A structurally derived model of subunit‐dependent NMDA receptor function

NMDA receptors (NMDARs) are tetrameric complexes comprising two glycine‐binding GluN1 and two glutamate‐binding GluN2 subunits. Four GluN2 subunits encoded by different genes can produce up to 10 different di‐ and triheteromeric receptors. In addition, some neurological patients contain a de novo mutation or inherited rare variant in only one subunit. There is currently no mechanistic framework to describe tetrameric receptor function that can be extended to receptors with two different GluN1 or GluN2 subunits. Here we use the structural features of glutamate receptors to develop a mechanism describing both single channel and macroscopic NMDAR currents. We propose that each agonist‐bound subunit undergoes some rate‐limiting conformational change after agonist binding, prior to channel opening. We hypothesize that this conformational change occurs within a triad of interactions between a short helix preceding the M1 transmembrane helix, the highly conserved M3 motif encoded by the residues SYTANLAAF, and the linker preceding the M4 transmembrane helix of the adjacent subunit. Molecular dynamics simulations suggest that pre‐M1 helix motion is uncorrelated between subunits, which we interpret to suggest independent subunit‐specific conformational changes may influence these pre‐gating steps. According to this interpretation, these conformational changes are the main determinants of the key kinetic properties of NMDA receptor activation following agonist binding, and so these steps sculpt their physiological role. We show that this structurally derived tetrameric model describes both single channel and macroscopic data, giving a new approach to interpreting functional properties of synaptic NMDARs that provides a logical framework to understanding receptors with non‐identical subunits

Disruption of the MDM2–p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway

Wild-type p53 has a major role in the response and execution of apoptosis after chemotherapy in many cancers. Although high levels of wild-type p53 and hardly any TP53 mutations are found in testicular cancer (TC), chemotherapy resistance is still observed in a significant subgroup of TC patients. In the present study, we demonstrate that p53 resides in a complex with MDM2 at higher cisplatin concentrations in cisplatin-resistant human TC cells compared with cisplatin-sensitive TC cells. Inhibition of the MDM2–p53 interaction using either Nutlin-3 or MDM2 RNA interference resulted in hyperactivation of the p53 pathway and a strong induction of apoptosis in cisplatin-sensitive and -resistant TC cells. Suppression of wild-type p53 induced resistance to Nutlin-3 in TC cells, demonstrating the key role of p53 for Nutlin-3 sensitivity. More specifically, our results indicate that p53-dependent induction of Fas membrane expression (∼threefold) and enhanced Fas/FasL interactions at the cell surface are important mechanisms of Nutlin-3-induced apoptosis in TC cells. Importantly, an analogous Fas-dependent mechanism of apoptosis upon Nutlin-3 treatment is executed in wild-type p53 expressing Hodgkin lymphoma and acute myeloid leukaemia cell lines. Finally, we demonstrate that Nutlin-3 strongly augmented cisplatin-induced apoptosis and cell kill via the Fas death receptor pathway. This effect is most pronounced in cisplatin-resistant TC cells

Antibody responses induced by SHIV infection are more focused than those induced by soluble native HIV-1 envelope trimers in non-human primates

The development of an effective human immunodeficiency virus (HIV-1) vaccine is a high global health priority. Soluble native-like HIV-1 envelope glycoprotein trimers (Env), including those based on the SOSIP design, have shown promise as vaccine candidates by inducing neutralizing antibody responses against the autologous virus in animal models. However, to overcome HIV-1’s extreme diversity a vaccine needs to induce broadly neutralizing antibodies (bNAbs). Such bNAbs can protect non-human primates (NHPs) and humans from infection. The prototypic BG505 SOSIP.664 immunogen is based on the BG505 env sequence isolated from an HIV-1-infected infant from Kenya who developed a bNAb response. Studying bNAb development during natural HIV-1 infection can inform vaccine design, however, it is unclear to what extent vaccine-induced antibody responses to Env are comparable to those induced by natural infection. Here, we compared Env antibody responses in BG505 SOSIP-immunized NHPs with those in BG505 SHIV-infected NHPs, by analyzing monoclonal antibodies (mAbs). We observed three major differences between BG505 SOSIP immunization and BG505 SHIV infection. First, SHIV infection resulted in more clonal expansion and less antibody diversity compared to SOSIP immunization, likely because of higher and/or prolonged antigenic stimulation and increased antigen diversity during infection. Second, while we retrieved comparatively fewer neutralizing mAbs (NAbs) from SOSIP-immunized animals, these NAbs targeted more diverse epitopes compared to NAbs from SHIV-infected animals. However, none of the NAbs, either elicited by vaccination or infection, showed any breadth. Finally, SOSIP immunization elicited antibodies against the base of the trimer, while infection did not, consistent with the base being placed onto the virus membrane in the latter setting. Together these data provide new insights into the antibody response against BG505 Env during infection and immunization and limitations that need to be overcome to induce better responses after vaccination

