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See detailTargeting autophagy inhibits growth by enhancing NK cells infiltration in a CCL5-dependent manner
Mgrditchian, T; Arakelian, T; Paggetti, J et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 114((44)), 9271-9279

While blocking tumor growth by targeting autophagy is well established, its role on the infiltration of natural killer (NK) cells into tumors remains unknown. Here, we investigate the impact of targeting ... [more ▼]

While blocking tumor growth by targeting autophagy is well established, its role on the infiltration of natural killer (NK) cells into tumors remains unknown. Here, we investigate the impact of targeting autophagy gene Beclin1 (BECN1) on the infiltration of NK cells into melanomas. We show that, in addition to inhibiting tumor growth, targeting BECN1 increased the infiltration of functional NK cells into melanoma tumors. We provide evidence that driving NK cells to the tumor bed relied on the ability of autophagy-defective tumors to transcriptionally overexpress the chemokine gene CCL5 Such infiltration and tumor regression were abrogated by silencing CCL5 in BECN1-defective tumors. Mechanistically, we show that the up-regulated expression of CCL5 occurred through the activation of its transcription factor c-Jun by a mechanism involving the impairment of phosphatase PP2A catalytic activity and the subsequent activation of JNK. Similar to BECN1, targeting other autophagy genes, such as ATG5, p62/SQSTM1, or inhibiting autophagy pharmacologically by chloroquine, also induced the expression of CCL5 in melanoma cells. Clinically, a positive correlation between CCL5 and NK cell marker NKp46 expression was found in melanoma patients, and a high expression level of CCL5 was correlated with a significant improvement of melanoma patients' survival. We believe that this study highlights the impact of targeting autophagy on the tumor infiltration by NK cells and its benefit as a novel therapeutic approach to improve NK-based immunotherapy. [less ▲]

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See detailTargeting histone lysine demethylases - progress, challenges, and the future.
Thinnes, Cyrille UL; England, Katherine S.; Kawamura, Akane et al

in Biochimica et biophysica acta (2014), 1839(12), 1416-32

N-Methylation of lysine and arginine residues has emerged as a major mechanism of transcriptional regulation in eukaryotes. In humans, N(epsilon)-methyllysine residue demethylation is catalysed by two ... [more ▼]

N-Methylation of lysine and arginine residues has emerged as a major mechanism of transcriptional regulation in eukaryotes. In humans, N(epsilon)-methyllysine residue demethylation is catalysed by two distinct subfamilies of demethylases (KDMs), the flavin-dependent KDM1 subfamily and the 2-oxoglutarate- (2OG) dependent JmjC subfamily, which both employ oxidative mechanisms. Modulation of histone methylation status is proposed to be important in epigenetic regulation and has substantial medicinal potential for the treatment of diseases including cancer and genetic disorders. This article provides an introduction to the enzymology of the KDMs and the therapeutic possibilities and challenges associated with targeting them, followed by a review of reported KDM inhibitors and their mechanisms of action from kinetic and structural perspectives. [less ▲]

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See detailTargeting in Outer Space: Legal Aspects of Operational Military Actions in Space
Blount, Percy UL

in Harvard National Security Journal (2012)

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See detailTargeting of Listeria monocytogenes ActA protein to the plasma membrane as a tool to dissect both actin-based cell morphogenesis and ActA function.
Friederich, Evelyne UL; Gouin, E.; Hellio, R. et al

in The EMBO journal (1995), 14(12), 2731-44

Actin assembly on the surface of Listeria monocytogenes in the cytoplasm of infected cells provides a model to study actin-based motility and changes in cell shape. We have shown previously that the ActA ... [more ▼]

Actin assembly on the surface of Listeria monocytogenes in the cytoplasm of infected cells provides a model to study actin-based motility and changes in cell shape. We have shown previously that the ActA protein, exposed on the bacterial surface, is required for polarized nucleation of actin filaments. To investigate whether plasma membrane-associated ActA can control the organization of microfilaments and cell shape, variants of ActA, in which the bacterial membrane signal had been replaced by a plasma membrane anchor sequence, were produced in mammalian cells. While both cytoplasmic and membrane-bound forms of ActA increased the F-actin content, only membrane-associated ActA caused the formation of plasma membrane extensions. This finding suggests that ActA acts as an actin filament nucleator and shows that permanent association with the inner face of the plasma membrane is required for changes in cell shape. Based on the observation that the amino-terminal segment of ActA and the remaining portion which includes the proline-rich repeats cause distinct phenotypic modifications in transfected cells, we propose a model in which two functional domains of ActA cooperate in the nucleation and dynamic turnover of actin filaments. The present approach is a new model system to dissect the mechanism of action of ActA and to further investigate interactions of the plasma membrane and the actin cytoskeleton during dynamic changes of cell shape. [less ▲]

