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Zhu, Helen, Liis Uusküla-Reimand, Keren Isaev, Lina Wadi, Azad Alizada, Shimin Shuai, Vincent Huang, et al. "Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks." Molecular Cell 77, no. 6 (March 2020): 1307–21. http://dx.doi.org/10.1016/j.molcel.2019.12.027.
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Tao, Pengfei, Hongyu Hu, Zhenhai Gao, Xin Liu, Xianmin Song, Yan Xing, Yuzhou Duan, and Fulu Wei. "The Research of the Driver Attention Field Modeling." Discrete Dynamics in Nature and Society 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/270616.
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For expanding the application scope of car-following, based on the basic idea of the noncontact interaction of the objects in physics, establish an attention field model to describe the driving behavior. Firstly, propose the time distance concept to describe the degree of driver perception to the front one-dimensional space and extend its application range to the two-dimensional space. Secondly, connect the point which has the same time distance to constitute the equipotential line of drivers’ attention field equipotent, and establish a model to describe it. Thirdly, define the effective range of the driver’s psychological field with the feature of the driver’s visual distance range increasing and the angle decreasing. Finally, design the calculation method to collect projection of the object in the psychological field scope and calculate the curve points to determine the object’s intensity of psychological field. Preliminarily build the driving behavior model and use the numerical simulation method to simulate the simple transport scenarios; initially verify the validity of the model.
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Wallang, Paul, and Richard Taylor. "Psychiatric and psychological aspects of fraud offending." Advances in Psychiatric Treatment 18, no. 3 (May 2012): 183–92. http://dx.doi.org/10.1192/apt.bp.111.008946.
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SummaryThere has been little research into the interaction between fraud offences and mental health. Fraud is perpetrated on a massive scale and a number of offenders will have psychiatric pathology either as a primary driver of the offence or as an associated phenomenon that will require psychiatric care and treatment. This article reviews the broad range of psychiatric conditions that have been associated with fraud offending, comments on management and discusses methods of psychiatric assessment in fraud offences.
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Wheeler, William A., John D. Lee, Mireille Raby, Rhonda A. Kinghorn, Alvah C. Bittner, and Marvin C. McCallum. "Predicting Driver Behavior using Advanced Traveler Information Systems." Proceedings of the Human Factors and Ergonomics Society Annual Meeting 38, no. 16 (October 1994): 1057–61. http://dx.doi.org/10.1177/154193129403801614.
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As a part of the Intelligent Vehicle Highway System (IVHS), Advanced Traveler Information Systems (ATIS) will offer tomorrow's drivers significantly expanded capabilities for getting where they want to go safely and efficiently. Vehicle-based navigation systems combined with information on highway conditions and services have the potential for improving driver performance. Though ATIS may offer considerable advantages, the system design must be consistent with the primary tasks of controlling and operating the vehicle. This paper describes an attempt to identify the likely interaction between what a driver must do to operate the vehicle safely while at the same time using the various ATIS systems. As such, it is an attempt to visualize what driving with these advanced systems will be like and to translate that vision into standard human factors task analytic techniques. Though a broad range of ATIS systems and functions were addressed in this project, this paper will address the macro-level task analyses that resulted from the examination of 165 tasks related to ATIS use.
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Cavalli, Valeria, Pekka Kujala, Judith Klumperman, and Lawrence S. B. Goldstein. "Sunday Driver links axonal transport to damage signaling." Journal of Cell Biology 168, no. 5 (February 28, 2005): 775–87. http://dx.doi.org/10.1083/jcb.200410136.
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Neurons transmit long-range biochemical signals between cell bodies and distant axonal sites or termini. To test the hypothesis that signaling molecules are hitchhikers on axonal vesicles, we focused on the c-Jun NH2-terminal kinase (JNK) scaffolding protein Sunday Driver (syd), which has been proposed to link the molecular motor protein kinesin-1 to axonal vesicles. We found that syd and JNK3 are present on vesicular structures in axons, are transported in both the anterograde and retrograde axonal transport pathways, and interact with kinesin-I and the dynactin complex. Nerve injury induces local activation of JNK, primarily within axons, and activated JNK and syd are then transported primarily retrogradely. In axons, syd and activated JNK colocalize with p150Glued, a subunit of the dynactin complex, and with dynein. Finally, we found that injury induces an enhanced interaction between syd and dynactin. Thus, a mobile axonal JNK–syd complex may generate a transport-dependent axonal damage surveillance system.
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Söffker, Dirk, Xingguang Fu, Andreas Hasselberg, and Marcel Langer. "Modeling of Complex Human-Process Interaction as Framework for Assistance and Supervisory Control of Technical Processes." International Journal of Information Technology and Web Engineering 7, no. 1 (January 2012): 46–66. http://dx.doi.org/10.4018/jitwe.2012010104.
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Interactive processes are omnipresent in fields dealing with automation of complex technical processes, allowing a wide range of application scenarios of assistance systems to support human operators. However, the definition and description of the interaction strongly depends on the application. The description of Human-Process-Interaction (HPI) in most cases is the key for the development of interaction models leading to a framework for the development of assistance systems. The goal of such assistance systems is to support human operators, or human factors, and thereby improve the considered process in parallel. For the purpose of creating a framework for the development of assistance systems, the Situation-Operator-Model (SOM) approach is applied. The SOM approach is capable of modeling HPI in a net-like structure representing the complex environment (or process) and human interactions. By this formal modeling of HPI for the development of human-centered assistance systems based on the underlying modeled interaction is available. In this contribution illustrative examples of different applications for the proposed approach are given by a cognitive, individualized driver assistance system for lane changing maneuvers, by the assessment of operator decisions in air traffic control as well as the operator supervision in semi-automated production process.
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Kohl, Ondrej, Lubomír Pešík, and Antonin Skarolek. "Driver Seat Differential Pneumatic System with Air Damping." Applied Mechanics and Materials 732 (February 2015): 191–94. http://dx.doi.org/10.4028/www.scientific.net/amm.732.191.
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The paper shows a possibility of the tuning mechanical system by means of two pneumatic springs in a differential configuration connected with a throttle valve. The springs are inserted into the lead mechanism and connected to its parts, and to its supporting platform. The vibrations, transferred from the kinematic excitation of the base, are intended to be minimized. The vibration isolation by means of pneumatic springs is available in many technical systems, e.g. in supports of heavy machinery as well as in systems characterized by the human interaction, such as driver seats, ambulance couchettes, etc. The pneumatic springs provide the option of adaption of the stiffness, and herewith the adaption of the natural frequency of the system according to the exciting frequency. In cases of application of the object vibration isolation, they can change the load characteristics in a relative large range. In the studied case of the differential spring configuration, the springs are connected with an air pipe to the throttle valve. The air being exchanged during the motion period comes through the valve, the cross-section of which determines the time delay of the pneumatic sub-system thus creating a hysteresis of load characteristic of the spring support. This brings an additional, controllable damping to such a system that is profitable in most vibration isolation cases.
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Zhang, Yiqi, Changxu Wu, Chunming Qiao, and Yunfei Hou. "Effects of Warning Characteristics on Driver Performance in Connected Vehicle Systems with Missing Warnings." Proceedings of the Human Factors and Ergonomics Society Annual Meeting 62, no. 1 (September 2018): 1827. http://dx.doi.org/10.1177/1541931218621415.
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The connected vehicle systems (CVS) aim to provide drivers with information in a timely and reliable way to improve transportation safety. With the emerging wireless communication technologies, the vehicles will be equipped with the ability to communicate with each other about the surrounding traffic situations by exchanging vehicle status and motion data via Dedicated Short-Range Communications (DSRC) network (Kenney, 2011). With the assistance of the cooperative collision warnings, the impact of designed warning parameters on driver performance is increasingly important. Existing empirical studies have studied the warning timing and warning reliability in determining the effectiveness of the collision warning systems in advanced driver assistance systems (ADAS). In terms of warning timing, the studies in reached consistent conclusions that early warnings induced more timely braking and longer braking process, resulted in higher trust of the warning systems, and reduced collision rates (for example, Abe & Richardson, 2006a; Lee, McGehee, Brown, & Reyes, 2002; Yan, Xue, Ma, & Xu, 2014; Yan, Zhang, & Ma, 2015; Wan, Wu, and Zhang, 2016). In terms of the warning reliability, research has shown that warnings with a higher reliability increased driver’s trust of the warning systems, led to higher frequency in warning responses, and reduced crash rates (for example, Abe, Itoh, & Yamamura, 2009; Bliss & Acton, 2003; Maltz & Shinar, 2007; Sullivan, Tsimhoni, & Bogard, 2008). However, the interaction effects of warning lead time and warning reliability on driver performance was not examined especially under the connected vehicle settings. The current research investigated the interaction effects of warning lead time (2.5s vs. 4.5s), warning reliability (73% vs. 89%), and speech warning style (command vs. notification) on driver performance and subjective evaluation of warnings in CVS. A driving simulator study with thirty-two participants was conducted to simulate a connected vehicle environment with missing warnings due to the failures in the data transmission within the communication network of the CVS. The results showed command warnings led to a smaller collision rate compared to notification warnings with the warning lead time of 2.5s, whereas notification warnings resulted in a smaller collision rate compared to command warning with the warning lead time of 4.5s. These results suggested notification warnings should be selected when warning lead time is longer and warning reliability is higher, which resulted in higher safety benefits and higher subjective ratings. Command warnings could be selected when warning lead time is shorter since they led to more safety benefits. However, such selection has to be made with caution since command warnings may limit drivers’ response type and were perceived as less helpful than notification warnings.
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Stanton, Neville A., James W. Brown, Kirsten M. A. Revell, Jed Clark, Joy Richardson, Pat Langdon, Mike Bradley, Nermin Caber, Lee Skrypchuk, and Simon Thompson. "Modelling Automation–Human Driver Handovers Using Operator Event Sequence Diagrams." Future Transportation 1, no. 2 (September 1, 2021): 351–69. http://dx.doi.org/10.3390/futuretransp1020020.
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This research aims to show the effectiveness of Operator Event Sequence Diagrams (OESDs) in the normative modelling of vehicle automation to human drivers’ handovers and validate the models with observations from a study in a driving simulator. The handover of control from automation to human operators has proved problematic, and in the most extreme circumstances catastrophic. This is currently a topic of much concern in the design of automated vehicles. OESDs were used to inform the design of the interaction, which was then tested in a driving simulator. This test provided, for the first time, the opportunity to validate OESDs with data gathered from videoing the handover processes. The findings show that the normative predictions of driver activity determined during the handover from vehicle automation in a driving simulator performed well, and similar to other Human Factors methods. It is concluded that OESDs provided a useful method for the human-centred automation design and, as the predictive validity shows, can continue to be used with some confidence. The research in this paper has shown that OESDs can be used to anticipate normative behaviour of drivers engaged in handover activities with vehicle automation in a driving simulator. Therefore, OESDs offer a useful modelling tool for the Human Factors profession and could be applied to a wide range of applications and domains.
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Porter, Richard J., Eric T. Donnell, and John M. Mason. "Geometric Design, Speed, and Safety." Transportation Research Record: Journal of the Transportation Research Board 2309, no. 1 (January 2012): 39–47. http://dx.doi.org/10.3141/2309-05.
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A performance-based approach to the interaction of geometric design, speed, and safety is considered given the availability of two key documents: the Highway Safety Manual and Modeling Operating Speed: Synthesis Report. A historical look at the concept of design speed shows that although the definition of design speed has changed on more than one occasion, the same basic philosophy that related design speed to a safe speed is still reflected in current policy in supplemental guidance related to the selection of design speed. A conservative approach to establishing design criteria, used to address the range of driver, vehicle, and roadway conditions and capabilities that a designer must consider, is demonstrated. Operating speeds are shown to be higher than design speeds for design speeds of approximately 55 mph or less. This outcome may be considered undesirable, but that categorization seems to be based more on subjective judgments of what is desirable than on actual safety findings. Finally, the idea of speed management through the use of roadway geometrics (i.e., geometric designs that influence driver selection of operating speed)—one component of self-enforcing, self-explaining roadway design—is explored. Findings uncover possible challenges to implementing this idea. Five related questions are addressed: (a) What is known about the relationships between road geometry and operating speeds? (b) To what degree does road geometry influence operating speeds? (c) How are safety and security influenced by road geometry? (d) What are the potential impacts on large vehicles? and (e) What is the nature of the speed–safety trade-off?
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Chipengo, Ushemadzoro, Peter M. Krenz, and Shawn Carpenter. "From Antenna Design to High Fidelity, Full Physics Automotive Radar Sensor Corner Case Simulation." Modelling and Simulation in Engineering 2018 (December 27, 2018): 1–19. http://dx.doi.org/10.1155/2018/4239725.
