Dissection of complex biological systems requires target-specific control of the function or abundance of proteins. Genetic perturbations are limited by off-target effects, multicomponent complexity, ...and irreversibility. Most limiting is the requisite delay between modulation to experimental measurement. To enable the immediate and selective control of single protein abundance, we created a chemical biology system that leverages the potency of cell-permeable heterobifunctional degraders. The dTAG system pairs a novel degrader of FKBP12
with expression of FKBP12
in-frame with a protein of interest. By transgene expression or CRISPR-mediated locus-specific knock-in, we exemplify a generalizable strategy to study the immediate consequence of protein loss. Using dTAG, we observe an unexpected superior antiproliferative effect of pan-BET bromodomain degradation over selective BRD4 degradation, characterize immediate effects of KRAS
loss on proteomic signaling, and demonstrate rapid degradation in vivo. This technology platform will confer kinetic resolution to biological investigation and provide target validation in the context of drug discovery.
Autophagy has been shown to be elevated in pancreatic ductal adenocarcinoma (PDAC), and its role in promoting established tumor growth has made it a promising therapeutic target. However, due to ...limitations of prior mouse models as well as the lack of potent and selective autophagy inhibitors, the ability to fully assess the mechanistic basis of how autophagy supports pancreatic cancer has been limited. To test the feasibility of treating PDAC using autophagy inhibition and further our understanding of the mechanisms of protumor effects of autophagy, we developed a mouse model that allowed the acute and reversible inhibition of autophagy. We observed that autophagy inhibition causes significant tumor regression in an autochthonous mouse model of PDAC. A detailed analysis of these effects indicated that the tumor regression was likely multifactorial, involving both tumor cell-intrinsic and host effects. Thus, our study supports that autophagy inhibition in PDAC may have future utility in the treatment of pancreatic cancer and illustrates the importance of assessing complex biological processes in relevant autochthonous models.
This work demonstrates that autophagy is critical pancreatic tumor maintenance through tumor cell-intrinsic and -extrinsic mechanisms. These results have direct clinical relevance to ongoing clinical trials as well as drug-development initiatives.
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With the ever-increasing demand for wireless traffic and quality of services (QoS), wireless local area networks (WLANs) have developed into one of the most dominant wireless networks that fully ...influence human life. As the most widely used WLANs standard, IEEE 802.11 will release the upcoming next generation WLANs standard amendment: IEEE 802.11ax. Thus, this article briefly surveys the key technologies of IEEE 802.11ax. Furthermore, performance requirements of IEEE 802.11ax are evaluated via a proposed systems and link-level integrated simulation platform (SLISP). Simulations results confirm that IEEE 802.11ax significantly improves the user experience in high-density deployment, while successfully achieves the average per user throughput requirement in project authorization request (PAR) of IEEE 802.11ax by four times compared to the legacy IEEE 802.11. To the best of our knowledge, this article is the first work to thoroughly and deeply evaluate the compliance of the performance requirements of IEEE 802.11ax.
Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support ...proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel therapeutic opportunities. Here we show that the dependence on oncogenic KRAS correlates with specific metabolic profiles that involve maintenance of nucleotide pools as key mediators of KRAS-dependence. KRAS promotes these effects by activating a MAPK-dependent signaling pathway leading to MYC upregulation and transcription of the non-oxidative pentose phosphate pathway (PPP) gene RPIA, which results in nucleotide biosynthesis. The use of MEK inhibitors recapitulates the KRAS-dependence pattern and the expected metabolic changes. Antagonizing the PPP or pyrimidine biosynthesis inhibits the growth of KRAS-resistant cells. Together, these data reveal differential metabolic rewiring between KRAS-resistant and sensitive cells, and demonstrate that targeting nucleotide metabolism can overcome resistance to KRAS/MEK inhibition.
In this paper, a grouping-based uplink orthogonal frequency division multiple access (OFDMA) random access method is studied which can improve users’ satisfaction in the next generation wireless ...local area networks (WLANs). The next generation WLANs standard, IEEE 802.11ax introduces a random access mechanism, uplink OFDMA random access (UORA), to allow users to access channel randomly. Although UORA has the advantages of low signaling overhead, no need to report uplink transmission requirements, it does not have any characteristics to improve users’ satisfaction. Because the AP can’t allocate resources to users adopting UORA, some users’ quality of experience (QoE) will decline greatly. In this paper, a grouping-based UORA (G-UORA) method is proposed. The AP determines the number of groups, and then clusters users to different groups according to their utility. Then, the AP assigns resources to these groups to maximize the total utility of all users. We present a theoretical utility prediction model of G-UORA and propose the corresponding resource allocation algorithm based on utility. According to simulation results, the algorithm achieves better users’ satisfaction and fairness than the traditional UORA mechanism in IEEE 802.11ax and the user utility gain is 1.6 times. Therefore, the proposed method has greater practical significance.
