The stem cell factor (SCF)/c-Kit receptor tyrosine kinase complex-with its significant roles in hematopoiesis and angiogenesis-is an attractive target for rational drug design. There is thus a need to map, in detail, the SCF/c-Kit interaction sites and the mechanisms that modulate this interaction. While most residues in the direct SCF/c-Kit binding interface can be identified from the existing crystal structure of the complex, other residues that affect binding through protein unfolding, intermolecular interactions, allosteric or long-distance electrostatic effects cannot be directly inferred. Here, we describe an efficient method for protein-wide epitope mapping using yeast surface display. A library of single SCF mutants that span the SCF sequence was screened for decreased affinity to soluble c-Kit. Sequencing of selected clones allowed the identification of mutations that reduce SCF binding affinity to c-Kit. Moreover, the screening of these SCF clones for binding to a structural antibody helped identify mutations that result in small or large conformational changes in SCF. Computational modeling of the experimentally identified mutations showed that these mutations reduced the binding affinity through one of the three scenarios: through SCF destabilization, through elimination of favorable SCF/c-Kit intermolecular interactions, or through allosteric changes. Eight SCF variants were expressed and purified. Experimentally measured in vitro binding affinities of these mutants to c-Kit confirmed both the yeast surface display selection results and the computational predictions. This study has thus identified the residues crucial for c-Kit/SCF binding and has demonstrated the advantages of using a combination of computational and combinatorial methods for epitope mapping.
For better or for worse, online social networks have become adolescents’ new town square. Teenagers and young adults use SNS technology for various social activities, but most notably for selfpresentation, emotional self-disclosure and frustration ״venting, maintaining and creating social relations and affiliations, and even sharing learning materials. In popular media outlets, the negative effects and danger of SNS usage on teenagers’ social life are often highlighted (e.g., online bullying, sexting, privacy invasions, and procrastination). In the present chapter, we offer a complementary, novel approach for research on the relation between SNS use and psychological well-being: Since teenagers’ online SNS activities are logged and preserved, access to this information allows us to unobtrusively watch, monitor and learn about different facets of adolescents’ social and personal lives. We present first findings of a research program, that specifically focuses on detection of adolescents’ psycho-social distress, based on their SNS activities. We triangulate data obtained from expert judgments, interviews and self-report questionnaires, as well as computerized language processing methods. Finally, we offer a brief review on online counselling psychology and the various venues open to adolescents who seek emotional support via social networks.
M. M Kasliwal, Nakar, E. , Singer, L. P, Kaplan, D. L, Cook, D. O, Van Sistine, A. , Lau, R. M, Fremling, C. , Gottlieb, O. , Jencson, J. E, Adams, S. M, Feindt, U. , Hotokezaka, K. , Ghosh, S. , Perley, D. A, Yu, P. -C, Piran, T. , Allison, J. R, Anupama, G. C, Balasubramanian, A. , Bannister, K. W, Bally, J. , Barnes, J. , Barway, S. , Bellm, E. , Bhalerao, V. , Bhattacharya, D. , Blagorodnova, N. , Bloom, J. S, Brady, P. R, Cannella, C. , Chatterjee, D. , Cenko, S. B, Cobb, B. E, Copperwheat, C. , Corsi, A. , De, K. , Dobie, D. , Emery, S. WK, Evans, P. A, Fox, O. D, Frail, D. A, Frohmaier, C. , Goobar, A. , Hallinan, G. , Harrison, F. , Helou, G. , Hinderer, T. , Ho, A. YQ, Horesh, A. , Ip, W. -H, Itoh, R. , Kasen, D. , Kim, H. , Kuin, N. PM, Kupfer, T. , Lynch, C. , Madsen, K. , Mazzali, P. A, Miller, A. A, Mooley, K. , Murphy, T. , Ngeow, C. -C, Nichols, D. , Nissanke, S. , Nugent, P. , Ofek, E. O, Qi, H. , Quimby, R. M, Rosswog, S. , Rusu, F. , Sadler, E. M, Schmidt, P. , Sollerman, J. , Steele, I. , Williamson, A. R, Xu, Y. , Yan, L. , Yatsu, Y. , Zhang, C. , ו Zhao, W.. 2017. “Illuminating Gravitational Waves: A Concordant Picture Of Photons From A Neutron Star Merger”. Science, 358, Pp. 1559-1565. doi:10.1126/science.aap9455.