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Advanced driver assistance systems (ADAS) have recently been thrust into the spotlight in the automotive industry as carmakers and technology companies pursue effective active safety systems and fully autonomous vehicles. Various sensors such as lidar (light detection and ranging), radar (radio detection and ranging), ultrasonic, and optical cameras are employed to provide situational awareness to vehicles in a highly dynamic environment. Radar has emerged as a primary sensor technology for both active/passive safety and comfort-advanced driver-assistance systems. Physically building and testing radar systems to demonstrate reliability is an expensive and time-consuming process. Simulation emerges as the most practical solution to designing and testing radar systems. This paper provides a complete, full physics simulation workflow for automotive radar using finite element method and asymptotic ray tracing electromagnetic solvers. The design and optimization of both transmitter and receiver antennas is presented. Antenna interaction with vehicle bumper and fascia is also investigated. A full physics-based radar scene corner case is modelled to obtain high-fidelity range-Doppler maps. Finally, this paper investigates the effects of inclined roads on late pedestrian detection and the effects of construction metal plate radar returns on false target identification. Possible solutions are suggested and validated. Results from this study show how pedestrian radar returns can be increased by over 16 dB for early detection along with a 27 dB reduction in road construction plate radar returns to suppress false target identification. Both solutions to the above corner cases can potentially save pedestrian lives and prevent future accidents.
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Creanza, Nicole, Oren Kolodny, and Marcus W. Feldman. "Greater than the sum of its parts? Modelling population contact and interaction of cultural repertoires." Journal of The Royal Society Interface 14, no. 130 (May 2017): 20170171. http://dx.doi.org/10.1098/rsif.2017.0171.
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Evidence for interactions between populations plays a prominent role in the reconstruction of historical and prehistoric human dynamics; these interactions are usually interpreted to reflect cultural practices or demographic processes. The sharp increase in long-distance transportation of lithic material between the Middle and Upper Palaeolithic, for example, is seen as a manifestation of the cultural revolution that defined the transition between these epochs. Here, we propose that population interaction is not only a reflection of cultural change but also a potential driver of it. We explore the possible effects of inter-population migration on cultural evolution when migrating individuals possess core technological knowledge from their original population. Using a computational framework of cultural evolution that incorporates realistic aspects of human innovation processes, we show that migration can lead to a range of outcomes, including punctuated but transient increases in cultural complexity, an increase of cultural complexity to an elevated steady state and the emergence of a positive feedback loop that drives ongoing acceleration in cultural accumulation. Our findings suggest that population contact may have played a crucial role in the evolution of hominin cultures and propose explanations for observations of Palaeolithic cultural change whose interpretations have been hotly debated.
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Sun, Yan, Carine Beuchat, and Heinz Müller-Schärer. "Is biocontrol efficacy rather driven by the plant or the antagonist genotypes? A conceptual bioassay approach." NeoBiota 63 (December 8, 2020): 81–100. http://dx.doi.org/10.3897/neobiota.63.54962.
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In the new range, invasive species lack their specialist co-evolved natural enemies, which then might be used as biocontrol agents. Populations of both a plant invader in the introduced range and its potential biocontrol agents in the native range may be genetically differentiated among geographically distinct regions. This, in turn, is expected to affect the outcome of their interaction when brought together, and by this the efficacy of the control. It further raises the question, is the outcome of such interactions mainly driven by the genotype of the plant invader (some plant genotypes being more resistant/tolerant to most of the antagonist genotypes), or by the antagonist genotype (some antagonist genotypes being more effective against most of the plant genotypes)? This is important for biocontrol management, as only the latter is expected to result in more effective control, when introducing the right biocontrol agent genotypes. In a third scenario, where the outcome of the interaction is driven by a specific plant by antagonist genotype interactions, an effective control will need the introduction of carefully selected multiple antagonist genotypes. Here, we challenged in a complete factorial design 11 plant genotypes (mainly half-siblings) of the invasive Ambrosia artemisiifolia with larvae of eight genotypes (full-siblings) of the leaf beetle Ophraella communa, a potential biocontrol insect, and assessed larval and adult performance and leaf consumption as proxies of their expected impact on the efficacy of biological control. Both species were collected from several locations from their native (USA) and introduced ranges (Europe and China). In summary, we found O. communa genotype to be the main driver of this interaction, indicating the potential for at least short-term control efficacy when introducing the best beetle genotypes. Besides the importance of investigating the genetic structure both among and within populations of the plant invader and the biocontrol agent during the pre-release phase of a biocontrol program, we advocate integrating such bioassays, as this will give a first indication of the probability for an – at least – short- to mid-term efficacy when introducing a potential biocontrol agent, and on where to find the most efficient agent genotypes.
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Barriga, Jhonattan J., Juan Sulca, José León, Alejandro Ulloa, Diego Portero, José García, and Sang Guun Yoo. "A Smart Parking Solution Architecture Based on LoRaWAN and Kubernetes." Applied Sciences 10, no. 13 (July 7, 2020): 4674. http://dx.doi.org/10.3390/app10134674.
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Finding a parking space in a city is one of the most common activities of a driver. This becomes more difficult when the city is unknown or has huge vehicular congestion. A solution to address this issue is called smart parking. Smart parking solutions rely on Internet of Things (IoT) and several technologies to achieve their purpose. This paper proposes an architecture for deploying a smart parking solution based on Long-Range Wide Area Network (LoRaWAN) sensors, LoRaWAN and a cluster of Kubernetes. This approach provides an open architecture able to share information with other parties through a REST API interface. Likewise, it contains a mobile and a web application for user interaction. This solution provides an administration interface for managing parking lots. The user interface lets a user to find, view information, display available spaces and rate a parking lot in real time. This solution could be used as an application as service parking system. The proposed architecture is fully portable and scalable due to the use of Kubernetes.
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Ng, Benjamin, Stuart A. Cook, and Sebastian Schafer. "Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway." Experimental & Molecular Medicine 52, no. 12 (December 2020): 1871–78. http://dx.doi.org/10.1038/s12276-020-00531-5.
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AbstractInterleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFβ) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction.
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Blizinsky, Katherine D., Blanca Diaz-Castro, Marc P. Forrest, Britta Schürmann, Anthony P. Bach, Maria Dolores Martin-de-Saavedra, Lei Wang, John G. Csernansky, Jubao Duan, and Peter Penzes. "Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub." Proceedings of the National Academy of Sciences 113, no. 30 (July 11, 2016): 8520–25. http://dx.doi.org/10.1073/pnas.1607014113.
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The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission. However, disease-relevant cellular phenotypes of 16p11.2 microduplication and the driver gene(s) remain to be identified. We found increased dendritic arborization in isolated cortical pyramidal neurons from a mouse model of 16p11.2 duplication (dp/+). Network analysis identified MAPK3, which encodes ERK1 MAP kinase, as the most topologically important hub in protein–protein interaction networks within the 16p11.2 region and broader gene networks of schizophrenia-associated CNVs. Pharmacological targeting of ERK reversed dendritic alterations associated with dp/+ neurons, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.
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Chamberlain, K. J., J. Barclay, K. J. Preece, R. J. Brown, and J. P. Davidson. "Lower Crustal Heterogeneity and Fractional Crystallization Control Evolution of Small-volume Magma Batches at Ocean Island Volcanoes (Ascension Island, South Atlantic)." Journal of Petrology 60, no. 8 (August 1, 2019): 1489–522. http://dx.doi.org/10.1093/petrology/egz037.
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Abstract Ocean island volcanoes erupt a wide range of magmatic compositions via a diverse range of eruptive styles. Understanding where and how these melts evolve is thus an essential component in the anticipation of future volcanic activity. Here we examine the role of crustal structure and magmatic flux in controlling the location, evolution and ultimately composition of melts at Ascension Island. Located in the South Atlantic, Ascension Island is an ocean island volcano that has produced a continuum of eruptive compositions from basalt to rhyolite in its 1 Myr subaerial eruptive history. Volcanic rocks broadly follow a silica-undersaturated subalkaline evolutionary trend, and new data presented here show a continuous compositional trend from basalt through trachyte to rhyolite. Detailed petrographic observations are combined with in situ geochemical analyses of crystals and glass, and new whole-rock major and trace element data from mafic and felsic pyroclastic and effusive deposits that span the entire range in eruptive ages and compositions found on Ascension Island. These data show that extensive fractional crystallization is the main driver for the production of felsic melts for Ascension Island, a volcano built on thin, young, oceanic crust. Strong spatial variations in the compositions of erupted magmas reveal the role of a heterogeneous lower crust; differing degrees of interaction with a zone of plutonic rocks are responsible for the range in mafic lava compositions, and for the formation of the central and eastern felsic complexes. A central core of nested, small-scale plutonic, or mush-like, bodies inhibits the ascent of mafic magmas, allowing sequential fractional crystallization within the lower crust, and generating felsic magmas in the core of the island. There is no evidence for magma mixing preserved in any of the studied eruptions, suggesting that magma storage regions are transient, and material is not recycled between eruptions.
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Tawia Hagan, Daniel Fiifi, Guojie Wang, X. San Liang, and Han A. J. Dolman. "A Time-Varying Causality Formalism Based on the Liang–Kleeman Information Flow for Analyzing Directed Interactions in Nonstationary Climate Systems." Journal of Climate 32, no. 21 (October 7, 2019): 7521–37. http://dx.doi.org/10.1175/jcli-d-18-0881.1.
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Abstract The interaction between the land surface and the atmosphere is of significant importance in the climate system because it is a key driver of the exchanges of energy and water. Several important relations to heat waves, floods, and droughts exist that are based on the interaction of soil moisture and, for instance, air temperature and humidity. Our ability to separate the elements of this coupling, identify the exact locations where they are strongest, and quantify their strengths is, therefore, of paramount importance to their predictability. A recent rigorous causality formalism based on the Liang–Kleeman (LK) information flow theory has been shown, both theoretically and in real-world applications, to have the necessary asymmetry to infer the directionality and magnitude within geophysical interactions. However, the formalism assumes stationarity in time, whereas the interactions within the land surface and atmosphere are generally nonstationary; furthermore, it requires a sufficiently long time series to ensure statistical sufficiency. In this study, we remedy this difficulty by using the square root Kalman filter to estimate the causality based on the LK formalism to derive a time-varying form. Results show that the new formalism has similar properties compared to its time-invariant form. It is shown that it is also able to capture the time-varying causality structure within soil moisture–air temperature coupling. An advantage is that it does not require very long time series to make an accurate estimation. Applying a wavelet transform to the results also reveals the full range of temporal scales of the interactions.
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Assari, Shervin, and Golnoush Akhlaghipour MD. "Not Race or Age but Their Interaction Predicts Pre-Adolescents’ Inhibitory Control." Children and Teenagers 3, no. 2 (November 5, 2020): p50. http://dx.doi.org/10.22158/ct.v3n2p50.
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Background: African American pre-adolescents are at a higher risk of risky behaviors such as aggression, drug use, alcohol use, and subsequent poor outcomes compared to Caucasian pre-adolescents. All these high-risk behaviors are connected to low levels of Inhibitory Control (IC). Aim: We used the Adolescent Brain Cognitive Development (ABCD) data to compare Caucasian and African American pre-adolescents for the effect of age on pre-adolescents IC, a driver of high-risk behaviors. Methods: This cross-sectional analysis included 4,626 pre-adolescents between ages 9 and 10 from the ABCD study. Regression was used to analyze the data. The predictor variable was age measured in months. The main outcome was IC measured by a Stop-Signal Task (SST). Race was the effect modifier. Results: Overall, age was associated with IC. Race also showed a statistically significant interaction with age on pre-adolescents’ IC, indicating weaker effects of age on IC for African American than Caucasian pre-adolescents. Conclusion: Age-related changes in IC are more pronounced for Caucasian than African American pre-adolescents. To eliminate the racial gap in brain development between African American and Caucasian pre-adolescents, we should address structural and societal barriers that alter age-related development for racial minority pre-adolescents. Social and public policies, rather than health policies, are needed to address structural and societal barriers that hinder African American adolescents’ brain development. Interventions should add resources to the urban areas that many African American families live in so their children can have better age-related brain development. Such changes would be essential given IC in pre-adolescents is a predictor of a wide range of behaviors.
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Leigh, Catherine, Fran Sheldon, Richard T. Kingsford, and Angela H. Arthington. "Sequential floods drive 'booms' and wetland persistence in dryland rivers: a synthesis." Marine and Freshwater Research 61, no. 8 (2010): 896. http://dx.doi.org/10.1071/mf10106.