Towards an integrated crowdsourcing definition

Crowdsourcing is a relatively recent concept that encompasses many practices. This diversity leads to the blurring of the limits of crowdsourcing that may be identified virtually with any type of internet-based collaborative activity, such as co-creation or user innovation. Varying definitions of crowdsourcing exist, and therefore some authors present certain specific examples of crowdsourcing as paradigmatic, while others present the same examples as the opposite. In this article, existing definitions of crowdsourcing are analysed to extract common elements and to establish the basic characteristics of any crowdsourcing initiative. Based on these existing definitions, an exhaustive and consistent definition for crowdsourcing is presented and contrasted in 11 cases.Estelles Arolas, E.; González-Ladrón-De-Guevara, F. (2012). Towards an integrated crowdsourcing definition. Journal of Information Science. 32(2):189-200. doi:10.1177/0165551512437638S189200322Vukovic, M., & Bartolini, C. (2010). Towards a Research Agenda for Enterprise Crowdsourcing. Leveraging Applications of Formal Methods, Verification, and Validation, 425-434. doi:10.1007/978-3-642-16558-0_36Brabham, D. C. (2008). Crowdsourcing as a Model for Problem Solving. Convergence: The International Journal of Research into New Media Technologies, 14(1), 75-90. doi:10.1177/1354856507084420Vukovic, M. (2009). Crowdsourcing for Enterprises. 2009 Congress on Services - I. doi:10.1109/services-i.2009.56Doan, A., Ramakrishnan, R., & Halevy, A. Y. (2011). Crowdsourcing systems on the World-Wide Web. Communications of the ACM, 54(4), 86. doi:10.1145/1924421.1924442Brabham, D. C. (2008). Moving the crowd at iStockphoto: The composition of the crowd and motivations for participation in a crowdsourcing application. First Monday, 13(6). doi:10.5210/fm.v13i6.2159Huberman, B. A., Romero, D. M., & Wu, F. (2009). Crowdsourcing, attention and productivity. Journal of Information Science, 35(6), 758-765. doi:10.1177/0165551509346786Andriole, S. J. (2010). Business impact of Web 2.0 technologies. Communications of the ACM, 53(12), 67. doi:10.1145/1859204.1859225Denyer, D., Tranfield, D., & van Aken, J. E. (2008). Developing Design Propositions through Research Synthesis. Organization Studies, 29(3), 393-413. doi:10.1177/0170840607088020Egger, M., Smith, G. D., & Altman, D. G. (Eds.). (2001). Systematic Reviews in Health Care. doi:10.1002/9780470693926Tatarkiewicz, W. (1980). A History of Six Ideas. doi:10.1007/978-94-009-8805-7Cosma, G., & Joy, M. (2008). Towards a Definition of Source-Code Plagiarism. IEEE Transactions on Education, 51(2), 195-200. doi:10.1109/te.2007.906776Brabham, D. C. (2009). Crowdsourcing the Public Participation Process for Planning Projects. Planning Theory, 8(3), 242-262. doi:10.1177/1473095209104824Alonso, O., & Lease, M. (2011). Crowdsourcing 101. Proceedings of the fourth ACM international conference on Web search and data mining - WSDM ’11. doi:10.1145/1935826.1935831Bederson, B. B., & Quinn, A. J. (2011). Web workers unite! addressing challenges of online laborers. Proceedings of the 2011 annual conference extended abstracts on Human factors in computing systems - CHI EA ’11. doi:10.1145/1979742.1979606Grier, D. A. (2011). Not for All Markets. Computer, 44(5), 6-8. doi:10.1109/mc.2011.155Heer, J., & Bostock, M. (2010). Crowdsourcing graphical perception. Proceedings of the 28th international conference on Human factors in computing systems - CHI ’10. doi:10.1145/1753326.1753357Heymann, P., & Garcia-Molina, H. (2011). Turkalytics. Proceedings of the 20th international conference on World wide web - WWW ’11. doi:10.1145/1963405.1963473Kazai, G. (2011). In Search of Quality in Crowdsourcing for Search Engine Evaluation. Advances in Information Retrieval, 165-176. doi:10.1007/978-3-642-20161-5_17La Vecchia, G., & Cisternino, A. (2010). Collaborative Workforce, Business Process Crowdsourcing as an Alternative of BPO. Lecture Notes in Computer Science, 425-430. doi:10.1007/978-3-642-16985-4_40Liu, E., & Porter, T. (2010). Culture and KM in China. VINE, 40(3/4), 326-333. doi:10.1108/03055721011071449Oliveira, F., Ramos, I., & Santos, L. (2010). Definition of a Crowdsourcing Innovation Service for the European SMEs. Lecture Notes in Computer Science, 412-416. doi:10.1007/978-3-642-16985-4_37Porta, M., House, B., Buckley, L., & Blitz, A. (2008). Value 2.0: eight new rules for creating and capturing value from innovative technologies. Strategy & Leadership, 36(4), 10-18. doi:10.1108/10878570810888713Ribiere, V. M., & Tuggle, F. D. (Doug). (2010). Fostering innovation with KM 2.0. VINE, 40(1), 90-101. doi:10.1108/03055721011024955Sloane, P. (2011). The brave new world of open innovation. Strategic Direction, 27(5), 3-4. doi:10.1108/02580541111125725Wexler, M. N. (2011). Reconfiguring the sociology of the crowd: exploring crowdsourcing. International Journal of Sociology and Social Policy, 31(1/2), 6-20. doi:10.1108/01443331111104779Whitla, P. (2009). Crowdsourcing and Its Application in Marketing Activities. Contemporary Management Research, 5(1). doi:10.7903/cmr.1145Yang, J., Adamic, L. A., & Ackerman, M. S. (2008). Crowdsourcing and knowledge sharing. Proceedings of the 9th ACM conference on Electronic commerce - EC ’08. doi:10.1145/1386790.1386829Brabham, D. C. (2010). MOVING THE CROWD AT THREADLESS. Information, Communication & Society, 13(8), 1122-1145. doi:10.1080/13691181003624090Giudice, K. D. (2010). Crowdsourcing credibility: The impact of audience feedback on Web page credibility. Proceedings of the American Society for Information Science and Technology, 47(1), 1-9. doi:10.1002/meet.14504701099Stewart, O., Huerta, J. M., & Sader, M. (2009). Designing crowdsourcing community for the enterprise. 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The impact of egg incubation temperature on the personality of oviparous reptiles