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See detailTargeting of zyxin to sites of actin membrane interaction and to the nucleus.
Nix, D. A.; Fradelizi, J.; Bockholt, S. et al

in The Journal of biological chemistry (2001), 276(37), 34759-67

The localization of proteins to particular intracellular compartments often regulates their functions. Zyxin is a LIM protein found prominently at sites of cell adhesion, faintly in leading lamellipodia ... [more ▼]

The localization of proteins to particular intracellular compartments often regulates their functions. Zyxin is a LIM protein found prominently at sites of cell adhesion, faintly in leading lamellipodia, and transiently in cell nuclei. Here we have performed a domain analysis to identify regions in zyxin that are responsible for targeting it to different subcellular locations. The N-terminal proline-rich region of zyxin, which harbors binding sites for alpha-actinin and members of the Ena/VASP family, concentrates in lamellipodial extensions and weakly in focal adhesions. The LIM region of zyxin displays robust targeting to focal adhesions. When overexpressed in cells, the LIM region of zyxin causes displacement of endogenous zyxin from focal adhesions. Upon mislocalization of full-length zyxin, at least one member of the Ena/VASP family is also displaced, and the organization of the actin cytoskeleton is perturbed. Zyxin also has the capacity to shuttle between the nucleus and focal adhesion sites. When nuclear export is inhibited, zyxin accumulates in cell nuclei. The nuclear accumulation of zyxin occurs asynchronously with approximately half of the cells exhibiting nuclear localization of zyxin within 2.3 h of initiating leptomycin B treatment. Our results provide insight into the functions of different zyxin domains. [less ▲]

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See detailTargeting prohibitins at the cell surface prevents Th17-mediated autoimmunity.
Buehler, Ulrike; Schulenburg, Katharina; Yurugi, Hajime et al

in The EMBO journal (2018), 37(16),

T helper (Th)17 cells represent a unique subset of CD4(+) T cells and are vital for clearance of extracellular pathogens including bacteria and fungi. However, Th17 cells are also involved in ... [more ▼]

T helper (Th)17 cells represent a unique subset of CD4(+) T cells and are vital for clearance of extracellular pathogens including bacteria and fungi. However, Th17 cells are also involved in orchestrating autoimmunity. By employing quantitative surface proteomics, we found that the evolutionarily conserved prohibitins (PHB1/2) are highly expressed on the surface of both murine and human Th17 cells. Increased expression of PHBs at the cell surface contributed to enhanced CRAF/MAPK activation in Th17 cells. Targeting surface-expressed PHBs on Th17 cells with ligands such as Vi polysaccharide (Typhim vaccine) inhibited CRAF-MAPK pathway, reduced interleukin (IL)-17 expression and ameliorated disease pathology with an increase in FOXP3(+)-expressing Tregs in an animal model for multiple sclerosis (MS). Interestingly, we detected a CD4(+) T cell population with high PHB1 surface expression in blood samples from MS patients in comparison with age- and sex-matched healthy subjects. Our observations suggest a pivotal role for the PHB-CRAF-MAPK signalling axis in regulating the polarization and pathogenicity of Th17 cells and unveil druggable targets in autoimmune disorders such as MS. [less ▲]

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See detailTargeting the sarcolemmal calcium pump: a potential novel strategy for the treatment of cardiovascular disease.
Oceandy, Delvac; Mamas, Mamas A.; Neyses, Ludwig UL

in Cardiovascular and Hematological Agents in Medicinal Chemistry (2007), 5(4), 300-4

Intracellular calcium dynamics play a very important role in mediating contraction and signalling in cardiomyocytes and vascular smooth muscle cells. A number of calcium transporters have been identified ... [more ▼]