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Flow is a key driver regulating processes and diversity in river systems across a range of temporal and spatial scales. In dryland rivers, variability in the timing and scale of floods has specific ecological significance, playing a major role in sustaining biotic diversity across the river-floodplain mosaic. However, longitudinal effects of floods are equally important, delivering water downstream through channels and wetland complexes. Interaction among spatially distributed wetlands, their connecting channel and floodplain geomorphology and the temporally variable flow events not only creates the spatial complexity in dryland rivers but also determines temporal persistence of wetlands. These act as hydrological ‘sponges’, absorbing water from upstream and needing to fill before releasing water downstream. Sequential high flow events are essential for the ecological persistence of riverine wetlands and the transmission of flows further downstream through the channel network. These flood sequences maintain aquatic refugia and drive booms in productivity sustaining aquatic and terrestrial biota over large spatial and temporal scales. Disrupting the sequence, with modified flow regimes and water removal for diversion (e.g. irrigation), significantly reduces the opportunity for wetland replenishment. As a result, the benefits of sequential flooding to the wetland ‘sponges’ and their biotic communities will be lost.
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MOHAMMED, Adam Ahmed Qaid, Jiancheng Lv, and MD Sajjatul Islam. "A Deep Learning-Based End-to-End Composite System for Hand Detection and Gesture Recognition." Sensors 19, no. 23 (November 30, 2019): 5282. http://dx.doi.org/10.3390/s19235282.
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Recent research on hand detection and gesture recognition has attracted increasing interest due to its broad range of potential applications, such as human-computer interaction, sign language recognition, hand action analysis, driver hand behavior monitoring, and virtual reality. In recent years, several approaches have been proposed with the aim of developing a robust algorithm which functions in complex and cluttered environments. Although several researchers have addressed this challenging problem, a robust system is still elusive. Therefore, we propose a deep learning-based architecture to jointly detect and classify hand gestures. In the proposed architecture, the whole image is passed through a one-stage dense object detector to extract hand regions, which, in turn, pass through a lightweight convolutional neural network (CNN) for hand gesture recognition. To evaluate our approach, we conducted extensive experiments on four publicly available datasets for hand detection, including the Oxford, 5-signers, EgoHands, and Indian classical dance (ICD) datasets, along with two hand gesture datasets with different gesture vocabularies for hand gesture recognition, namely, the LaRED and TinyHands datasets. Here, experimental results demonstrate that the proposed architecture is efficient and robust. In addition, it outperforms other approaches in both the hand detection and gesture classification tasks.
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Sfodera, Fabiola, Alberto Mattiacci, Costanza Nosi, and Isabella Mingo. "Social networks feed the food supplements shadow market." British Food Journal 122, no. 5 (March 3, 2020): 1531–48. http://dx.doi.org/10.1108/bfj-09-2019-0663.
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PurposeThe paper investigates the role of social networks in the millennials’ decision-making process of illegal and unnotified food supplements purchase. The connections and interactions that (co) produce information are studied with a holistic perspective of social sustainability as a development driver of business model innovation.Design/methodology/approachAn exploratory qualitative multiple analysis study was conducted in two consecutive phases. Data from 23 semi-structured individual interviews were collected, followed by a netnographic analysis of the Facebook virtual community.FindingsThe results show that the decision-making process does not develop following the traditional sequence, as social networks modify the wellness meaning creation process and reduce risk perception. Moreover, social networks introduce the use of similar experiences of others and online information and emotional support on unethical and unhealthy behavior.Research limitations/implicationsDue to the application to a social network, the results should be understood within this context. Future studies would benefit by expanding the target and the range of social networks explored.Practical implicationsThe official information quality control, as a prerogative of public and professional health stakeholders, and the medialization of medicalization, contribute to the conscious development of their wellness meanings and values.Originality/valueThis work represents one of the first attempts to investigate resources integration through social networks in the pre-purchase decision-making process of unnotified and illegal food supplements. Unethical and unhealthy behavior develops through the interaction of actors, firms, influencers and individuals over social networks.
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Fenech, D. M., J. S. Clark, R. K. Prinja, S. Dougherty, F. Najarro, I. Negueruela, A. Richards, B. W. Ritchie, and H. Andrews. "An ALMA 3 mm continuum census of Westerlund 1." Astronomy & Astrophysics 617 (September 2018): A137. http://dx.doi.org/10.1051/0004-6361/201832754.
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Massive stars play an important role in both cluster and galactic evolution and the rate at which they lose mass is a key driver of both their own evolution and their interaction with the environment up to and including their terminal SNe explosions. Young massive clusters provide an ideal opportunity to study a co-eval population of massive stars, where both their individual properties and the interaction with their environment can be studied in detail. We aim to study the constituent stars of the Galactic cluster Westerlund 1 in order to determine mass-loss rates for the diverse post-main sequence population of massive stars. To accomplish this we made 3mm continuum observations with the Atacama Large Millimetre/submillimetre Array. We detected emission from 50 stars in Westerlund 1, comprising all 21 Wolf-Rayets within the field of view, plus eight cool and 21 OB super-/hypergiants. Emission nebulae were associated with a number of the cool hypergiants while, unexpectedly, a number of hot stars also appear spatially resolved. We were able to measure the mass-loss rates for a unique population of massive post-main sequence stars at every stage of evolution, confirming a significant increase as stars transitioned from OB supergiant to WR states via LBV and/or cool hypergiant phases. Fortuitously, the range of spectral types exhibited by the OB supergiants provides a critical test of radiatively-driven wind theory and in particular the reality of the bi-stability jump. The extreme mass-loss rate inferred for the interacting binary Wd1-9 in comparison to other cluster members confirmed the key role binarity plays in massive stellar evolution. The presence of compact nebulae around a number of OB and WR stars is unexpected; by analogy to the cool super-/hypergiants we attribute this to confinement and sculpting of the stellar wind via interaction with the intra-cluster medium/wind. Given the morphologies of core collapse SNe depend on the nature of the pre-explosion circumstellar environment, if this hypothesis is correct then the properties of the explosion depend not just on the progenitor, but also the environment in which it is located.
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Farroni, Flavio, Nicolò Mancinelli, and Francesco Timpone. "A Real-Time Thermal Model for the Analysis of Tire/Road Interaction in Motorcycle Applications." Applied Sciences 10, no. 5 (February 28, 2020): 1604. http://dx.doi.org/10.3390/app10051604.
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While in the automotive field the relationship between road adherence and tire temperature is mainly investigated with the aim to enhance the vehicle performance in motorsport, the motorcycle sector is highly sensitive to such theme also from less extreme applications. The small extension of the footprint, along with the need to guarantee driver stability and safety in the widest possible range of riding conditions, requires that tires work as most as possible at a temperature able to let the viscoelastic compounds-constituting the tread and the composite materials of the whole carcass structure-provide the highest interaction force with road. Moreover, both for tire manufacturing companies and for single track vehicles designers and racing teams, a deep knowledge of the thermodynamic phenomena involved at the ground level is a key factor for the development of optimal solutions and setup. This paper proposes a physical model based on the application of the Fourier thermodynamic equations to a three-dimensional domain, accounting for all the sources of heating like friction power at the road interface and the cyclic generation of heat because of rolling and to asphalt indentation, and for the cooling effects because of the air forced convection, to road conduction and to turbulences in the inflation chamber. The complex heat exchanges in the system are fully described and modeled, with particular reference to the management of contact patch position, correlated to camber angle and requiring the adoption of an innovative multi-ribbed and multi-layered tire structure. The completely physical approach induces the need of a proper parameterization of the model, whose main stages are described, both from the experimental and identification points of view, with particular reference to non-destructive procedures for thermal parameters definition. One of the most peculiar and challenging features of the model is linked with its topological and analytical structure, allowing to run in real-time, usefully for the application in co-simulation vehicle dynamics platforms, for performance prediction and setup optimization applications.
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Hayman, James, Kent A. Griffith, Reshma Jagsi, Mary Uan-Sian Feng, Jean M. Moran, Tania L. Piotrowski, and Lori J. Pierce. "Variation in the use of intensity-modulated radiation therapy (IMRT) in the state of Michigan: 2005-2010." Journal of Clinical Oncology 30, no. 34_suppl (December 1, 2012): 219. http://dx.doi.org/10.1200/jco.2012.30.34_suppl.219.
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219 Background: Interest is growing in value in health care, defined as better outcomes at lower costs. A primary driver of cost in radiation oncology is the use of IMRT. We examined the patterns and correlates of use of IMRT across Michigan using publicly available data. Methods: As a certificate of need state, Michigan requires every radiation oncology facility to report yearly the number of external beam and IMRT treatments delivered. Data for 2005-2008 were obtained through a Freedom of Information Act request of the Michigan Department of Community Health, while 2009-2010 data were available at its website. Percentage of external beam treatments delivered using IMRT (IMRT%) was examined across centers over time and repeated-measures longitudinal linear regression was used to identify factors associated with use. Results: During 2005-2010, 48 to 65 centers reported data. Median IMRT% (range) rose steadily during the study period: 2005 16% (0-64); 2006 21% (0-57); 2007 27% (0-79); 2008 37% (7-85); 2009 41% (0-87) 2010 45% (7-100). There was also significant between-center variation (see table). Regression modeling demonstrated that IMRT% was associated with year (+6.7% per year, p<0.0001), facility type (+7.1% freestanding versus hospital, p<0.11), facility annual volume (+5.0% high volume: 7,000+ versus low: <7,000, p=0.01) and the interaction between year and volume (low volume +2.4% per year versus high volume p<0.02). The significant interaction between year and volume suggests that the greatest IMRT% growth was in low volume centers (6.7% per year versus 4.3% per year for high volume). Conclusions: IMRT utilization has grown steadily across Michigan between 2005 and 2010. There is significant variation in its use that appears to be related in part to facility characteristics. The newly established Michigan Radiation Oncology Quality Collaborative (MROQC) is beginning to explore the use of IMRT in patients with breast and lung cancer statewide to identify those groups of patients where improved outcomes may justify its higher cost. [Table: see text]
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Skaret, G., GO Johansen, E. Johnsen, J. Fall, Ø. Fiksen, G. Englund, P. Fauchald, H. Gjøsæter, GJ Macaulay, and E. Johannesen. "Diel vertical movements determine spatial interactions between cod, pelagic fish and krill on an Arctic shelf bank." Marine Ecology Progress Series 638 (March 19, 2020): 13–23. http://dx.doi.org/10.3354/meps13254.
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Predator-prey spatial interactions are essential to understand ecosystem processes like predation rates and trophic interaction strength. In marine systems, such spatial interactions are highly dynamic and difficult to observe, as predators, prey and resources are mobile and responsive to each other, and also since shifting vertical light gradients strongly affect the space use of visual predators and their prey. We visited a bank area in the northern Barents Sea with cold bottom waters (~1°C), and combined conventional trawl and acoustic sampling with broadband hydroacoustics to obtain long-range, fine-scale observations of interactions between cod, their planktivore prey (capelin and polar cod) and krill. We caught cod in demersal trawl hauls but could not detect them with the vessel acoustics. However, broadband acoustics mounted on a submersible probe allowed us to track individual cod, revealing that they remained mostly within 10 m of the bottom throughout the diel cycle. In the morning, cod lifted slightly from the seabed indicating feeding activity, which corresponded with more fresh prey in cod stomachs in the morning. During daylight, krill pushed towards the bottom, sharing habitat with cod, while the planktivores aggregated in pelagic schools at the cost of lost feeding opportunities, overlapping with their krill prey only during twilight hours. The diel light cycle was an important driver of the spatial movements and aggregations, and krill appear to hide from capelin among the cod near bottom, while cod take advantage of descending pelagic fish after dawn to feed with a minimum of effort.
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Gorter, Florien A., Michael Manhart, and Martin Ackermann. "Understanding the evolution of interspecies interactions in microbial communities." Philosophical Transactions of the Royal Society B: Biological Sciences 375, no. 1798 (March 23, 2020): 20190256. http://dx.doi.org/10.1098/rstb.2019.0256.
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Microbial communities are complex multi-species assemblages that are characterized by a multitude of interspecies interactions, which can range from mutualism to competition. The overall sign and strength of interspecies interactions have important consequences for emergent community-level properties such as productivity and stability. It is not well understood how interspecies interactions change over evolutionary timescales. Here, we review the empirical evidence that evolution is an important driver of microbial community properties and dynamics on timescales that have traditionally been regarded as purely ecological. Next, we briefly discuss different modelling approaches to study evolution of communities, emphasizing the similarities and differences between evolutionary and ecological perspectives. We then propose a simple conceptual model for the evolution of interspecies interactions in communities. Specifically, we propose that to understand the evolution of interspecies interactions, it is important to distinguish between direct and indirect fitness effects of a mutation. We predict that in well-mixed environments, traits will be selected exclusively for their direct fitness effects, while in spatially structured environments, traits may also be selected for their indirect fitness effects. Selection of indirectly beneficial traits should result in an increase in interaction strength over time, while selection of directly beneficial traits should not have such a systematic effect. We tested our intuitions using a simple quantitative model and found support for our hypotheses. The next step will be to test these hypotheses experimentally and provide input for a more refined version of the model in turn, thus closing the scientific cycle of models and experiments. This article is part of the theme issue ‘Conceptual challenges in microbial community ecology’.
