An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis

Publisher Copyright: © 2022, The Author(s).Lipid remodeling is crucial for malignant cell transformation and tumorigenesis, but the precise molecular processes involved and direct evidences for these in vivo remain elusive. Here, we report that oxysterol-binding protein (OSBP)-related protein 4 L (ORP4L) is expressed in adult T-cell leukemia (ATL) cells but not normal T-cells. In ORP4L knock-in T-cells, ORP4L dimerizes with OSBP to control the shuttling of OSBP between the Golgi apparatus and the plasma membrane (PM) as an exchanger of phosphatidylinositol 4-phosphate [PI(4)P]/cholesterol. The PI(4)P arriving at the PM via this transport machinery replenishes phosphatidylinositol 4,5-bisphosphate [PI(4,5)P-2] and phosphatidylinositol (3,4,5) trisphosphate [PI(3,4,5)P-3] biosynthesis, thus contributing to PI3K/AKT hyperactivation and T-cell deterioration in vitro and in vivo. Disruption of ORP4L and OSBP dimerization disables PI(4)P transport and T-cell leukemogenesis. In summary, we identify a non-vesicular lipid transport machinery between Golgi and PM maintaining the oncogenic signaling competence initiating T-cell deterioration and leukemogenesis. The oxysterol-binding protein-related protein 4 (ORP4L) is expressed in T-cell acute lymphoblastic leukemia and is required for leukemogenesis. Here the authors show that ORP4L orchestrates the transport of the phospholipid PI(4)P from Golgi to the plasma membrane, contributing to PI3K/AKT hyperactivation and T-cell leukemogenesis.Peer reviewe

ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLC beta 3 Catalysis : Targeting It Eradicates Leukemia Stem Cells

Leukemia stem cells (LSCs) are a rare subpopulation of abnormal hematopoietic stem cells (HSCs) that propagates leukemia and are responsible for the high frequency of relapse in therapies. Detailed insights into LSCs' survival will facilitate the identification of targets for therapeutic approaches. Here, we develop an inhibitor, LYZ-81, which targets ORP4L with high affinity and specificity and selectively eradicates LCSs in vitro and in vivo. ORP4L is expressed in LSCs but not in normal HSCs and is essential for LSC bioenergetics and survival. It extracts PIP2 from the plasma membrane and presents it to PLC beta 3, enabling IP3 generation and subsequentCa(2+)-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP2 and blocks PIP2 hydrolysis, resulting in defective Ca2+ signaling. The results provide evidence that LSCs can be eradicated through the inhibition of ORP4L by LYZ-81, which may serve as a starting point of drug development for the elimination of LSCs to eventually cure leukemia.Peer reviewe

A Computing Model of Selective Attention for Service Robot Based on Spatial Data Fusion

Robots and humans are facing the same problem: they all need to face a lot of perceptual information and choose valuable information. Before the robots provide services, they need to complete a robust real-time selective attention process in the domestic environment. Visual attention mechanism is an important part of human perception, which enables humans to select the visual focus on the most potential interesting information. It also could dominate the allocation of computing resource. It also could focus human’s attention on valuable objects in the home environment. Therefore we are trying to transfer visual attention selection mechanism to the scene analysis of service robots. This will greatly improve the robot’s efficiency in perception and processing information. We proposed a computing model of selective attention which is biologically inspired by visual attention mechanism, which aims at predicting focus of attention (FOA) in a domestic environment. Both static features and dynamic features are composed in attention selection computing process. Information from sensor networks is transformed and incorporated into the model. FOA is selected based on a winner-take-all (WTA) network and rotated by inhibition of return (IOR) principle. The experimental results showed that this approach is robust to the partial occlusions, scale-change illumination, and variations. The result demonstrates the effectiveness of this approach with available literature on biological evidence. Some specific domestic service tasks are also tailored to this model

Landmark-Centric Routing for Wireless Sensor Networks in Mobile Delay Tolerant Environments

Wireless sensor networks (WSNs) have wide applications in many fields sharing common grounds as their major technical challenges. This paper focuses on a high-level information association issue and designs an efficient routing protocol accordingly for delay tolerant mobile sensor networks (DTMSNs). In this paper, after making an analysis about the effect of social network theory on forwarding scheme and node mobility, we exploit landmark, a new social-aware metric indicating the geographical location corresponding to a node interest or a node community. To the best of our knowledge, this is the first work in which landmark is utilized to assist message forwarding in DTMSNs. Additionally, we propose the landmark-centric routing protocol utilizing the metric to accurately predict node mobility geographically. We can take full advantage of node mobility in our protocol while preserving the positive effects of existing social-aware metrics on protocol performance. Simulation results show that the proposed protocol achieves the highest packet delivery ratio outperforming SocialCast and doubling SGBR with more than 50% delivery cost reducing

An Optimized Strategy Coverage Control Algorithm for WSN

The problem of using lesser wireless sensor network nodes to achieve coverage and connection of certain areas under given coverage conditions is a priority and hotspot issue of WSN. For this reason, in this paper, an optimized strategy coverage control (OSCC) algorithm is proposed. First of all, a relation mapping model of sensor nodes and target nodes is established by OSCC which is based on geometric figure and related theories, probability theory, converge property, and so forth to complete effective reasoning and calculate certain network models. Secondly, OSCC makes efficient analysis of the calculating results figure out the least number of sensor nodes to cover specific monitoring area. Thirdly, OSCC picks out the optimal routing solution while conducting combinatorial optimization of routing path using ant colony optimization (ACO) algorithm, thus reducing the energy spending of whole network. In the end, this paper verifies OSCC algorithm by simulation experiment and proves it can use least sensor nodes to effectively cover target area. Also, OSCC helps greatly reduce network energy consuming, minimize network resources layout costs, and enhance network life cycle, simultaneously

Higgs Boson Studies at the Tevatron

We combine searches by the CDF and D0 Collaborations for the standard model Higgs boson with mass in the range 90--200 GeV$/c^2$ produced in the gluon-gluon fusion, $WH$, $ZH$, $t{\bar{t}}H$, and vector boson fusion processes, and decaying in the $H\rightarrow b{\bar{b}}$, $H\rightarrow W^+W^-$, $H\rightarrow ZZ$, $H\rightarrow\tau^+\tau^-$, and $H\rightarrow \gamma\gamma$ modes. The data correspond to integrated luminosities of up to 10 fb$^{-1}$ and were collected at the Fermilab Tevatron in $p{\bar{p}}$ collisions at $\sqrt{s}=1.96$ TeV. The searches are also interpreted in the context of fermiophobic and fourth generation models. We observe a significant excess of events in the mass range between 115 and 140 GeV/$c^2$. The local significance corresponds to 3.0 standard deviations at $m_H=125$ GeV/$c^2$, consistent with the mass of the Higgs boson observed at the LHC, and we expect a local significance of 1.9 standard deviations. We separately combine searches for $H \to b\bar{b}$, $H \to W^+W^-$, $H\rightarrow\tau^+\tau^-$, and $H\rightarrow\gamma\gamma$. The observed signal strengths in all channels are consistent with the presence of a standard model Higgs boson with a mass of 125 GeV/$c^2$