IEEE 802.11ax, an emerging standard for the next-generation wireless local area networks (WLANs), pursues to improve network throughput in high-density deployment scenarios by introducing ...high-efficiency mechanisms into both media access control (MAC) layer and physical (PHY) layer. In IEEE 802.11ax, high-efficiency multi-user media access control (MU-MAC) is adopted for both uplink and downlink access mechanisms. As for the uplink MU-MAC, it can be further subdivided into two categories, uplink orthogonal frequency division multiple access (OFDMA) scheduling access (UOSA) and uplink OFDMA random access (UORA). How to effectively measure and optimize the joint carrying capacity (JCC) of the networks where both scheduling access mode and random access mode are supported is a key problem for the design of the uplink access mechanism of the 802.11ax. Firstly, in this paper, the concept of capacity entropy for multi-user access (CEM) is proposed to quantitatively measure the JCC of the networks. Secondly, the UORA is modeled and analyzed and we get the access probability of UORA (
P
U
O
R
A
) by using an enhanced Markov chain, then we can calculate the capacity entropy of UORA. Based on it, the CEM of the 802.11ax is further analyzed. Finally, based on the adopted MU-MAC framework in 802.11ax standard draft, an efficient hybrid access strategy (HAS) is proposed, which combines a greedy scheduling strategy based on capacity constraints and a method based on channel quality perception of stations (STAs) in UORA. Simulation results show that HAS achieves higher CEM. In summary, it is believed that the proposed concept of CEM will pave a new technical way to investigate problems of how to optimize the JCC for the next-generation WLANs.
Internet of Things (IoT) is a kind of information carrier, which enables for all ordinary objects that can perform independent functions to realize interconnection. The standardization process of ...wireless local area networks (WLANs) which is an important network system of IoT is gradually advancing. IEEE 802.11ax will replace IEEE 802.11a/b/g/n/ac as the latest WLANs standard. The uplink transmission of IEEE 802.11ax adopts a hybrid access mode. The mode means that the stations (STAs) can access the network adopting either scheduling access mode or random access mode. Since the hybrid access mode supports both the scheduling and random access, how to allocate the resources among the STAs which adopt the two access modes is the first problem to be solved. In particular, IEEE 802.11ax focuses more on the network performance of the high-dense deployment scenarios. The characteristic of the interference of the overlapping basic service set (OBSS) situation is the key factor of the efficiency of resource allocation algorithm. Therefore, firstly, this paper combines capacity entropy multi-user access (CEM) with utility function, and defines a metric value to measure the utility of two kinds of users. Secondly, the simulation-assisted method is used to obtain the probability distribution characteristic of the interference power random variables from dense multi-cell scenarios of IEEE 802.11ax. Then, based on interference power random variables which generated by the probability density curve obtained by simulation, we propose an algorithm which can maximizetotal utility of scheduling and random access STAs, i.e., to maximize the total satisfaction of all STAs. The authors believe that the research can enhance the quality of experience (QoE) of users in dense multi-cell scenarios for the next generation WLANs.
From the perspective of media protocol control and routing of directional wireless ad hoc sensors networks, neighbor discovery protocol is an important problem to be solved first. In the past period ...of time, some methods have been studied on neighbor discovery protocol, but they have a common defect of link collision. The collision is caused by mutual interference of multiple transmitting nodes which are in one reception beam of the receiving node. To solve this problem, we propose a neighbor discovery algorithm using a bi-directional carrier sense collision avoidance and multi subchannels based on a scan-based algorithm (BD-SBA). Based on a scan-based algorithm (SBA), bi-directional carrier sense of the BD-SBA algorithm is performed in the first broadcast step which can reduce the collision of broadcasting the scanning request (SREQ) frames. In the second step (the reply step), the mechanism of multiple subchannels and multiple slots is applied to reduce the collision of the scanning response (SRES) frames. From the analysis and simulation, we can see that nodes using proposed algorithm can discover their neighbor nodes in fewer time. Moreover, the proposed algorithm has better performance for different beamwidths and densely distributed scenes. So it has great significance in engineering application.
With the increasing diversity of wireless services and explosive growth of traffic, Wireless Local Area Network (WLAN) has become the main carrier of wireless traffics. Therefore, how to ensure the ...quality of service (QoS) requirements of high priority traffics is one of the momentous targets of the next generation WLAN. The Orthogonal Frequency Division Multiple Access (OFDMA) has been introduced into the next generation WLAN as the key technology and has become an important feature. However, less attention is played to the QoS-guaranteed and fairness-guaranteed in the existing OFDMA-based Media Access Control (MAC) protocols. This article proposes a double random access QoS oriented OFDMA MAC protocol for the next generation WLAN, named DRA-OFDMA. What different from the existing work is that the idea of two phases for parallel OFDMA random access is introduced in the protocol. The traffic priorities are not distinguished in the first phase of the random access, thus fairness of traffic is ensured at some extent. Users, which are failed to be accessed in the first phase, with high priority are allowed to be accessed in the second phase on the remaining available sub-channels, thus the QoS for the high priority traffic is well guaranteed. The DRA-OFDMA MAC protocol proposed in this paper has good compatibility advantage. It can completely reuse available frame defined by 802.11ax standard. In addition, the Markov chain based theoretical analysis model for the proposed protocol is formulated and the corresponding network performance is also analyzed in our paper. Finally, the correctness of theoretical analysis model and performance analysis are verified by simulation. Simultaneously, the simulation results show that the throughput of DRA-OFDMA with high priority traffic is enhanced 22.05% and 89.6% than that of RA-OFDMA and OMAX respectively, and the fairness of low priority traffic is also well guaranteed.
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