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Gui, Bin, Fu Gui, Tomoaki Takai, Chao Feng, Xiao Bai, Ladan Fazli, Xuesen Dong, et al. "Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function." Proceedings of the National Academy of Sciences 116, no. 29 (July 2, 2019): 14573–82. http://dx.doi.org/10.1073/pnas.1908547116.
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Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.
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Fernández-Pérez, Laura, Miguel Ángel Zavala, Pedro Villar -Salvador, and Jaime Madrigal-González. "Divergent Last Century Tree Growth along An Altitudinal Gradient in A Pinus sylvestris Dry-edge Population." Forests 10, no. 7 (June 26, 2019): 532. http://dx.doi.org/10.3390/f10070532.
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Research Highlights: This research highlights the importance of environmental gradients in shaping tree growth responses to global change drivers and the difficulty of attributing impacts to a single directional driver. Background and Objectives: Temperature increases associated with climate change might strongly influence tree growth and forest productivity in temperate forest species. However, the direction and intensity of these effects at the dry edge of species range are still unclear, particularly given the interaction between local factors and other global change drivers such as land use change, atmospheric CO2 increase and nitrogen deposition. While recent studies suggest that tree growth in cool temperate forests has accelerated during the last decades of the 20th century, other studies suggest a prevalence of declining growth, especially in dry-edge populations. Materials and Methods: Using historical forest inventories, we analyzed last century tree growth trends (1930–2010) along an elevation gradient (1350–1900 meters above sea level (m a.s.l.)) in a dry edge scots pine (Pinus sylvestris L.) forest in Central Iberian Peninsula. Growth was estimated as decadal volume increments in harvested trees of different size classes from 1930 to 2010 (1930–1940, 1939–1949, 1949–1959, 1959–1968, 1989–1999, 2000–2010). Results: Our results showed opposite growth trends over time depending on elevation. While tree growth has accelerated in the low end of the altitudinal gradient, tree growth slowed down at higher elevations (1624–1895 m a.s.l.). Moreover, the magnitude of growth reduction along the altitudinal gradient increased with tree age. Conclusions: Throughout the last 80 years, growth trends in a rear-edge Pinus. sylvestris forest has shown divergent patterns along an altitudinal gradient. Specifically, environmental conditions have become more adverse for growth at high altitudes and have improved at low altitudes. This suggests that local factors such as topography can modulate the impact of climate change on forest ecosystems.
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Teodosio, Luigi, Giuseppe Alferi, Andrea Genovese, Flavio Farroni, Benedetto Mele, Francesco Timpone, and Aleksandr Sakhnevych. "A numerical methodology for thermo-fluid dynamic modelling of tyre inner chamber: towards real time applications." Meccanica 56, no. 3 (February 2, 2021): 549–67. http://dx.doi.org/10.1007/s11012-021-01310-w.
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AbstractThe characterization and reproduction of tyre behaviour for vehicle modelling is a topic of particular interest both for real-time driver in the loop simulations and for offline performance optimization algorithms. Since the accuracy of the tyre forces and moments can be achieved by the accurate physical modelling of all the phenomena concerning the tyre-road interaction, the link between the tyre thermal state and the tyre frictional performance turns into a crucial factor. An integrated numerical methodology, allowing to couple the full 3D CFD (Computational Fluid Dynamics) flux within the internal chamber of the tyre with an equivalent discrete 3D structure model, is proposed with the aim to completely represent the tyre thermodynamic convective behaviour in the steady-state operating conditions. 3D CFD model enables the evaluation of the internal distribution of the gas temperature and of the thermal powers exchanged at each sub-wall in detail. This allows to increase the reliability of the tyre thermodynamic modelling with a particular reference to the proper managing of the aero-thermal flow of the brake disc impact on the rim temperature and therefore on the internal gas dynamics in terms of temperature and pressure, being able to optimize the tyre overall dynamic performance in both warm-up and stabilized thermal conditions. The steady RANS (Reynolds Averaged Navier–Stokes) simulations have been performed employing the 3D CFD model in a wide range of angular velocities with the aim to calculate the convective thermal flux distributions upon rim and inner liner surfaces. The simulation results have been then exploited to derive the convective heat transfer coefficients per each sub domain to be employed within the real-time tyre physical thermal model, with the peculiar advantage of an enhanced model reliability for thermal characteristics. To validate the proposed methodology, the tyre thermal model outputs, in terms of temperatures of internal and external layers, have been validated towards the acquired ones within the specific routine performed on tyre force and moment test bench, confirming an excellent agreement with the experimental data in the entire range of operating conditions explored.
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Петренко, Людмила А. "ФОРМУВАННЯ КОНКУРЕНТНИХ ПЕРЕВАГ ПІДПРИЄМСТВ НА ОСНОВІ ІННОВАЦІЙ В УМОВАХ ЕКОНОМІКИ ЗНАНЬ." Bulletin of the Kyiv National University of Technologies and Design. Series: Economic sciences 141, no. 6 (July 14, 2020): 47–59. http://dx.doi.org/10.30857/2413-0117.2019.6.5.
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The article explores the role of innovations in enhancing business competitiveness. An emphasis is put on rapidly growing need for innovations in modern economic realia. It is argued that innovations are critical for raising enterprise capitalization, in particular, while business is expanding the effect from innovations is also increasing, thus spurring innovation processes within companies. The mechanism of innovation effects on company financial performance is mediated by the market which shapes competitive advantages. Accordingly, the specified mechanism for developing competitive advantages for businesses based on innovation is crucial for value creation. Given that in the knowledge economy environment the organizational learning has become a key driver for development, it is assumed that the organizational learning capability triggers its capacity to generate innovations which in turn contributes to gaining competitive edge and market success in the future. Accordingly, this study aims to determine the key components in the process of building competitive advantages based on innovation in the contemporary knowledge economy settings. In the frameworks of this study, an in-depth analysis of scholarly publications in the area of competitive advantage theory and innovation has been carried out. To attain the research objectives, the methods of analysis and synthesis were applied. A nexus that underpins the basis for developing a unified synthetic theory of innovation-based competitive advantages is the resource-based view (RBV) along with its derivative, the dynamic capability-based view (DCV). The study findings have identified a range of factors that have strong influence on creating competitive advantages for a company based on innovations in a knowledge economy. Among them are the following: firstly, entrepreneurship as a driving force for innovation, the search for new combinations of resources (combinatorial capacity) and further development of competitive advantages; secondly, organizational learning, which in terms of the dynamic capabilities theory could be interpreted as "learning capabilities" in such priority areas for an innovative business as: 1) learning capability based on comprehension of previous experience and using it to develop innovations; 2) the capability to learn in the process of interaction with key stakeholders (partners, suppliers, consumers, competitors) and implementation of ideas gleaned from such interaction to create innovations. The research results provide evidence that companies with effectively developed internal entrepreneurship practices and innovation policies as the key areas of their competitive strategy should also design and boost a set of dynamic capabilities (learning capabilities) that will contribute to enhancing innovative development and gaining sustainable competitive advantages in the future.
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Villiers, William, Paul Lavender, Audrey Kelly, Michael Lim, Cameron Osborne, and Richard Dillon. "Untangling the Transcriptional Mis-Regulation Driven By Pml;rara." Blood 134, Supplement_1 (November 13, 2019): 282. http://dx.doi.org/10.1182/blood-2019-125555.
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Background:The PML;RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL). The fusion disrupts retinoic acid signalling, leading to the proliferation of myeloid precursors halted at the promyelocyte stage of maturation. Chromatin conformation plays a fundamental role in controlling regulatory networks driving cell differentiation, however the genome wide organisational changes that occur during the PML;RARA differentiation block remains to be elucidated. Aims: We have aimed to characterise three hallmarks of PML;RARA driven transcriptional mis-regulation: transcription factor binding, epigenetic remodelling and higher order chromatin organisation. Methods: To a PML;RARA inducible U937-PR9 cell line model (Figure 1a), we have applied 1) Promoter Capture Hi-C (PCHi-C) to characterise long-range regulatory interactions, 2) Cut&Run, a newly described chromatin profiling technique, and 3) RNA-seq. All datasets are paired and have been modelled as induced vs non-induced. Results: PML;RARA induction resulted in 855 significantly differentially expressed genes (DEGs, adjusted pvalue < 0.01). Up regulated genes (457) were enriched for genes involved in proliferative and oncogenic pathways. Down regulated genes (398) were enriched for drivers of cell differentiation, including the master regulators of myeloid differentiation: CEBPE, CEBPB and CEBPA. We identified 15,412 PML;RARA binding sites using Cut&Run (n=2). These sites encompassed 95% of previously uncovered PML;RARA binding sites, in addition to ~12,000 novel sites. 53% of these regions were distributed at gene promoters, 23% were intergenic and 24% at gene bodies. We observed a global decrease in H3k27ac after PML;RARA induction (86% regional loss), a significant proportion of these regions coincide with PML;RARA binding (Fisher's test 2.2-16). 1,900 PML;RARA peaks were associated with 66% DEGs. Interestingly, a significant proportion of PML;RARA peaks were not associated with DEGs. Applying PCHi-C (n=3) we identified >60,000 consistent differential interactions (DIs, ihw < 0.01), with a mean interaction distance of 100kb. 30,039 interactions increased and 30,403 interactions decreased after PML;RARA induction. Over half of DIs directly involved 8,066 PML;RARA binding sites (Fisher's test 2.2-16). We observed that genes losing long-range interactions were more likely to have decreased expression (59%) and this observation increased if a gene is also bound by PML;RARA (65%). SPI1, ID2, CEBPA, CEBPB, CEBPE, EGR1, and TFEB, key regulators of myeloid differentiation, display this pattern of PML;RARA driven negative regulation. We also observed that genes with increased expression were more likely to gain long-range interactions (60%). The top ranked gene across all datasets was the prostaglandin receptor 4 (PTGER4), a G-Protein coupled receptor highly expressed in AML and upregulated in our datasets (3.1 fold) (figure 1b). PTGER4 gained long-range interactions with an intergenic region ~300kb downstream of its promoter. This intergenic region is highly enriched for both H3k27ac and PML;RARA. This suggests that PML;RARA facilitates the long-range activation of PTGER4. We see a similar pattern to PTGER4 in 15% of DEGs where PML;RARA is anchored to both ends of the DI. Summary/Conclusion: Applying novel NGS techniques to a simple model, we have highlighted that specific chromosome conformations are pivotal to the transcriptional mis-regulation driven by PML;RARA. We show PML;RARA may be directly involved in the re-organisation of the genome and this 3D architecture is pivotal in driving the Leukemia differentiation block. Disclosures Dillon: Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria.
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Wan, Youzhong, Michael S. Lawrence, Lili Wang, Petar Stojanov, Carrie Sougnez, Kristen Stevenson, Lillian Werner, et al. "Large-Scale CLL Genome Analysis Reveals Novel Cancer Genes, Including SF3B1." Blood 118, no. 21 (November 18, 2011): 463. http://dx.doi.org/10.1182/blood.v118.21.463.463.