Quantized magnetic vortices driven by electric current determine key electromagnetic properties of superconductors. While the dynamic behavior of slow vortices has been thoroughly investigated, the physics of ultrafast vortices under strong currents remains largely unexplored. Here, we use a nanoscale scanning superconducting quantum interference device to image vortices penetrating into a superconducting Pb film at rates of tens of GHz and moving with velocities of up to tens of km/s, which are not only much larger than the speed of sound but also exceed the pair-breaking speed limit of superconducting condensate. These experiments reveal formation of mesoscopic vortex channels which undergo cascades of bifurcations as the current and magnetic field increase. Our numerical simulations predict metamorphosis of fast Abrikosov vortices into mixed Abrikosov-Josephson vortices at even higher velocities. This work offers an insight into the fundamental physics of dynamic vortex states of superconductors at high current densities, crucial for many applications.
Background: Mood disorders are dynamic disorders characterized by multimodal symptoms. Clinical assessment of symptoms is currently limited to relatively sparse, routine clinic visits, requiring retrospective recollection of symptoms present in the weeks preceding the visit. Novel advances in mobile tools now support ecological momentary assessment of mood, conducted frequently using mobile devices, outside the clinical setting. Such mood assessment may help circumvent problems associated with infrequent reporting and better characterize the dynamic presentation of mood symptoms, informing the delivery of novel treatment options. Objectives: The aim of our study was to validate the Immediate Mood Scaler (IMS), a newly developed, iPad-deliverable 22-item self-report tool designed to capture current mood states. Methods: A total of 110 individuals completed standardized questionnaires (Patient Health Questionnaire, 9-item [PHQ-9]; generalized anxiety disorder, 7-Item [GAD-7]; and rumina
The gene coding the transcription factor HNF-4α is located on chromosome 20q and is expressed in the liver, pancreas, kidneys, stomach and in the small and large intestine, where it controls important aspects related to morphogenesis and epithelial function. Mucin type MUC4 and MUC2, and β-catenin are representative genes controlled by HNF-4α and expressed in colonic tissue. We used in the present study immunohistochemical analyses to detect different levels of expression of the above mentioned proteins in colonic tissues of colorectal cancer and ulcerative colitis patients. We demonstrate high expression levels of HNF-4α in normal colon tissue, however, in adenoma, HNF-4α levels of expression decreased and in carcinoma of the large intestine; the levels were very low or invisible. Similarly, in ulcerative colitis patients the expression HNF-4α levels of the protein were significantly lower than the control group. Expression levels of MUC2 and MUC4 levels were significantly lower in the adenocarcinoma and ulcerative colitis groups than in the control group. In contrast, the expression level of β-catenin increased and changed from a membrane to a nuclear localization in the adenocarcinoma group only. We surmise that HNF-4α plays an important role in prevention of ulcerative colitis and colorectal cancer in humans. As a result, altered expression of the proteins MUC2 and MUC4 controlled by HNF-4α indicate that the defensive role attributed to them is not properly performed. In contrast, the Wnt / β-catenin pathway controlled by HNF-4α becomes active in samples from the stage of the adenoma and reached its peak in the carcinoma samples.
This paper articulates the disproportionate policy perspective and uses it to mount four challenges for the new policy design orientation. First, in contrast to the new policy design thinking, disproportionate policy options may be systematically designed, and at times, successfully implemented. Second, in contrast to the new policy design thinking, there are certain conditions under which policymakers may tend to develop effective response, with cost considerations becoming only secondary in importance if at all (read, policy overreaction), or cost-conscious response, with effectiveness considerations becoming only secondary in importance if at all (read, policy underreaction). Third, in contrast to the new policy design thinking, disproportionate policy options may be designed for purposes other than implementation (e.g., to be used as signaling devices or as context-setters). Fourth, in contrast to new policy design thinking, there are certain conditions under which the emotional arena of policy may be equally, if not more, important than the substantive one. The paper concludes that so far the literature on new policy design has not responded to the emergence of the disproportionate policy perspective, but a robust research agenda awaits those answering this paper’s call for action.
