Discovery of Small Molecules Targeting the Synergy of Cardiac Transcription Factors GATA4 and NKX2-5

Transcription factors are pivotal regulators of gene transcription, and many diseases are associated with the deregulation of transcriptional networks. In the heart, the transcription factors GATA4 and NKX2-5 are required for cardiogenesis. GATA4 and NKX2-5 interact physically, and the activation of GATA4, in cooperation with NKX2-5, is essential for stretch-induced cardiomyocyte hypertrophy. Here, we report the identification of four small molecule families that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy. A fragment-based screening, reporter gene assay, and pharmacophore search were utilized for the small molecule screening, identification, and optimization. The compounds modulated the hypertrophic agonist-induced cardiac gene expression. The most potent hit compound, N-[4-(diethylamino)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide (3, IC50 = 3 mu M), exhibited no activity on the protein kinases involved in the regulation of GATA4 phosphorylation. The identified and chemically and biologically characterized active compound, and its derivatives may provide a novel class of small molecules for modulating heart regeneration.Peer reviewe

Resource management in cooperative MIMO-OFDM cellular systems

Abstract Radio resource management techniques for broadband wireless systems beyond the existing cellular systems are developed while considering their special characteristics such as multi-carrier techniques, adaptive radio links and multiple-input multiple-output (MIMO) antenna techniques. Special focus is put on the design of linear transmission strategies in a cooperative cellular system where signal processing can be performed in a centralised manner across distributed base station (BS) antenna heads. A time-division duplex cellular system based on orthogonal frequency division multiplexing (OFDM) with adaptive MIMO transmission is considered in the case where the received signals are corrupted by non-reciprocal inter-cell interference. A bandwidth efficient closed-loop compensation algorithm combined with interference suppression at the receiver is proposed to compensate for the interference and to guarantee the desired Quality of Service (QoS) when the interference structure is known solely at the receiver. A greedy beam ordering and selection algorithm is proposed to maximise the sum rate of a multiuser MIMO downlink (DL) with a block zero forcing (ZF) transmission. The performance of the block-ZF transmission combined with the greedy scheduling is shown to approach the sum capacity as the number of users increases. The maximum sum rate is often found to be achieved by transmitting to a smaller number of users or beams than the spatial dimensions allow. In addition, a low complexity algorithm for joint user, bit and power allocation with a low signalling overhead is proposed. Different linear transmission schemes, including the ZF as a special case, are developed for the scenario where the cooperative processing of the transmitted signal is applied to users located within a soft handover (SHO) region. The considered optimisation criteria include minimum power beamformer design; balancing the weighted signal-to-interference-plus-noise ratio (SINR) values per data stream; weighted sum rate maximisation; and balancing the weighted rate per user with additional QoS constraints such as guaranteed bit rate per user. The method can accommodate supplementary constraints, e.g., per antenna or per BS power constraints, and upper/lower bounds for the SINR values of the data streams. The proposed iterative algorithms are shown to provide powerful solutions for difficult non-convex transceiver optimisation problems. System level evaluation is performed in order to assess the impact of a realistic multi-cell environment on the performance of a cellular MIMO-OFDM system. The users located in the SHO region are shown to benefit from greatly increased transmission rates. Consequently, significant overall system level gains result from cooperative SHO processing. The proposed SHO scheme can be used for providing a more evenly distributed service over the entire cellular network

An iterative approach for inter-group interference management in two-stage precoder design

Abstract We consider a single cell downlink (DL) massive multiple-input multiple-output (MIMO) set up with user clustering based on statistical information. The problem is to design a fully digital two stage beamforming consisting of slow varying channel statistics based outer beamformer (OBF) and an inner beamformer (IBF) accounting for fast channel variations aiming to reduce the complexity involved in the conventional MIMO processing. Two different methods are considered to design the OBF matrix, so as to reduce the size of the effective channel used for IBF design. A group specific two-stage optimization problem with weighted sum rate maximization (WSRM) objective is formulated to find the IBF for fixed OBF. We begin by proposing centralized IBF design were the optimization is carried out for all sub group jointly with user specific inter-group interference constraints. In order to further reduce the complexity, we propose an iterative solution for group-specific beamformer design via the Karush-Kuhn-Tucker (KKT) conditions for fixed inter group interference (IGI) values with per group transmit power constraint. A low complexity heuristic iterative method is also proposed for managing the inter-group interference. In spite of incurring a small loss in performance, the computational complexity can be saved to a large extent with the group specific processing. The sum rate behavior of various proposed schemes are illustrated using numerical simulations

Interference management via user clustering in two-stage precoder design

Abstract We consider a single cell downlink (DL) massive multiple-input multiple-output (MIMO) set-up with user clustering based on statistical information. The problem is to design a fully digital two-stage beamforming aiming to reduce the complexity involved in the conventional MIMO processing. The fully digital two-stage beamforming consists of a slow varying channel statistics based outer beamformer (OBF) and an inner beamformer (IBF) accounting for fast channel variations. Two different methods are presented to design the OBF matrix, so as to reduce the size of effective channel used for IBF design. A group specific two-stage optimization problem with weighted sum rate maximization (WSRM) objective is formulated to find the IBF for fixed OBF. We begin by proposing centralized IBF design were the optimization is carried out for all sub group jointly with user specific inter-group interference constraints. In order to further reduce the complexity, we also propose a group specific IBF design by fixing the inter group interference to a constant or by ignoring them from the problem altogether. In spite of incurring a small loss in performance, the computational complexity can be saved to a large extent with the group specific processing. Numerical experiments are used to demonstrate the performance of various proposed schemes by comparing the total sum rate of all users and the design complexity