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Abstract Abstract 463 The somatic genetic basis of chronic lymphocytic leukemia (CLL), a common and clinically heterogenous adult leukemia, remains poorly understood. Massively parallel sequencing technology provides a method for systematic discovery of genetic alterations that underlie disease, and for uncovering new therapeutic targets and biomarkers. We therefore performed DNA sequencing of 91 CLL samples with matched germline, consisting of 88 exomes and 3 genomes. Samples were collected from patients displaying a range of characteristics representing the broad clinical spectrum of CLL. Libraries were constructed and sequenced on an Illumina GA-II sequencer to deep coverage. Point mutations and indels were detected by comparing sequences of each tumor to its corresponding normal. We detected 1828 non-silent mutations in protein-coding sequences, corresponding to an average somatic mutation rate of 0.72/Mb (range 0.075–2.14). Nine cancer genes were identified, as they were mutated significantly more often than the background rate given their sequence composition across all 91 CLL/normal pairs. Four have been previously described in CLL (TP53, ATM, MYD88 and NOTCH1); the others were novel (SF3B1, ZMYM3, MAPK1, FBXW7 and DDX3X). Strikingly, SF3B1, which functions at the catalytic core of the spliceosome, was mutated the second most frequently (15%). All 14 identified mutations localized to a discrete region (exons 12–18), and 7 were recurrent (K700E). We additionally validated the SF3B1-K700E mutation through genotyping of 101 independent CLL samples. The 9 significantly mutated genes fell into 5 core signaling pathways, in which the genes play established roles: DNA damage repair and cell-cycle control (TP53, ATM), Notch signaling (FBXW7, NOTCH1), inflammatory pathways (MYD88, DDX3X, MAPK1) and RNA splicing/processing (SF3B1, DDX3X). The common cytogenetic aberrations in CLL carry strong prognostic significance, implying that they reflect distinct pathogenesis. Supporting this hypothesis, we discovered strong associations between different driver mutations and key FISH abnormalities. Most TP53 mutations were in samples with del(17p) (p<0.001), resulting in homozygous p53 inactivation. Del(11q) was marginally associated with mutation in ATM which lies in the minimally deleted region of chr. 11q (p=0.09); but clearly associated with SF3B1 mutation (p=0.004), suggesting interaction within this clinical subgroup of CLL. NOTCH1 and FBXW7 mutations (present in independent samples) were associated with trisomy 12 (p=0.009 and 0.05), suggesting that aberrant Notch signaling plays an important role in this clinical subgroup. Finally, all detected mutations in MYD88 (known to be activating for the NFkB pathway) were present in samples harboring heterozygous del(13q) (p=0.009) with mutated IGHV status (p=0.002). These findings suggest that NFkB activation plays a driving role in this low risk clinical subgroup. To define the impact of the mutated cancer genes on disease outcome, we constructed a Cox multivariable regression model for factors contributing to earlier time to first therapy (TTFT) in the 91 CLLs. SF3B1 mutation was predictive of poor prognosis (HR 3.17, p=0.004), independent of other established markers (i.e. IGVH mutation; del(17p); ATM mutation). Consistent with this analysis, patients harboring the SF3B1 mutation alone had short TTFT, as did patients with del(11q) or del(11q)+SF3B1 mutation. All 3 groups demonstrated significantly shorter TTFT than patients without either SF3B1 mutation or del(11q). Because SF3B1 encodes a splicing factor, we looked for functional evidence of splicing alterations associated with SF3B1 mutation. Indeed, mRNA targets of the spliceosome exhibited greater intron retention in CLLs with mutated vs nonmutated SF3B1, confirming alteration in normal SF3B1 function. Understanding the mutational landscape of CLL provides a starting point for systematic analyses to address fundamental questions in CLL, including how mutated genes alter cellular networks and phenotypes, and thereby contribute to disease heterogeneity. Our discovery of striking associations between driver mutations and standard CLL prognostic markers (cytogenetic aberrations, IGVH mutational status) suggest synergistic interactions. In particular, our studies highlight pre-mRNA splicing as a critical but thus far unexplored cellular process contributing to CLL. Disclosures: No relevant conflicts of interest to declare.
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Ventura, Alison, and Megan Hupp. "A Within-Subject Comparison of Maternal Sensitivity to Infant Cues and Infant Intake During Breastfeeding Versus Bottle-feeding Interactions." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1094. http://dx.doi.org/10.1093/cdn/nzaa054_166.
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Abstract Objectives Bottle-fed infants are at higher risk for overfeeding and rapid weight gain compared to breastfed infants. However, given evidence illustrating sociodemographic and psychosocial differences between breastfeeding and bottle-feeding mothers, it is unclear whether feeding mode versus unmeasured covariates are the primary driver of differences between breast- and bottle-feeding. The objective of the present study was to use a within-subject experimental approach to describe whether and how breastfeeding versus bottle-feeding impacts early feeding interactions. Methods Mothers and their young infants (n = 46) visited our laboratory two times for counterbalanced, video-recorded feeding observations. Mothers breastfed their infants during one visit and bottle-fed their infants expressed breast milk during the other visit. Trained raters blinded to study aims later coded videos to assess maternal sensitivity to infant cues using the Nursing Child Assessment Parent-Child Interaction Feeding Scale. Infant intake was assessed by weighing the baby before and after the feeding. Maternal reported level of pressuring feeding style was assessed via the Infant Feeding Styles Questionnaire and tested as a possible moderator of effects of feeding mode on maternal sensitivity to infant cues and infant intake. Results Infants were 3.2 ± 1.4 months of age (range = 0.8–5.7 months). Mothers were 32.2 ± 4.2 years of age, 67.4% (n = 31) were non-Hispanic white, and 53.3% (n = 24) were primiparous. Mothers exhibited significantly lower sensitivity to infant cues during bottle- vs breastfeeding (P = .005). Infant intake did not differ between bottle- (87.4 ± 5.1 ml) and breastfeeding (90.7 ± 5.1 ml; P = .641). Effects of feeding mode on maternal sensitivity to infant cues or infant intake were not moderated by pressuring feeding style, but mothers who reported greater levels of pressuring feeding style fed their infants more during both conditions compared to mothers with lower levels of pressuring feeding style (P = .047). Conclusions Mothers were less sensitive to infant cues during bottle- compared to breastfeeding, but pressuring feeding style, rather than the act of bottle-feeding, per se, was associated with greater intakes across both modes of feeding. Funding Sources Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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Kalantar-Zadeh, Kamyar, Gregory G. Schwartz, Stephen J. Nicholls, Kevin A. Buhr, Henry N. Ginsberg, Jan O. Johansson, Ewelina Kulikowski, et al. "Effect of Apabetalone on Cardiovascular Events in Diabetes, CKD, and Recent Acute Coronary Syndrome." Clinical Journal of the American Society of Nephrology 16, no. 5 (April 27, 2021): 705–16. http://dx.doi.org/10.2215/cjn.16751020.
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Background and objectivesCKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events (i.e., cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial.Design, setting, participants, & measurementsBETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR <60 ml/min per 1.73 m2 at baseline. The primary end point in BETonMACE was the time to the first major adverse cardiovascular event, with a secondary end point of time to hospitalization for heart failure.ResultsMedian follow-up was 27 months (interquartile range, 20–32 months). In participants with CKD, apabetalone compared with placebo was associated with fewer major adverse cardiovascular events (13 events in 124 patients [11%] versus 35 events in 164 patients [21%]; hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.96) and fewer heart failure–related hospitalizations (three hospitalizations in 124 patients [3%] versus 14 hospitalizations in 164 patients [9%]; hazard ratio, 0.48; 95% confidence interval, 0.26 to 0.86). In the non-CKD group, the corresponding hazard ratio values were 0.96 (95% confidence interval, 0.74 to 1.24) for major adverse cardiovascular events, and 0.76 (95% confidence interval, 0.46 to 1.27) for heart failure–related hospitalization. Interaction of CKD on treatment effect was P=0.03 for major adverse cardiovascular events, and P=0.12 for heart failure–related hospitalization. Participants with CKD showed similar numbers of adverse events, regardless of randomization to apabetalone or placebo (119 [73%] versus 88 [71%] patients), and there were fewer serious adverse events (29% versus 43%; P=0.02) in the apabetalone group.ConclusionsApabetalone may reduce the incidence of major adverse cardiovascular events in patients with CKD and type 2 diabetes who have a high burden of cardiovascular disease.
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Schepanski, Kerstin, Bernd Heinold, and Ina Tegen. "Harmattan, Saharan heat low, and West African monsoon circulation: modulations on the Saharan dust outflow towards the North Atlantic." Atmospheric Chemistry and Physics 17, no. 17 (September 1, 2017): 10223–43. http://dx.doi.org/10.5194/acp-17-10223-2017.
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Abstract. The outflow of dust from the northern African continent towards the North Atlantic is stimulated by the atmospheric circulation over North Africa, which modulates the spatio-temporal distribution of dust source activation and consequently the entrainment of mineral dust into the boundary layer, as well as the transport of dust out of the source regions. The atmospheric circulation over the North African dust source regions, predominantly the Sahara and the Sahel, is characterized by three major circulation regimes: (1) the harmattan (trade winds), (2) the Saharan heat low (SHL), and (3) the West African monsoon circulation. The strength of the individual regimes controls the Saharan dust outflow by affecting the spatio-temporal distribution of dust emission, transport pathways, and deposition fluxes.This study aims at investigating the atmospheric circulation pattern over North Africa with regard to its role favouring dust emission and dust export towards the tropical North Atlantic. The focus of the study is on summer 2013 (June to August), during which the SALTRACE (Saharan Aerosol Long-range TRansport and Aerosol-Cloud interaction Experiment) field campaign also took place. It involves satellite observations by the Spinning Enhanced Visible and InfraRed Imager (SEVIRI) flying on board the geostationary Meteosat Second Generation (MSG) satellite, which are analysed and used to infer a data set of active dust sources. The spatio-temporal distribution of dust source activation frequencies (DSAFs) allows for linking the diurnal cycle of dust source activations to dominant meteorological controls on dust emission. In summer, Saharan dust source activations clearly differ from dust source activations over the Sahel regarding the time of day when dust emission begins. The Sahara is dominated by morning dust source activations predominantly driven by the breakdown of the nocturnal low-level jet. In contrast, dust source activations in the Sahel are predominantly activated during the second half of the day, when downdrafts associated with deep moist convection are the major atmospheric driver. Complementary to the satellite-based analysis on dust source activations and implications from their diurnal cycle, simulations on atmosphere and dust life cycle were performed using the mesoscale atmosphere–dust model system COSMO-MUSCAT (COSMO: COnsortium for Small-scale MOdelling; MUSCAT: MUltiScale Chemistry Aerosol Transport Model). Fields from this simulation were analysed regarding the variability of the harmattan, the Saharan heat low, and the monsoon circulation as well as their impact on the variability of the Saharan dust outflow towards the North Atlantic. This study illustrates the complexity of the interaction among the three major circulation regimes and their modulation of the North African dust outflow. Enhanced westward dust fluxes frequently appear following a phase characterized by a deep SHL. Ultimately, findings from this study contribute to the quantification of the interannual variability of the atmospheric dust burden.
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Hassan, Rayya A., and Kerry McManus. "Assessment of Interaction Between Road Roughness and Heavy Vehicles." Transportation Research Record: Journal of the Transportation Research Board 1819, no. 1 (January 2003): 236–43. http://dx.doi.org/10.3141/1819b-30.
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Road surface roughness excites low- and high-frequency vibration modes of a heavy articulated vehicle body. These vibrations result in motions in all directions that detract from the driver’s perceived ride and comfort and increase pavement damage due to dynamic wheel loads (DWLs). A subjective assessment survey was conducted to identify surface roughness characteristics that mainly influence the perceptions of heavy-vehicle drivers of pavement rideability and their comfort. The latter was achieved by correlating drivers’ ratings to roughness contents in different roughness wavebands. The results indicated that the drivers mainly object to low-frequency body vibrations excited by roughness wavelengths in the range of 4.88 to 19.5 m. Roughness content in this band was used to establish a new profile-based index called the profile index for truck ( PIt). Drivers consider pavement rideability to be poor when PIt exceeds 2.75 m/km. PIt provides better predictions of heavy vehicle ride than the international roughness index (IRI). The methodology for developing the PIt and assessment of its reliability as a measure of heavy vehicle ride are described. The latter was achieved by testing the statistical significance of the effects of factors other than road roughness that influence the perceived ride of truck drivers. They include factors related to the vehicle, the road, and the driver as well as situational factors. In addition, PIt was found to be a better indicator than IRI of the levels of whole body vibrations transmitted to the driver through the seat and a better predictor of the magnitude of DWL to which the test pavements are subject.
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Tong, Wei-Gang, William G. Wierda, Neby Bekele, Shao-Qing Kuang, Michael J. Keating, and Guillermo Garcia-Manero. "Genome-Wide DNA Methylation Profile of CLL with 17p del Allowed Identification of Multiple Epigenetically Inactivated Molecular Pathways with Prognostic Value in Human Leukemia." Blood 110, no. 11 (November 16, 2007): 492. http://dx.doi.org/10.1182/blood.v110.11.492.492.