Intracellular calcium dynamics play a very important role in mediating contraction and signalling in cardiomyocytes and vascular smooth muscle cells. A number of calcium transporters have been identified that orchestrate a complex process of excitation-contraction coupling and molecular signalling. Despite the variability of the calcium transporters expressed in cardiomyocytes, most calcium channel blockers used therapeutically target the L-type calcium channel and exhibit antihypertensive and/or vasodilating activities. Recently, another calcium pump which is located in the sarcolemma has been shown to mediate cardiac contractility and vascular tone. Interestingly, this sarcolemmal calcium pump (also known as Plasma Membrane Calcium/calmodulin dependent ATPase or PMCA) exerts its function not by altering global calcium concentration, but by mediating signal transduction pathways. This review will discuss recent advances that support the key roles of PMCA as signalling molecule and the potential to target this calcium pump as a novel approach for the treatment of cardiovascular disease. [less ▲]

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See detailTargeting the “I” in “Identity” – A Paradigmatic Shift in Curating?
Kmec, Sonja UL

in Whitehead, Christopher; Mason, Rhiannon; Eckersley, Susannah (Eds.) et al "Placing" Europe in the Museum: People(s), Places, Identities (2013)

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See detailTarzan and chain: exploring the ICO jungle and evaluating design archetypes
Bachmann, Nina M.; Drasch, Benedict; Fridgen, Gilbert UL et al

in Electronic Markets (2022), 32

The phenomenon of a blockchain use case called initial coin offering (ICO) is drawing increasing attention as a novel funding mechanism. ICO is a crowdfunding type that utilizes blockchain tokens to allow ... [more ▼]

The phenomenon of a blockchain use case called initial coin offering (ICO) is drawing increasing attention as a novel funding mechanism. ICO is a crowdfunding type that utilizes blockchain tokens to allow for truly peer-to-peer investments. Although more than \$7bn has been raised globally via ICOs as at 2018, the concept and its implications are not yet entirely understood. The research lags behind in providing in-depth analyses of ICO designs and their long-term success. We address this research gap by developing an ICO taxonomy, applying a cluster analysis to identify prevailing ICO archetypes, and providing an outlook on the token value market performance for individual archetypes. We identify five ICO design archetypes and display their secondary market development from both a short-term and a long-term perspective. We contribute to an in-depth understanding of ICOs and their implications. Further, we offer practitioners tangible design and success indications for future ICOs. [less ▲]

Detailed reference viewed: 129 (5 UL)
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See detailTask and category fit as determinants of information processing: The case of forensic psychologists.
Glock, Sabine; Kneer, Julia; Krolak-Schwerdt, Sabine UL

Scientific Conference (2012, July)

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See detailTask instructions determine the visuo-spatial and verbal-spatial nature of number-space associations
Georges, Carrie UL; Schiltz, Christine UL; Hoffmann, Danielle UL

Poster (2014, April)

Evidence for number-space associations comes from the spatial-numerical association of response-codes (SNARC) effect, consisting in faster reaction times (RTs) to small/large digits with the left/right ... [more ▼]

Evidence for number-space associations comes from the spatial-numerical association of response-codes (SNARC) effect, consisting in faster reaction times (RTs) to small/large digits with the left/right hand respectively. Classically, they are thought to result from numerical coding along a left-to-right-oriented mental number line (visuo-spatial account; Dehaene et al., 1993). Recently, an association between the verbal concepts “small”/“left” and “large”/“right” has been suggested as an alternative explanation (verbal-spatial account; Gevers et al., 2010). Since the predominance of these accounts remains debated, we aimed to determine whether task instructions influence their extent of explaining the SNARC effect. A magnitude comparison task where the verbal labels “left”/“right” were displayed on the left/right response side alternatively allowed us to directly contrast the two accounts by comparing verbal SNARC slopes (based on differences in RTs to the labels “left” and “right”) with classical spatial SNARC slopes (based on differences in RTs to the left and right response side). In the verbal condition, participants (41 students, 20 female, mean age=21.6) responded to the assigned labels irrespective of their side of appearance, whereas the spatial condition required responding to the left or right response side irrespective of the displayed label. Under verbal instructions, only the verbal slope was significantly negative (verbal slope=-67.54, spatial slope=-4.82). Conversely, no significant difference was observed between verbal and spatial slopes under spatial instructions – both slopes being significantly negative (verbal slope=-15.12, spatial slope=-29.39). Taken together, number-space associations arise from verbal coding regardless of task instructions, while spatial coding only occurs under spatial instructions. [less ▲]