The dominant view of cognitive aging holds that while controlled processes (e.g., working memory and executive functions) decline with age, implicit (automatic) processes do not. In this paper we challenge this view by arguing that high-level automatic processes (e.g., implicit motivation) decline with age, and that this decline plays an important and as yet unappreciated role in cognitive aging. Specifically, we hypothesized that due to their decline, high-level automatic processes are less likely to be spontaneously activated in old age, and so their subtle, external activation should have stronger effects on older (vs. younger) adults. In two experiments we used different methods of implicitly activating motivation, and measured executive functions of younger and older adults via the Wisconsin Card Sorting Test. In Experiment 1 we used goal priming to subtly increase achievement motivation. In Experiment 2 motivation was manipulated by subtly increasing engagement in the task. More specifically, we introduce the Jerusalem Face Sorting Test (JFST), a modified version of the WCST that uses cards with faces instead of geometric shapes. In both experiments, implicitly induced changes in motivation improved older- but not younger- adults executive functioning. The framework we propose is general, and it has implications as to how we view and test cognitive functions. Our case study of older adults offers a new look at various aspects of cognitive aging. Applications of this view to other special populations (e.g., ADHD, schizophrenia) and possible interventions are discussed.
This paper discusses the reinvention of the humanist ideas and values in the Soviet post-World War II and post-Stalinist culture (the 1950s and the1960s) with the help of Renaissance plots and images in Soviet semi-official art, the main examples being Pavel Antokolsky’s poem Hieronymus Bosch (1957), the Strugatsky brothers’ novel Hard to Be a God (1963), and Grigory Kozintsev’s films based on Shakespeare’s Hamlet (1964) and King Lear (1970), as well as David Samoilov’s poem Bertold Schwarz: A Monologue, set in the late Middle Ages. The paper isolates an aesthetic movement that developed in the Soviet culture of those decades; I propose to call this movement “posttraumatic humanism.” It was based on the new aesthetic idiom of “gloomy Renaissance,” including images of conflagration, ruins, violence. The works of this movement did not use the Aesopian language — or, at least, did not use it as a primary or only tool. Rather, it involves a covert comparison of the Soviet present with the European pre-Enlightenment past and aesthetical valorization and sublimation of 20th-century catastrophic experience. Images of “gloomy Renaissance” conveyed the erosion the Soviet belief in progress and moral modernization as inevitable consequences of Bolsheviks’ revolution. One of the earliest mature works of posttraumatic humanism in Soviet culture was Vasily Grossman’s essay The Sistine Madonna (1955). Alexei German Sr.’s film Hard to Be a God (2013) can be regarded as the concluding and summarizing work in this movement.
June 2017: Ilya Kukulin received his PhD in literary theory at the Russian State University for the Humanities, Moscow. His monograph Machines of the Noisy Time: How the Soviet Montage Became an Aesthetic Method of the Unofficial Culture (Moscow, 2015, in Russian) was awarded the Andrei Bely Prize. He has co-edited six volumes focused on topics from the history of schooling in the 20th Century Eastern Europe to the cultural practices of the internal colonization in Russia. He is also the author of a number of articles on Russian literature, unofficial social thought in 20th-century Russia, and political discourses of the Russian social media, published in Russia, Germany, Norway, China, Lithuania, Armenia, and the USA. At present he is Associate Professor at the Department of Cultural Studies of the National Research University – Higher School of Economics (HSE, Moscow), Senior Researcher at the International Center for the History and Sociology of World War II and Its Consequences (HSE), and Senior Researcher at the School of Advanced Studies in the Humanities, Russian Academy of National Economy and Public Administration (Moscow).