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Abstract Aberrant DNA methylation of multiple promoter associated CpG islands is a very prevalent phenomenon in human leukemias. Data from our laboratory indicates that methylation profiling allows the identification of leukemia patients with different risk and prognosis. Despite the advances in the understanding of the molecular biology of CLL, few studies of DNA methylation have been performed in CLL. In the current study, we have developed a new assay combining MCA (Methylated CpG island Amplification) with the Agilent promoter CpG array to identify simultaneously hundreds of abnormally methylated CpG islands in CLL. To perform this, we compared DNA from two CLL patients with 17p del (tester) with that of CD19+ B cells from two age-matched controls (driver). We identified 280 promoter CpG islands differentially methylated in CLL compared to normal controls. Most of these genes are located on chromosomes 19 (16%), 16 (11%), 17 (10%) and 11 (9%). We also performed interaction pathway and functional analysis of these 280 genes using the online Ingenuity Pathway Analysis tools. The initial analysis divided these genes into 25 functional networks, with the majority of genes fall into top 10 networks. The major functions of genes in these interaction networks involve cancer, organ development, cell death, drug metabolism, DNA replication and repair. We validated 22 of these genes (ADCY5, R-spondin1, LHX1, GALGT2, TFAP2C, ING1, SOX11, SOX14, SALL1, LTBP2, APP, DXL1, DLX4, KLK10, BCL11B, NR2F2, FAM62T, HAND2, BNC1, SPOCK, Prima1 and MLL1) in samples from 78 CLL patients and 10 age-matched normal controls. The characteristics of the 78 patients are: median age 59 (range 39–79), male 70%, Rai stage 0–II/III–IV (83%/17%), IgVH unmutated 49%, ZAP-70 positive 33%. Our results indicate that most of the genes identified by the array are frequently hypermethylated in CLL patients compared with healthy controls. Methylation frequency ranged from 20%–100% in CLL patients. Expression analysis of four selected genes (LHX1, GALGT2, TFAP2C and Prima1) in human leukemia cell lines and CLL patient samples by real-time PCR further confirmed methylation associated gene silencing, and treatment of these cell lines with hypomethylating agent 5-aza-2′-deoxycitidine with or without the HDAC inhibitor Trichostatin A resulted in gene re-expression and induction of DNA hypomethylation. We also analyzed the association of methylation status of these genes with IgVH mutation status, ZAP70 expression and patient survival. Unmutated IgVH was associated with increased methylation levels of LINE (p<0.0001), which is a marker for global gene methylation and SALL1 (p=0.00008). Expression of ZAP-70 (>20%) was associated with increased methylation levels of LINE (p<0.00001), MLL (p=0.02) and SALL1 (p=0.048). Further analysis showed that methylation status of LINE (p=0.007), SALL1 (p=0.019), ADCY5 (p=0.021), R-spondin1 (p=0.002) and APP (p=0.002) correlated with survival. In conclusion, our studies indicate that MCA/promoter array technique allows the identification of large number of promoter CpG islands aberrantly methylated in CLL and also the identification of novel tumor suppressors and signaling pathways that could be important in the tumorigenesis of CLL and other hematological malignancies.
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N., VEDMID, BOIKO M., and ROMANCHUK L. "MARKETING TECHNOLOGIES OF CONSUMERS SEGMENTATION OF RESORT AND RECREATIONAL SERVICE." Herald of Kyiv National University of Trade and Economics 138, no. 4 (September 10, 2021): 91–100. http://dx.doi.org/10.31617/visnik.knute.2021(138)07.
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Background. Using marketing technologies to segment consumers is a key resource for actively and quickly responding to consumer needs. Segmentation allows to identify differences in the response of consumers to services, implement the targeted marketing principles, develop a range of services in accordance with the consumers needs. The aim of the paper is to studydevelopment of methodological foundations of marketing technologies for consumers segmentation, taking into account the key features of resort and recreational services, which ensure scientific approaches development to consumer segments assessment and allows proactively adjusting the offer of resort and recreationnal services, especially during periods of seasonal fluctuations. Materials and methods. The theoretical and methodological basis of the article are the results of theoretical and applied research of Ukrainian and foreign scientists on consumer segmentation. The behavioral method was used to analyze consumer behavior and needs. Special methods for ratings, sample observations, comparative analysis, grouping based on the use of general and special Google Analytic software, CoSchedule were used. Results. The problem of effective segmentation of consumers of resort and recreational services is very important in a situation of aggravated competition for the consumer, since the definition of target segments is the basis for the formation of effective and targeted marketing activities. The expediency of using the VALS model has been proven. The VALS model is proposed to be improved by adding a stage that allows to determine the level of customer satisfaction with resort services based on the CSAT Composite Customer Satisfaction Score method. This method allows to determine the compliance of the received services with the expectations of consumers and to identify the level of service processes. The driver of the effective impact of marketing communications on consumer segments is digitalization. This is manifested in the creation of an immersive environment for a resort and recreation enterprise. This is due to the fact that immersive environment simulators offer a personalized and efficient mechanism for introducing consumers to the spa and recreational service through visualization. Conclusion. The use of marketing technologies for consumers segmentation of resort and recreational services is influenced by the digitalization of marketing activities and leads to new methods of collecting and analyzing data for segmentation. These methods allow to accumulate quickly information about consumers in the digital space for segmentation and proactive interaction with target audiences, as well as reduce time it takes for a new service to enter the market. In the context of digitalization, further research to conduct marketing technologies for segmentation of consumers of resort and recreational services should develop the priority of using digital sources of dynamic information about consumer characterristics in a virtual environment; determine the features of the combination of static (offline consumer features) and dynamic (online consumer features) segmentation features. Keywords: segmentation, marketing technologies, digitalization, immersive environment, consumer, resort and recreational service
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Ortiz, Maria, Fadi Towfic, Mehmet Kemal Samur, Erin Flynt, In Sock Jang, Kai Wang, Cody Ashby, et al. "A High-Risk Multiple Myeloma Group Identified By Integrative Multi-Omics Segmentation of Newly Diagnosed Patients." Blood 132, Supplement 1 (November 29, 2018): 3165. http://dx.doi.org/10.1182/blood-2018-99-117114.
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Abstract There is currently no standard approach to classify high-risk newly diagnosed Multiple Myeloma (ndMM). Various efforts have yielded approaches based on single molecular data types, including gene expression (GE), mutation (SNV), copy number alteration (CNA), and structural variation (SV) profiling. A comprehensive classification integrating heterogeneous molecular information may improve prognosis and treatment of high-risk ndMM patients. Clinical data (ISS, Age, Sex), genomics datasets, and clinical outcomes were assembled. 18 common structural variants were derived from whole genome and whole exome data. CNAs were aggregated into cytobands and SNVs into pathways. Two multi-omics integrative clustering methods (Cluster of Clusters and iClusterPlus) were applied to the integrated dataset to identify patient subgroups. Each algorithm was run 1000 times, using patient and feature resampling and optimized over a range of pre-defined clusters (K=[2,20]). Selection of clusters was based on Bayesian Information Criterion and Normalized Mutual Information. Patient subgroups defined using coherence across the outputs. Biological interpretation of the high-risk group was performed using differential expression analysis (voom-limma), gene set enrichment of canonical pathways, master regulator (MR) inference to identify putative drivers, protein-protein interaction network (PPIn) analysis for identification of downstream effects, and Fisher's test for SNV, SV and CNA association. A relevance network topology-based method (DART) was used to compare results against previous high-risk GE signatures. Hypergeometric tests were applied to identify DNA signature enrichment across patient subgroups. Multi-dimensional unsupervised analysis identified 12 stable patient subgroups (≥~5% of samples) including patient tumors enriched in t(4;14) and t(11;14), various patient subgroups stratified by CNAs including Del1p, Del13q, Del14q, Amp1q and amplifications of odd chromosomes, and distinct GE patterns. Association of patient subgroups with PFS identified one high-risk group (median PFS < 505 days, referred to here as C8) which contains 11% of samples and is defined by a combination of genomic features including Del1p/13q/14q/17p and Amp1q, combination of t(4;14) and t(11;14) translocations, down-regulation of related gene expression profiles, and up-regulation of cell cycle related genes. An MR analysis of C8 tumors versus all others identified 10 potential driver genes including E2F2 and CKS1B. C8 displays significant enrichment in GE signatures including EMC92, UAMS70, UAMS PR (proliferative) and M9. Published high-risk GE signatures overlap substantially with genes downstream of the MRs identified as driving C8, suggesting regulatory association with previously defined signatures (based on supervised analysis). C8 also showed a significant enrichment on t(4;14) with low FGFR3 expression versus the rest of t(4;14) patients, suggesting that not all t(4;14) patients are high-risk. Finally, the amp1q+ISS3 group and one third of bi-TP53 is significantly associated to C8, indicating that the bi-TP53 factor is a high-risk marker but not a driver of a patient sub-group. C8 showed significant association to previously described high-risk signatures; importantly however, not all patients with high-risk markers (eg, t(4;14) and Double Hit patients) were present in this subgroup. The separation of t(4;14) and Double Hit patients into multiple subgroups with differing clinical outcome suggests a separation between high-risk biology and key poor prognosis markers. While these high-risk prognostic biomarkers may impact clinical outcome, our unsupervised analysis suggests that there is an interplay between these biomarkers and biological disease drivers that determine the poor prognosis of these patients. Analysis of SVs, CNAs and GE differences identified 12 patient subgroups driven by SVs, CNAs, and GE profiles. In contrast, SNVs contributed less to the variance observed across and between MM subgroups. These analyses revealed potential biological drivers underlying a high-risk patient sub-group. The novel molecularly-defined subgroups identified will be further validated. This analysis provides an opportunity to identify biological drivers within molecularly-defined patient subgroups that can lead to development of novel therapies in MM. Disclosures Ortiz: Celgene Research SL (Spain), part of Celgene Corporation: Employment, Equity Ownership. Towfic:Celgene Corporation: Employment, Equity Ownership. Flynt:Celgene Corporation: Employment, Equity Ownership. Jang:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Trotter:Celgene Research SL (Spain), part of Celgene Corporation: Employment, Equity Ownership. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria. Munshi:OncoPep: Other: Board of director. Thakurta:Celgene Corporation: Employment, Equity Ownership.
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Au, Wee Chan, and Pervaiz Khalid Ahmed. "Relationships between superior support, work role stressors and work-life experience." Personnel Review 45, no. 4 (June 6, 2016): 782–803. http://dx.doi.org/10.1108/pr-08-2014-0175.
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Purpose – The purpose of this paper is to examine the effect of superior support, in the presence of a range of work role stressors, on both conflict and enrichment aspects of work-life interface simultaneously. The paper frames the research narrative of superior support by contextualizing it within superior’s dichotomous and opposing roles of organizational performance driver and support provider. Design/methodology/approach – Survey data was collected from Malaysian work adults. Drawing on a sample of 1,051 cases, structural equation modeling technique is used to examine the effect of superior support, with the presence of work role stressors, on individuals’ work-life experience. Three alternate models are compared: superior support as moderator of stressors-strain relationship; both superior support and work stressors as direct antecedents of work-life experience; and superior support as indirect antecedent (mediated by work role stressors) of work-life experience. Findings – Findings evidence the favorable model of superior support as indirect antecedent (mediated by work role stressors) of work-life experience. In addition, superior support has significant impact on work role ambiguity and work-life enrichment, however, its effect on work role conflict, work role overload and work-life conflict is not significant. Findings of the study also demonstrate the distinct effect of work role stressors on work-life experience in terms of direction and strength of impact. Practical implications – While superior support promotes greater work-life enrichment, its effect on work-life conflict is limited. Therefore, instead of superior support, employers have to identify alternate resources to assist employees to deal with conflict and interference of work-life interface. Distinctiveness of various work role stressors and interaction between these work role stressors offer practical implications to employer that all stressors at workplace should not be treated as identical and common to each other. Distinct effort should be taken to address different forms of work role stressors so that work-life conflict (resource depletion) can be minimized while work-life enrichment (resource gaining) can be enhanced. Originality/value – The research investigates superior support in relation to work stressor and work-life experience by scrutinizing the role of supervisors from the vantage point of supervisors as performance drivers as well as support providers. This provides a balanced narrative as compared to previous research focussing solely on either the support perspective or the employee effort extraction perspective. In its execution, the research incorporates enrichment aspect of work-life experience, in addition to the conflict and negative effect. Drawing on the Conservation of Resources Theory, the study teases out important implication for employers and researchers to show that superior support and work role stressors come together to shape individuals’ work-life experience by depleting resources (work-life conflict) and gaining resources (work-life enrichment) simultaneously, as well as drawing out the dilemma of supervisors as performance drivers and support providers at the same time.
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Brumby, Duncan P., Dario D. Salvucci, Walt Mankowski, and Andrew Howes. "A Cognitive Constraint Model of the Effects of Portable Music-Player Use on Driver Performance." Proceedings of the Human Factors and Ergonomics Society Annual Meeting 51, no. 24 (October 2007): 1531–35. http://dx.doi.org/10.1177/154193120705102404.
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We describe an approach to modeling strategic variations in how people might select media content from an Apple iPod portable music player while driving. An experiment was conducted to determine the time required to select a target from a list using the scroll wheel on the iPod. It was found that a linear model accurately predicted the time to scroll through a list to a target. This model was then used in conjunction with a previously reported steering control model to derive a priori predictions for dual-task performance over the entire range of possible multitasking strategies. From this set of strategies, we then focused on identifying the fastest and the safest strategies for completing both a simple selection task and also a more complex selection task. It was found that the model predictions bracketed the observed human data from a recent study that investigated the effects of using an iPod while driving. Moreover, the analysis suggests that in order to compensate for the inherent risks of using devices that demand longer interaction episodes to complete a task, people might adjust their multitasking strategy by giving more time up to steering control while completing the secondary task.