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See detailTask instructions determine the visuospatial and verbal-spatial nature of number-space associations
Georges, Carrie UL; Schiltz, Christine UL; Hoffmann, Danielle UL

in Quarterly Journal of Experimental Psychology (2015), 68(9),

Detailed reference viewed: 165 (24 UL)
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See detailTask interference and distraction efficacy in patients with fibromyalgia: an experimental investigation
Van Ryckeghem, Dimitri UL; Rost, Silke; Kissi, Ama et al

in Pain (2018), 159(6), 1119-1126

Pain has the capacity to interfere with daily tasks. Although task interference by pain is largely unintentional, it can be controlled to a certain extent. Such top-down control over pain has been thought ... [more ▼]

Pain has the capacity to interfere with daily tasks. Although task interference by pain is largely unintentional, it can be controlled to a certain extent. Such top-down control over pain has been thought to be reduced in fibromyalgia patients. In this study, we investigated task interference and distraction efficacy in fibromyalgia patients (FM) and a matched healthy control group. Forty-nine fibromyalgia patients and 49 heathy volunteers performed as quickly as possible (a) a visual localization task in the presence of non-painful vibrating or painful electric somatic stimuli, and (b) a somatosensory localization task (using non-painful or painful stimuli). Participants reported on their experience of the somatic stimuli on some of the trials during both localisation tasks. Results indicated that pain interferes with performance of the visual task, in both FM patients and healthy individuals. Furthermore, participants experienced the pain stimulus as less intense when directing attention away from the pain than when focusing on the pain. Overall, task performance of FM patients was slower compared to the task performance in the healthy control group. In contrast to our hypotheses, FM patients and healthy volunteers did not differ in the magnitude of the interference effect and distraction-efficacy. In conclusion, current study provides support for contemporary theories claiming that attention modulates the experience of pain and vice versa. However, no evidence was however found for an altered attentional processing of pain in fibromyalgia patients. Furthermore, results indicate that task interference and distraction-efficacy are not just two sides of the same coin. [less ▲]

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See detailTask Offloading and Resource Allocation for IoV Using 5G NR-V2X Communication
Raza, Salman; Wang, Shangguang; Ahmed, Manzoor et al

in IEEE Internet of Things Journal (2021)

Vehicular edge computing (VEC) is an innovative computing paradigm with an exceptional ability to improve the vehicles’ capacity to manage computation-intensive applications with both low latency and ... [more ▼]

Vehicular edge computing (VEC) is an innovative computing paradigm with an exceptional ability to improve the vehicles’ capacity to manage computation-intensive applications with both low latency and energy consumption. Vehicles require to make task offloading decisions in dynamic network conditions to obtain maximum computation efficiency. In this article, we analyze computation efficiency in a VEC scenario, where a vehicle offloads its tasks to maximize computation efficiency as a tradeoff between computation time and energy consumption. Although, it is quite a challenge to ensure the quality of experience of the vehicle due to diverse task requirements and the dynamic wireless conditions caused by vehicle mobility. To tackle this problem, a computation efficiency problem is formulated by jointly optimizing task offloading decision and computation resource allocation. We propose a mobility-aware computational efficiency-based task offloading and resource allocation (MACTER) scheme and develop a distributed MACTER algorithm that provides the near-optimal solution. We further consider the fifth-generation new-radio vehicle-to-everything communication model, i.e., cellular link and millimeter wave, to enhance the system performance. The simulation outcomes demonstrate that the proposed algorithm can efficiently enhance computation efficiency while satisfying computing time and energy consumption constraints. [less ▲]

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See detailTask-Oriented Communication Design in Cyber-Physical Systems: A Survey on Theory and Applications
Mostaani, Arsham UL; Vu, Thang Xuan UL; Sharma, Shree Krishna UL et al

in IEEE Access (2022)

Communication system design has been traditionally guided by task-agnostic principles, which aim at efficiently transmitting as many correct bits as possible through a given channel. However, in the era ... [more ▼]

