidated.
Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire
Tanya Dimova, Margreet Brouwer, Françoise Gosselin, Joël Tassignon, Oberdan Leo, Catherine Donner, Arnaud Marchant, and David Vermijlen
Despite their enormous potential for diversity (in excess of 1015 theoretical receptor specificities), the human γδ T-cell repertoire is dominated by a specific subset expressing the T-cell receptor containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2) known to react to a set of pathogen-derived small molecules (phosphoantigens). Overrepresentation of this restricted set of γδ T cells in adults has been thought to reflect an antigen-specific selection process resulting from postnatal exposure to pathogens. However, we demonstrate here (pp. E556–E565) that restricted Vγ9Vδ2 cells with preprogrammed effector function represent the predominant γδ T-cell subset circulating in human fetal blood. This observation suggests that, despite developing in a sterile environment, the human fetal γδ T cell repertoire is enriched for pathogen-reactive T cells well before pathogen exposure.
Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils
Amy-Jo Casbon, Damien Reynaud, Chanhyuk Park, Emily Khuc, Dennis D. Gan, Koen Schepers, Emmanuelle Passegué, and Zena Werb
We show that tumor reprogramming of hematopoiesis in bone marrow occurs at the onset of malignant conversion and results in systemic expansion of circulating activated neutrophils that preferentially accumulate in lungs (pp. E566–E575). Our data are, to our knowledge, the first to show that activation and not inhibition of myeloid differentiation is responsible for expansion and activity of T cell-suppressive myeloid cells; a tumor-derived factor targets the immature hematopoietic compartment to drive myeloid expansion; granulocyte-colony stimulating factor (G-CSF) is the only hematopoietic growth factor to increase in serum during early tumor development; prolonged G-CSF induces production of Rb1low neutrophils and not short-term mobilization; and G-CSF acts in a cell intrinsic manner to expand multipotent progenitors to increase production of tumor-derived Ly6G+ neutrophils.
Structure and mechanism of Staphylococcus aureus TarM, the wall teichoic acid α-glycosyltransferase
Solmaz Sobhanifar, Liam James Worrall, Robert J. Gruninger, Gregory A. Wasney, Markus Blaukopf, Lars Baumann, Emilie Lameignere, Matthew Solomonson, Eric D. Brown, Stephen G. Withers, and Natalie C. J. Strynadka
This paper (pp. E576–E585) describes the structure of Staphylococcus aureus TarM, an enzyme responsible for the glycosylation of wall teichoic acid that is important in pathological processes such as host immunity, phage binding, and antibiotic resistance in strains such as Methicillin-resistant S. aureus. The TarM structure is presented in an unusual ternary-like complex that features a polymeric acceptor substrate analogue and a trapped product of enzyme action, lending novel structural and mechanistic insight into the glycosylation of glycopolymers. More generally, the positioning of this product in the active site as well as the distorted conformation of its pyranose ring provide direct structural evidence for an internal substitution-like catalytic mechanism for retaining GT-B class enzymes.
Therapeutic mechanisms of high-frequency stimulation in Parkinson’s disease and neural restoration via loop-based reinforcement
Sabato Santaniello, Michelle M. McCarthy, Erwin B. Montgomery Jr., John T. Gale, Nancy Kopell, and Sridevi V. Sarma
We investigated the therapeutic mechanisms of high-frequency stimulation (HFS) in Parkinson’s disease by developing a computational model of the cortico-basal ganglia-thalamo-cortical loop in normal and parkinsonian conditions under the effects of stimulation at several frequencies. We found (pp. E586–E595) that the stimulation injected in the loop elicits neural perturbations that travel along multiple pathways with different latencies and rendezvous in striatum (one of the basal ganglia). If the stimulation frequency is high enough, these perturbations overlap (reinforcement) and cause more regular, stimulus-locked firing patterns in striatum. Overlap is maximal at clinically relevant HFS and restores more normal activity in the remaining structures of the loop. This suggests that neural restoration and striatal reinforcement may be a therapeutic merit and mechanism of HFS, respectively.