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Liu, Yu, John Easton, Ying Shao, Mark Wilkinson, Michael Edmonson, Xiaotu Ma, Malcolm A. Smith, et al. "The Genomic Landscape of Childhood T-Lineage Acute Lymphoblastic Leukemia." Blood 126, no. 23 (December 3, 2015): 691. http://dx.doi.org/10.1182/blood.v126.23.691.691.
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Abstract Comprehensive studies examining the genomic landscape of T-lineage ALL are lacking, but are important to identify all oncogenic drivers. Here we report sequencing of 264 T-ALL consecutive cases treated on the Children's Oncology Group AALL0434 clinical trial. Whole exome sequencing, copy number analysis using exome and single nucleotide polymorphism array analysis of tumor and remission DNA, and RNA-sequencing of tumor RNA were performed. Cases with immunophenotypic data (N=189) included 19 early T-cell precursor (ETP) cases, 24 near-ETP (with normal CD5 expression) and 146 Non-ETP cases. Median exomic coverage was 89% (72%-96%) of exons with at least 20-fold coverage. We identified 4657 non-synonymous clonal and subclonal somatic mutations (3926 single nucleotide variants (SNV) and 731 insertion-deletion mutations; indels) in 3030 genes, with a mean of 17.6 per case (range 1-50). 176 potential driver genes were identified statistical analysis or by known pathogenic role in cancer. These included NOTCH1 (n=194, 73%), FBXW7 (n=64, 24%), PHF6 (n=50, 19%), PTEN (n=37, 14%), USP7 (n=32, 12%), DNM2 (n=29, 11%) and BCL11B (n=27, 10%). New mutations in T-ALL included CCND3 (n=15, 6%), MYB (n=13, 5%), CTCF (n=13, 5%), MED12 (n=7, 3%), USP9X (n=7, 3%), SMARCA4 (n=7, 3%) and CREBBP (n=6, 2%). In addition to MYB amplification, we identified missense mutations and in-frame protein insertions at the N-terminus of MYB, with a hotspot at codon 14 in a region of six acidic residues in an otherwise hydrophilic N-terminal tail. These mutations resulted in a disordered region that is predicted to affect nuclear localization. The MYB mutations detected were enriched in non-ETP cases (n=13; 8 non-ETP, 1 near-ETP, 4 unknown). Other genes enriched in non-ETP cases included RPL10, CNOT3, MYCN and DDX3X. MED12 mutations were more common in ETP ALL. Sub-clonal mutations (mutant allele fraction of less than 30%) were identified in 111 of 176 driver genes in 198 (75%) cases including NOTCH1 (n=94), FBXW7 (n=29) and PTEN (n=17) indicating that sub-clonal evolution is a hallmark of T-ALL. In addition, multiple mutations in individual genes were commonly observed in single cases. For example, up to 3 different somatic NOTCH1 mutations were detected in each of 9 patients, with 2 different NOTCH1 mutations in 49 cases. Integration of sequence mutations with copy number aberration data showed the following pathways to be most frequently mutated: cell cycle/tumor suppression (N=225; CDKN2A/B (n=206), CDKN1B (n=35), RB1 (n=28)); NOTCH1/FBXW7 (n=212), PI3K-AKT (n=130), JAK-STAT (n=99) and Ras (n=51). Mutations in the PI3K-AKT, JAK-STAT and Ras signaling pathways were mutually exclusive. We identified a high frequency of mutations in transcriptional regulators in 222 cases, including 108 cases with mutations in a core regulatory complex comprising TAL1 (n=51), MYB (n=45) RUNX1 (n=18) and GATA3 (n=13). In 90 of these 108 cases (83%), only a single mutation was present in any of the four genes, consistent with a central role of this complex in leukemogenesis. Epigenetic alterations were identified in 178 cases, including PHF6 (n=63), SMARCA4 (n=23), KDM6A (n=22) and EZH2 (n=18), and new deletions and mutations in KMT2A (MLL; n=11). Interim analysis of transcriptome sequencing data of 126 T-ALL cases detected fusions in 61 (48%) samples, which could be separated into two categories. One weres in-frame fusions resulting in a chimeric protein. The most frequent included MLLT10 fusions (PICALM-MLLT10 (n=3), DDX3X-MLLT10 (n=2) and NAP1L1-MLLT10 (n=1)), KMT2A fusions (KMT2A-MLLT1 (n=4), MLLT6-KMT2A (n=1) and MKT2A-MLLT4 (n=1)), as well as internal tandem duplication mutations involving FLT3 (n=6; 3 ETP, 1 near-ETP, 1 non-ETP, 1 unknown) and NOTCH1 (n=2). We also identified novel fusions including ETV6-CTNNB1 and STMN1-SPI1 (n=1 each). The other category contains rearrangement-driven aberrant expression, including rearrangements in TLX1 (n=11), TLX3 (n=4), TAL1 (n=2), and TAL2 (n=3). Moreover, we found a novel TAL2 transcript in all the 3 cases with TAL2 rearrangement, hijacking a new exon 6kb upstream of the canonical TAL2 transcription start site and extending approximate 3.5kb downstream. These findings provide the first comprehensive landscape of genomic alterations in T-ALL and have provided new insights into the genes and pathways mutated in this disease, their interaction, and the nature of clonal heterogeneity in T-ALL. Disclosures Hunger: Spectrum Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Merck: Equity Ownership. Mullighan:Cancer Science Institute: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Loxo Oncology: Research Funding.
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Khovrak, Inna. "Higher education institutions as a driver of sustainable social development: Polish experience for Ukraine." Environmental Economics 11, no. 1 (March 4, 2020): 1–13. http://dx.doi.org/10.21511/ee.11(1).2020.01.
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The basis for sustainable and environmentally friendly development is gradually becoming aware of the importance of working more ethically and transparently and in a more humanistic way, as well as addressing the needs of people and society. In this case, the key challenge for higher education institutions (HEIs) is to train the conscious and responsible citizens who can take care of the country’s future. This article focuses on comparing the ability of HEIs in Poland and Ukraine to promote sustainable development (SD) by implementing the concept of social responsibility (SR). The research is based on the methods of statistical analysis, sociological survey, case study, abstract-logical, tabular and graphical method. The paper argues that HEIs have a wide range of tools to promote SD. These tools should be divided into three groups, namely: 1) including SD issues in educational programs; 2) developing knowledge and solutions for SD; 3) creation and participation in SR initiatives. The proposed mechanism of the impact of HEIs on SD through the implementation of the concept of SR will allow HEIs to take an active part in the life of the region and the country, namely: identify the needs, engage the stakeholders, facilitate the interaction, disseminate the effective practices, and develop SD strategies. The practical value of the obtained results is that the implementation of SR initiative by HEIs will promote the environmentally friendly development of the country and regions. As a result, it will increase the impact of HEIs on economic, technology and cultural development, human capital formation, solving social problems, building civil society, improving the environmental status.
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Uchida, Yuichiro, Makoto Yoshimitsu, Yuhei Kamada, Naosuke Arima, and Kenji Ishitsuka. "A Novel Recurrent Gain-of-Function Mutation of Rltpr Q575E in Adult T Cell Leukemia/Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 1489. http://dx.doi.org/10.1182/blood-2019-124641.
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Introduction: Adult T-cell leukemia/lymphoma (ATL) is an intractable T cell malignancy with regulatory T cell phenotype, which caused by long-term infection of human T-cell leukemia virus type-1 (HTLV-1). In addition to HTLV-1-derived oncogenic proteins such as Tax and HBZ, genomic aberrations including gain-of-function alterations in genes related to T-cell receptor (TCR) signaling pathway have been implicated in the pathogenesis of ATL. RLTPR is essential for CD28 co-stimulation in human T cells and loss-of-function mutations in RLTPR is reported to reduce proportions of regulatory T cells. The RLTPR p.Q575E has been reported as a recurrent mutation in cutaneous T cell lymphoma1. Here, we show that RLTPR p.Q575E is a novel recurrent gain-of-function mutation related to T-cell receptor co-stimulatory pathway in patients with acute type ATL. Methods To elucidate the genomic basis of ATL, we performed whole exome sequence (WES) in peripheral blood mononuclear cells (CD4/CD25 positive cells were sorted if ATL cell were not abundant) from 47 patients with acute-type ATL. Sequences were aligned against the reference genome (GRCh37/hg19) by using TMAP Alignment. Sanger sequencing was performed to confirm the variant obtained after WES genotyping for some genes including RLTPR. Clinical information regarding ATL cell phenotype, treatment and clinical course were also collected. To analyze the function of RLTPR Q575E, the human RLTPR isoform 3 wild type (WT) (most abundant isotype in lymphoid cells, RLTPR-WT hereafter) and RLTPR isoform 3 Q575E (RLTPR Q575E hereafter) expression retroviral vector were constructed. RLTPR isoform 1 WT and RLTPR isoform 1 Q575E were used as control. RLPTR WT or RLTPR Q575E transduced Jurkat cells were generated by retroviral transduction. NFAT, NF- κB or AP-1 promoter activity was measured as luciferase activity. Cells were stimulated with phorbol 12-myristate 13-acetate (PMA)/Ionomycin calcium salt for TCR stimulation and CD86 Fc chimera for CD28 stimulation. IL-2 mRNA was quantitated by using Taqman Gene Expression Assays. Results Exome analysis from 47 acute-type ATL samples revealed gene alterations precipitated in TCR signaling pathway (CARD11;30.0%, PLCG1;27.7%, PRKCB;21.3%, STAT3;21.3%, VAV1;19.1%, NOTCH1;19.1%, RELA;12.8%, CNSK1A1;8.5%, IRF4;6.4%, FYN;2.1%, CBLB;2.1%, IKBKB;2.1%). In addition to these previously reported driver genes, a novel mutation, RLTPR Q575E was discovered in 4 out of 47 acute-type ATL samples (8.5%) with median variant allele frequency 0.52 (range 0.11-0.68). Although RLTPR Q575E has been reported in cutaneous T cell lymphoma, 3 out of 4 ATL patients carrying RLTPR Q575E mutation have no skin involvement by ATL. ATL patients carrying RLTPR Q575E were also harboring CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations, which are related to TCR/NF-κB signaling pathway. We next performed luciferase reporter assay to evaluate NF-κB activity in transfected 293T cells with RLTPR Q575E cDNA to explore its function. 293T cells transfected with RLTPR Q575E cDNA has higher NF-κB activity than those transfected with RLTPR wild type cDNA. No significant increased promoter activity of AP-1 or NFAT was observed with RLTPR Q575E. IL-2 mRNA was significantly increased in RLTPR Q575E transduced Jurkat cells under PMA/ionomycin and CD86 co-stimulation. We immunoprecipitated FLAG-tagged RLTPR WT or RLTPR Q575E and blotted for CARD11. We found that the RLTPR Q575E increases interaction of RLTPR with CARD11. Previously identified gene alterations such as CARD11 and PRKCB in ATL have been reported as Tax interactome, thus we further analyzed the interaction of RLTPR with Tax. We immunoprecipitated FLAG-tagged WT RLTPR or RLTPR Q575E and blotted for Tax. We found that the RLTPR WT and Q575E increases interaction of RLTPR with Tax. Conclusions In patients with acute-type ATL, we have identified RLTPR Q575E, a novel gain of function mutation, and functionally validated this mutation. This mutation has minimal effect without TCR co-stimulation, but patients with this mutation harboring gain-of-function mutations in TCR signaling molecules. We also found direct interaction between Tax and RLTPR. In the presence of TCR activation by Tax or gain-of-function mutations in this signaling pathway, RLTPR Q575E mutation selectively upregulates the NF-κB signaling pathway and confers the oncogenic effect on the pathogenesis of ATL. Reference 1 Joonhee Park, Jingyi Yang, Alexander T. Wenzel, Akshaya Ramachandran, Wung J. Lee, Jay C. Daniels, Juhyun Kim, Estela Martinez-Escala, Nduka Amankulor, Barbara Pro, Joan Guitart, Marc L. Mendillo, Jeffrey N. Savas, Titus J. Boggon, Jaehyuk Choi; Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood 2017; 130 (12): 1430-1440. doi: https://doi.org/10.1182/blood-2017-02-768234 Disclosures Yoshimitsu: Novartis: Speakers Bureau; Bristol-Myer-Squibb,: Speakers Bureau; Shire: Speakers Bureau; Takeda: Speakers Bureau; Chugai: Speakers Bureau; Sanofi: Speakers Bureau. Ishitsuka:Novartis: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria; Janssen Pharmaceutical: Honoraria; Taiho Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Shire: Honoraria; mundiharma: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Teijin Pharma: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria; Otsuka Pharmaceutical: Honoraria; Teijin Pharma: Research Funding; Eli Lilly: Research Funding; Eisai: Honoraria, Research Funding; Mochida: Honoraria, Research Funding; sanofi: Honoraria; Pfizer: Honoraria; Alexion: Honoraria; Genzyme: Honoraria; Astellas Pharma: Honoraria, Research Funding; Asahi kasei: Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding; MSD: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Yakult: Research Funding; Bristol-Myers Squibb: Honoraria; Shire: Honoraria; Eli Lilly: Research Funding.