Communication system design has been traditionally guided by task-agnostic principles, which aim at efficiently transmitting as many correct bits as possible through a given channel. However, in the era of cyber-physical systems, the effectiveness of communications is not dictated simply by the bit rate, but most importantly by the efficient completion of the task in hand, e.g., controlling remotely a robot, automating a production line or collaboratively sensing through a drone swarm. In parallel, it is projected that by 2023, half of the worldwide network connections will be among machines rather than humans. In this context, it is crucial to establish a new paradigm for designing communication strategies for multi-agent cyber-physical systems. This is a daunting task, since it requires a combination of principles from information, communication, control theories and computer science in order to formalize a general framework for task-oriented communication designs. In this direction, this paper reviews and structures the relevant theoretical work across a wide range of scientific communities. Subsequently, it proposes a general conceptual framework for task-oriented communication design, along with its specializations according to targeted use cases. Furthermore, it provides a survey of relevant contributions in dominant applications, such as industrial internet of things, multi-unmanned aerial vehicle (UAV) systems, autonomous vehicles, distributed learning systems, smart manufacturing plants, 5G and beyond self-organizing networks, and tactile internet. Finally, this paper also highlights the most important open research topics from both the theoretical framework and application points of view. [less ▲]

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See detailTask-Oriented Data Compression for Multi-Agent Communications Over Bit-Budgeted Channels
Mostaani, Arsham UL; Vu, Thang Xuan UL; Chatzinotas, Symeon UL et al

in IEEE Open Journal of the Communications Society (2022)

Various applications for inter-machine communications are on the rise. Whether it is for autonomous driving vehicles or the internet of everything, machines are more connected than ever to improve their ... [more ▼]

Various applications for inter-machine communications are on the rise. Whether it is for autonomous driving vehicles or the internet of everything, machines are more connected than ever to improve their performance in fulfilling a given task. While in traditional communications the goal has often been to reconstruct the underlying message, under the emerging task-oriented paradigm, the goal of communication is to enable the receiving end to make more informed decisions or more precise estimates/computations. Motivated by these recent developments, in this paper, we perform an indirect design of the communications in a multi-agent system (MAS) in which agents cooperate to maximize the averaged sum of discounted one-stage rewards of a collaborative task. Due to the bit-budgeted communications between the agents, each agent should efficiently represent its local observation and communicate an abstracted version of the observations to improve the collaborative task performance. We first show that this problem can be approximated as a form of data-quantization problem which we call task-oriented data compression (TODC). We then introduce the state-aggregation for information compression algorithm (SAIC) to solve the formulated TODC problem. It is shown that SAIC is able to achieve near-optimal performance in terms of the achieved sum of discounted rewards. The proposed algorithm is applied to a geometric consensus problem and its performance is compared with several benchmarks. Numerical experiments confirm the promise of this indirect design approach for task-oriented multi-agent communications. [less ▲]

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See detailTasks, Technology, and Factor Prices in the Neoclassical Production Sector
Irmen, Andreas UL

in Journal of Economics (2020), 131(2), 101-121

This paper introduces tasks into the neoclassical production sector. Competitive firms choose the profit-maximizing amounts of factor-specific tasks that determine their factor demands and output supplies ... [more ▼]

This paper introduces tasks into the neoclassical production sector. Competitive firms choose the profit-maximizing amounts of factor-specific tasks that determine their factor demands and output supplies. We show that the effect of factor-augmenting technical change on relative and absolute factor prices can be decomposed into a productivity effect and a task-demand effect of opposite sign. These effects appear since the novel task-based approach distinguishes between the demands for tasks and the demands for factors. This perspective provides a new intuition for the emergence of relative and absolute factor biases and the role of the elasticity of substitution. [less ▲]

Detailed reference viewed: 17 (2 UL)
See detailTasks, Technology, and Factor Prices in the Neoclassical Production Sector
Irmen, Andreas UL

E-print/Working paper (2020)

This paper introduces tasks into the neoclassical production sector. Competitive firms choose the profit-maximizing amounts of factor-specific tasks that determine their factor demands and output supplies ... [more ▼]

This paper introduces tasks into the neoclassical production sector. Competitive firms choose the profit-maximizing amounts of factor-specific tasks that determine their factor demands and output supplies. We show that the effect of factor-augmenting technical change on relative and absolute factor prices can be decomposed into a productivity effect and a task-demand effect of opposite sign. These effects appear since the novel task-based approach distinguishes between the demands for tasks and the demands for factors. This perspective provides a new intuition for the emergence of relative and absolute factor biases and the role of the elasticity of substitution. [less ▲]

Detailed reference viewed: 40 (0 UL)