TMEM27 Suppresses Tumor Development by Promoting Ret Ubiquitination, Positioning, and Degradation

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma

THE ROLE OF INTERDEPENDENCE IN THE MICRO-FOUNDATIONS OF ORGANIZATION DESIGN: TASK, GOAL, AND KNOWLEDGE INTERDEPENDENCE

Interdependence is a core concept in organization design, yet one that has remained consistently understudied. Current notions of interdependence remain rooted in seminal works, produced at a time when managers’ near-perfect understanding of the task at hand drove the organization design process. In this context, task interdependence was rightly assumed to be exogenously determined by characteristics of the work and the technology. We no longer live in that world, yet our view of interdependence has remained exceedingly task-centric and our treatment of interdependence overly deterministic. As organizations face increasingly unpredictable workstreams and workers co-design the organization alongside managers, our field requires a more comprehensive toolbox that incorporates aspects of agent-based interdependence. In this paper, we synthesize research in organization design, organizational behavior, and other related literatures to examine three types of interdependence that characterize organizations’ workflows: task, goal, and knowledge interdependence. We offer clear definitions for each construct, analyze how each arises endogenously in the design process, explore their interrelations, and pose questions to guide future research

Synthesis of novel cytotoxic tetracyclic acridone derivatives and study of their molecular docking, ADMET, QSAR, bioactivity and protein binding properties

Acridone based synthetic and natural products with inherent anticancer activity advancing the research and generating a large number of structurally diversified compounds. In this sequence we have designed, synthesized a series of tetracyclic acridones with amide framework viz., 3-(alkyloyl/ aryloyl/ heteroaryloyl/ heteroaryl)-2,3-dihydropyrazino[3,2,1-de]acridin-7(1H)-ones and screened for their in vitro anti-cancer activity. The in vitro study revealed that compounds with cyclopropyl-acetyl, benzoyl, p-hydroxybenzoyl, p-(trifluoromethyl)benzoyl, p-fluorobenzoyl, m-fluorobenzoyl, picolinoyl, 6-methylpicolinoyl and 3-nicotinoyl groups are active against HT29, MDAMB231 and HEK293T cancer cell lines. The molecular docking studies performed for them against 4N5Y, HT29 and 2VWD revealed the potential ligand–protein binding interactions among the neutral aminoacid of the enzymes and carbonyl groups of the title compounds with a binding energy ranging from − 8.1394 to − 6.9915 kcal/mol. In addition, the BSA protein binding assay performed for them has confirmed their interaction with target proteins through strong binding to BSA macromolecule. The additional studies like ADMET, QSAR, bioactivity scores, drug properties and toxicity risks ascertained them as newer drug candidates. This study had added a new collection of piperazino fused acridone derivatives to the existing array of other nitrogen heterocyclic fused acridone derivatives as anticancer agents. © 2020, The Author(s).The authors thank GVK Biosciences Pvt. Ltd., Nacharam, Hyderabad, India for sponsoring chemicals and analytical data. Authors Dr. Avula Vijaya Kumar Reddy and Prof. Dr. Grigory V. Zyryanov thank Ural Federal University for support and acknowledge the financial support of the Russian Science Foundation, Moscow, Russian Federation (RSF Grant No.: 18-13-00365). The corresponding author Dr. Visweswara Rao Pasupuleti thank Universiti Malaysia Sabah for the financial support

Fragile finance: The revenue models of oppositional news outlets in repressive regimes

For journalists promoting the free flow of information in repressive or restrictive media environments, the issue of financial sustainability is complex. Both media in exile (out-of-country news outlets feeding independent information into the country of origin) and news outlets in restrictive news environments (in-country providing counter-information) exist in flawed market situations and often rely on grant funding. This is the first academic study of the revenue streams of these media, providing scarce empirical data and a typology of funding structures of these media. This article examines three main revenue categories: grant funding, earned income and donations. The major factors influencing revenue streams compared to online media startups in open markets are discussed. The article finds significant barriers to revenue creation and identifies the need for alternative approaches, particularly partnerships, to promote economic resilience for media under threat

A comparative study of non-covalent encapsulation methods for organic dyes into silica nanoparticles

Numerous luminophores may be encapsulated into silica nanoparticles (< 100 nm) using the reverse microemulsion process. Nevertheless, the behaviour and effect of such luminescent molecules appear to have been much less studied and may possibly prevent the encapsulation process from occurring. Such nanospheres represent attractive nanoplatforms for the development of biotargeted biocompatible luminescent tracers. Physical and chemical properties of the encapsulated molecules may be affected by the nanomatrix. This study examines the synthesis of different types of dispersed silica nanoparticles, the ability of the selected luminophores towards incorporation into the silica matrix of those nanoobjects as well as the photophysical properties of the produced dye-doped silica nanoparticles. The nanoparticles present mean diameters between 40 and 60 nm as shown by TEM analysis. Mainly, the photophysical characteristics of the dyes are retained upon their encapsulation into the silica matrix, leading to fluorescent silica nanoparticles. This feature article surveys recent research progress on the fabrication strategies of these dye-doped silica nanoparticles

The interpretations and uses of fitness landscapes in the social sciences

__Abstract__ This working paper precedes our full article entitled “The evolution of Wright’s (1932) adaptive field to contemporary interpretations and uses of fitness landscapes in the social sciences” as published in the journal Biology & Philosophy (http://link.springer.com/article/10.1007/s10539-014-9450-2). The working paper features an extended literature overview of the ways in which fitness landscapes have been interpreted and used in the social sciences, for which there was not enough space in the full article. The article features an in-depth philosophical discussion about the added value of the various ways in which fitness landscapes are used in the social sciences. This discussion is absent in the current working paper. Th

Enabling and Enhancing Science Exploration Across the Solar System: Aerocapture Technology for SmallSat to Flagship Missions

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Darwinism, organizational evolution and survival: key challenges for future research

How do social organizations evolve? How do they adapt to environmental pressures? What resources and capabilities determine their survival within dynamic competition? Charles Darwin’s seminal work The Origin of Species (1859) has provided a significant impact on the development of the management and organization theory literatures on organizational evolution. This article introduces the JMG Special Issue focused on Darwinism, organizational evolution and survival. We discuss key themes in the organizational evolution research that have emerged in recent years. These include the increasing adoption of the co-evolutionary approach, with a particular focus on the definition of appropriate units of analysis, such as routines, and related challenges associated with exploring the relationship between co-evolution, re-use of knowledge, adaptation, and exaptation processes. We then introduce the three articles that we have finally accepted in this Special Issue after an extensive, multi-round, triple blind-review process. We briefly outline how each of these articles contributes to understanding among scholars, practitioners and policy makers of the continuous evolutionary processes within and among social organizations and systems

Behavior in behavioral strategy : capturing, measuring, analyzing

Measuring behavior requires research methods that can capture observed outcomes and expose underlying processes and mechanisms. In this chapter, we present a toolbox of instruments and techniques we designed experimental tasks to simulate decision environments and capture behavior. We deployed protocol analysis and text analysis to examine the underlying cognitive processes. In combination, these can simultaneously grasp antecedents, outcomes, processes, and mechanisms. We applied them to collect rich behavioral data on two key topics in strategic management: the exploration–exploitation trade-off and strategic risk-taking. This mix of methods is particularly useful in describing actual behavior as it is, not as it should be, replacing assumptions with data and offering a finer-grained perspective of strategic decision-making