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Grzes, Maria, Magdalena Oron, Zuzanna Staszczak, Akanksha Jaiswar, Magdalena Nowak-Niezgoda, and Dawid Walerych. "A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer." Cancers 12, no. 6 (June 11, 2020): 1532. http://dx.doi.org/10.3390/cancers12061532.
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The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.
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Belver, Laura, Alexander Y. Yang, Daniel Herranz, Aidan Quinn, Francesco G. Brundu, Pablo Perez-Duran, Silvia Alvarez, et al. "Suppression of GATA3 Binding Drives Selective Abrogation of NOTCH1-MYC Enhancer Activity By Nucleosome Invasion in Thymocyte Development and Leukemia." Blood 132, Supplement 1 (November 29, 2018): 545. http://dx.doi.org/10.1182/blood-2018-99-119423.
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Abstract Long range enhancers play critical roles in the control of gene expression during development and have emerged as key regulators of lineage commitment and oncogenic programs in hematopoiesis and leukemia. The MYC oncogene is dynamically regulated in the hematopoietic system under the control of a network of clustered distal enhancers, which provide modular regulation of MYC expression during lymphoid and myeloid development. In thymocyte development MYC transcription critically depends on the activity of N-Me, a distinct T-cell specific enhancer controlled by NOTCH1 signaling and located 1.4 Mb telomeric to the MYC transcription start site. Yet, the specific mechanisms governing N-Me enhancer activity and lineage specific control of MYC expression remain rudimentarily understood. Analysis of chromatin looping by 4C and chromatin accessibility by ATACseq revealed an unanticipated high density of chromatin contacts between N-Me and additional regulatory elements in the Myc locus and showed a distinct pattern of N-Me chromatin accessibility -opening as progenitors mature into T cell committed CD4 CD8 double negative (DN) 2b cells and returning to a closed configuration in CD4 CD8 double positive (DP) thymocytes-. To explore potential regulators of N-Me activity we performed Mass Spectrometry proteomic profiling of N-Me binding proteins and ChIPseq analyses identifying numerous factors involved in hematopoietic and lymphoid development (ERG, ETS1, GATA3, RUNX1, TCF3 and TCF12) and transcription factor oncogenes with prominent roles in the pathogenesis of T-ALL (HOXA9, MYB, MYC, LMO1, LMO2, TAL1 and TLX1). Moreover, phylogenetic footprinting analyses across vertebrate species identified two ultraconserved elements matching GATA factor binding motifs (GS1 and GS2). To test the functionality of these elements we introduced targeted mutations in the N-Me sequence at these sites using CRISPR/CAS9 directed mutagenesis. Mice homozygous for combined N-Me GS1 and GS2 mutations (GS1+2mut) revealed a marked defect in thymus cellularity with characteristic accumulation of DN and intermediate single positive (ISP) thymocytes and decreased numbers of more mature populations. Mechanistically, immunohistochemical, flow cytometry and single cell RNaseq analyses revealed decreased Myc protein levels in thymocyte poulations of GS1+2 mutant animals. In this context, we hypothesized that GATA3, a prominent N-Me binding transcription factor in our ChIP and proteomic analyses critically implicated in T-cell commitment, could play a major role in N-Me regulation via interaction with the GS1 and GS2 N-Me GATA sites. Consistent with this hypothesis analysis of Gata3 ChIPs from heterozygous GS1+2 mutant mice recovered only the N-Me wild type sequence, formally demonstrating the strict requirement of these sites for N-Me Gata3 binding. Mechanistically, ATACseq analysis revealed a marked reduction in chromatin accessibility and nucleosome invasion in thymocytes from GS1+2 mutant mice in support of a critical pioneering activity for GATA3 in the control of N-Me activity. Finally, given the important role of NOTCH1 induced MYC upregulation in the pathogenesis of T-ALL, we hypothesized that disruption of N-Me activity via targeted mutation of N-Me GATA sites could effectively impair the development of NOTCH1-driven T-ALL in N-Me GS1+2 mutant mice. To test this possibility we infected hematopoietic progenitors from N-Me wild type and N-Me GS1+2 homozygous mice with retroviruses driving the expression of an oncogenic constitutively active form of NOTCH1 (DE-NOTCH1) and transplanted them into sublethally irradiated recipients. In these experiments, mice transplanted with DE-NOTCH1 infected N-Me wild type cells developed overt T-ALL 6 weeks postransplant with 100% penetrance. In contrast, mice transplanted with DE-NOTCH1-expressing N-Me GS1+2 homozygous cells showed complete protection from NOTCH1 induced T-ALL (P <0.001). In all these results identify GATA3 binding to the N-Me enhancer as a critical driver of nucleosome eviction and enhancer activation strictly required for thymocyte development and NOTCH1-induced T-cell transformation. Disclosures No relevant conflicts of interest to declare.
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Yoda, Akinori, Guillaume Adelmant, Nobuaki Shindoh, Bjoern Chapuy, Yuka Yoda, Oliver Weigert, Nadja Kopp, et al. "The Beta-Subunit Of Heterotrimeric G Proteins Harbors Gain-Of-Function Mutations In Multiple Hematologic Malignancies." Blood 122, no. 21 (November 15, 2013): 2510. http://dx.doi.org/10.1182/blood.v122.21.2510.2510.
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Abstract To identify new oncogene alleles directly from primary tumor specimens, we generate and screen cDNA libraries from patient samples for gain-of-function alterations that can substitute for cytokine signaling in cytokine-dependent cells. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia of plasmacytoid dendritic cells with a dismal prognosis. No driver oncogenes have been identified in cases of BPDCN. Screening of a cDNA library generated from a BPDCN resulted in multiple cytokine-independent clones that expressed a full-length transcript of GNB1 with a K89E mutation. GNB1 encodes a beta subunit of the heterotrimeric G-protein, a binding complex that transduces signals from G-protein coupled receptors to multiple downstream pathways. Gain-of-function mutations have been reported in alpha subunits of the G-protein, including GNAQ/GNA11 in uveal melanoma and GNAS in pituitary tumors, however, the contributions of beta subunits to cancer remains undefined. To investigate downstream signaling from GNB1 K89E, we performed gene expression profiling and mass spectrometry (MS)-based phosphoproteomics and found significant activation of RAS/MAPK and PI3K/AKT pathways in GNB1 K89E-expressing cells compared to isogenic cells expressing wild-type GNB1. ERK and AKT activation by GNB1 K89E were confirmed by western blotting. To target GNB1 K89E signaling, we screened kinase inhibitors using a multiplex assay of small molecules and found selective sensitivity of GNB1 K89E cells to MEK and pan-PI3-kinase inhibitors. To assay the transforming effects of GNB1 K89E in vivo, we transduced GNB1 (wild-type or K89E) into bone marrow from Cdkn2a-deficient donors after 5-FU treatment and transplanted into wild-type recipients. We opted to utilize Cdkn2a-deficient donors as the loss of CDKN2A is common in cases of BPDCN. Within 4 months after transplantation, all mice (n=10) that received bone marrow transduced with GNB1 K89E developed a lethal malignancy characterized by pancytopenia and massive hepatosplenomegaly. Spleens were infiltrated by large, spindly cells with extensive dendritic projections, as well as extensive fibrosis that completely effaced the normal splenic architecture. The cells were negative for T-cell (CD2, CD3) and B-cell (CD19, B220) markers but positive for the dendritic cell/macrophage markers MAC-2 and MAC-3. Further characterization by flow cytometry demonstrated that the cells infiltrating the spleen were CD8, CD103, MHC class II, CD26, FLT3 and CD11c positive, consistent with neoplastic dendritic cells. Serial transplantation of splenic cells from five different GNB1 K89E-transplanted mice into secondary wild-type recipients resulted in 100% fatality within 50 days. We searched published datasets from exome, transcriptome and whole genome sequencing of hematologic malignancies for GNB1 mutations. We identified one case of K89E in B-cell acute lymphoblastic leukemia (ALL), four cases with I80T/N in chronic lymphocytic leukemia or B-cell lymphomas, six cases with K57E/T in myeloid neoplasms, and D76G in T-cell ALL. Expression of any of these alleles but not wild-type GNB1 was sufficient to promote cytokine-independent growth of human TF1 cells. The published structure of GNB1 (Ford et al. Science 1998) reported a small number of residues, including K57, I80 and K89 that mediate interactions with both G-alpha subunits and effector proteins. In fact, affinity purification followed by MS using tagged GNB1 (wild-type, I80T and K89E) demonstrated that, unlike wild-type GNB1, the GNB1 mutants fail to bind distinct Gα subunits. The repertoire of protein interactors, which includes potential G protein effectors, also differed between different GNB1 alleles. Thus, gain-of-function mutations in GNB1 occur across a broad range of hematologic malignancies, modify essential interaction G-protein subunit interactions, can drive in vivo transformation, and activate targetable downstream kinases. Disclosures: Tyner: Incyte Corporation: Research Funding.
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Ezrokh, Yuriy. "Implementation of retail payments by QR-code in Russia as a driver for the development of national payment system (economic aspects)." Moscow University Economics Bulletin, no. 1 (February 28, 2021): 168–88. http://dx.doi.org/10.38050/01300105202118.
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Problem statement. Drawing on macroeconomic analysis (2011-2019), the author formulates the key problems in the functioning of retail segment of the national payment system: a) differentiation of regions according to the degree of payment infrastructure development; b) disproportion in the availability of trace elements of the payment infrastructure; c) high cost of acquiring services. The underlying scientific hypothesis is the possibility to overcome the above-mentioned problems by introducing retail payments using QR codes. The study examines economic relations arising in calculations using QR codes in Russia’s retail payment system. The methodological base of the study includes theoretical assumptions of banking management, as well as a problem-oriented approach. The study identifies a range of economic problems in the implementation of QR settlements in Russia which include: the need to upgrade mobile banking; banks’ lack of interest in promoting QR code settlements due to fears of lower transaction returns; a decrease in citizens’ interest in cashless payments caused by a contraction in bank loyalty programs; the inertia of entrepreneurs unwilling to switch from cash-based interaction with customers; the inertia of some customers and their lack of financial literacy; cyber threats; risks of unfair behavior of buyers. The author offers and justifies the ways to overcome them. The findings may help improve state regulation in Russia’s financial and banking sector.
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Gould, Charlotte, and Paul Sermon. "The immersive environment as a driver for environmental change; addressing the Out of Sight, Out of Mind impacts of the Anthropocene on the Mar Menor, Spain." Virtual Creativity 10, no. 2 (December 1, 2020): 141–61. http://dx.doi.org/10.1386/vcr_00029_1.
Full textAbstract:
Out of Sight, Out of Mind is a unique interactive 360° video experience of the Mar Menor that manifests the Anthropocene effects on the landscape as augmented, surreal and metaphysical interpretations of the artist’s experiences, during their residency and available secondary scientific data of the Mar Menor ecosystem. Through environmental, social, economic and cultural observations and encounters the team developed an immersive 360° environment that incorporates video and audio recordings with augmented, imaginary and predicted realities transformed from scientific data in obscure and profound guises. This 360° telematic installation incorporating live audience interaction within the original 360° video experience was exhibited at the Centro Cultural Puertas de Castilla in Murcia in May 2019. This collaborative project was developed following a ten-day residency on the Mar Menor, a 170 km² saltwater lagoon on the south-east coast of Spain in September 2018, where the majority of the primary research took place by gathering 360° video material from observations, experiences and interviews. The project has been developed by a team of three UK artists, each bringing specialist experience and knowledge of 360° video to undertake the research and create a unique understanding and manifestation of the changing ecosystem of the Mar Menor. This collaborative project includes and combines Paul Sermon’s co-located telematic experiences in 360° live video environments, Charlotte Gould’s immersive 360° animated augmented reality and Jeremiah Ambrose’s gaze-controlled navigation through 360° video narratives. This practice-based team of artists undertook this research using a range of video and gaming software and advanced hardware devices, including Insta360 Pro 8K video cameras and Oculus Rift head-mounted-displays in conjunction with live video switchers. This has produced a range of ultra HD 360° outputs involving stereo 8K and real-time 4K environments with augmented live 360° video and animation sequences through live chroma-keying effects.