Personality traits, defined as differences in the behavior of individual animals of the same species that are consistent over time and context, such as ‘boldness,’ have been shown to be both heritable and be influenced by external factors, such as predation pressure. Currently, we know very little about the role that early environmental factors have upon personality. Thus, we investigated the impact of incubation temperature upon the boldness on an oviparous reptile, the bearded dragon (Pogona vitticeps). Eggs, from one clutch, were incubated at two different average temperatures within the normal range. After hatching the lizards were raised under the same environmental conditions. Novel object and novel environment tests were used to assess personality. Each test was repeated in both the short term and the long term. The results revealed that incubation temperature did impact upon ‘boldness’ but only in the short term and suggests that, rather than influencing personality, incubation temperature may have an effect on the development of behavioral of oviparous reptiles at different stages across ontogeny

Mercury in Nelson's Sparrow Subspecies at Breeding Sites

Background: Mercury is a persistent, biomagnifying contaminant that can cause negative effects on ecosystems. Marshes are often areas of relatively high mercury methylation and bioaccumulation. Nelson’s Sparrows (Ammodramus nelsoni) use marsh habitats year-round and have been documented to exhibit tissue mercury concentrations that exceed negative effects thresholds. We sought to further characterize the potential risk of Nelson’s Sparrows to mercury exposure by sampling individuals from sites within the range of each of its subspecies

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Social Interactions of Juvenile Brown Boobies at Sea as Observed with Animal-Borne Video Cameras

While social interactions play a crucial role on the development of young individuals, those of highly mobile juvenile birds in inaccessible environments are difficult to observe. In this study, we deployed miniaturised video recorders on juvenile brown boobies Sula leucogaster, which had been hand-fed beginning a few days after hatching, to examine how social interactions between tagged juveniles and other birds affected their flight and foraging behaviour. Juveniles flew longer with congeners, especially with adult birds, than solitarily. In addition, approximately 40% of foraging occurred close to aggregations of congeners and other species. Young seabirds voluntarily followed other birds, which may directly enhance their foraging success and improve foraging and flying skills during their developmental stage, or both

Age and sex influence marmot antipredator behavior during periods of heightened risk

Animals adjust their antipredator behavior according to environmental variation in risk, and to account for their ability to respond to threats. Intrinsic factors that influence an animal’s ability to respond to predators (e.g., age, body condition) should explain variation in antipredator behavior. For example, a juvenile might allocate more time to vigilance than an adult because mortality as a result of predation is often high for this age class; however, the relationship between age/vulnerability and antipredator behavior is not always clear or as predicted. We explored the influence of intrinsic factors on yellow-bellied marmot (Marmota flaviventris) antipredator behavior using data pooled from 4 years of experiments. We hypothesized that inherently vulnerable animals (e.g., young, males, and individuals in poor condition) would exhibit more antipredator behavior prior to and immediately following conspecific alarm calls. As expected, males and yearlings suppressed foraging more than females and adults following alarm call playbacks. In contrast to predictions, animals in better condition respond more than animals in below average condition. Interestingly, these intrinsic properties did not influence baseline time budgets; animals of all ages, sexes, and condition levels devoted comparable amounts of time to foraging prior to alarm calls. Our results support the hypothesis that inherent differences in vulnerability influence antipredator behavior; furthermore, it appears that a crucial, but poorly acknowledged, interaction exists between risk and state-dependence. Elevated risk may be required to reveal the workings of state-dependent behavior, and studies of antipredator behavior in a single context may draw incomplete conclusions about age- or sex-specific strategies

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

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