Capacity approaching low density spreading in Uplink NOMA via asymptotic analysis

Abstract Low-density spreading non-orthogonal multiple-access (LDS-NOMA) is considered where K single-antenna user-equipments (UEs) communicate with a base-station (BS) over F fading sub-carriers. Each UE k spreads its data symbols over dk≪F sub-carriers. The performance of LDS-NOMA system depends on the allocation of the non-zero elements in the LDS-codes. We aim to identify the LDS resource allocations, based solely on pathlosses, that maximize the ergodic mutual information (EMI). This problem can be solved only via an exhaustive search. Thus, relying on analysis in the regime where F , K , and dk,∀k converge to +∞ at the same rate, we present EMI as a deterministic equivalent plus a residual term. The deterministic equivalent is a function of pathloss values and LDS-codes, and the small residual term scales as O(1min(d2k)) . First, we formulate an optimization problem to identify the resource allocations that maximize the deterministic equivalent of EMI. The Karush-Kuhn-Tucker conditions give a simple resource allocation rule that facilitates the construction of desired LDS-codes via an efficient partitioning algorithm. The finite-regime analysis shows that such sparse solutions additionally harness the small incremental gain inherent in the residual term, and thus, provides a near-optimal performance. The spectral efficiency enhancement relative to regular and random spreading is validated numerically

A user cooperative beamforming approach to PAPR reduction in MIMO-OFDM uplink

Abstract We consider a scheme for PAPR reduction based on user cooperation in a single-cell multi-user MIMO-OFDM uplink system. The idea is to utilize the unused space-frequency resources induced by collaborative beamforming to transmit dummy symbols, resulting in a transmit signal with reduced per-antenna peak powers. Traditionally collaborative beamforming has been used to acquire beamforming gain, i.e., extended cell coverage and improved rates, while our approach also in addition reduces the transmit signal PAPR of individual user antennas. The reduced PAPR enables the users to allocate more power to data transmission, resulting in a higher system sum-rate for a fixed peak transmit power budget while also relaxing the strict linearity requirements of the user equipment RF components. We also account for the power required to exchange data between cooperating users by utilizing a simple AWGN channel model between users. We formulate the PAPR minimization problem as a convex optimization problem that reduces the PAPR of a given time domain transmit signal provided there are subcarriers with no previous bit allocations, which is a valid assumption especially at mid- and low-SNR regimes

Two-stage beamformer design via deterministic equivalents

Abstract Complexity reduction of optimal linear receiver is considered in a scenario where both the number of single antenna user equipments (UEs) K and base station (BS) antennas N are large. Two-stage beamforming (TSB) greatly alleviates the high implementation complexity of large scale multiantenna receiver by concatenating a statistical outer beamformer (OBF) with an instantaneous inner beamformer (IBF) design. Using asymptotic large system analysis, we propose a novel TSB method that adjusts the dimensions of user specific OBF matrices based on the projection of the optimal minimum mean square error (MMSE) vectors into the beam domain. The beam domain is first divided into S narrow sectors such that each sector contains D DFT beams. Then, so called deterministic equivalents are computed for the amplitude-projection of the optimal MMSE vectors into each sector in asymptotic regime where N, K and D grow large with a non-trivial ratio N/K = C and N/D = S. Given the approximations for the sector specific values, the structure and dimension of each UE specific OBF vector are optimized based on the statistical channel properties and the amount of overlap among users in angular domain. The numerical analysis shows that the attained SINR values closely follow the optimal MMSE receiver while the computational burden is greatly reduced

Dynamic UL/DL mode selection and resource allocation in multi-cell MIMO TDD systems

Abstract This paper considers joint uplink/downlink mode selection and resource allocation problem in multi-cell systems for flexible TDD frame structures. To combat the difficult interference characteristics of such systems, a dynamic mode selection and resource allocation scheme is derived using Lyapunov optimization. The result is a cross-layer optimization scheme, where a long-term time-average utility function of flow rates and interference penalty is optimized by solving a series of instantaneous subproblems. The proposed dynamic algorithm provides a solution for the UL/DL mode selection and resource allocation, guided by the accumulating network layer queues and virtual queues. Furthermore, a heuristic method is considered to decouple the difficult power constraint in the resource allocation subproblem

Rate maximization via PAPR reduction in MIMO-OFDM uplink:a user cooperation approach

Abstract In this paper, we propose a novel user cooperation framework aimed at optimizing power efficiency in MIMO-OFDM uplink, where cooperation is directed towards minimizing the transmit signal PAPR at all cooperating users. We consider different degrees of cooperation: 1) joint data transmission with PAPR reduction, 2) only joint data transmission and 3) the reference non-cooperative case based on a zero forcing receiver at the base station. In the cooperative case, we also account for the power required to exchange data between users. The main idea of our scheme is to exploit the unused space-frequency resources induced by the user cooperation to assign dummy symbols on the empty subcarriers and optimize these symbols to affect the outbound waveform. This is achieved as a result for a convex optimization problem which aims to simultaneously minimize the transmit PAPR and dummy symbol power allocation. We further introduce a rate maximization scheme, which maximizes the data power allocation for a given transmit peak power constraint by executing a one-dimensional search. The results show that our proposed PAPR minimizing bit and power allocation scheme can achieve significantly higher throughput at short and medium UE-UE distances

Multi-antenna coded caching at finite-SNR:breaking down the gain structure

Abstract Multi-antenna coded caching (CC) techniques are considered viable options for achieving higher data rates in future networks, especially for the prominent use case of multimedia-driven applications. However, despite their information-theoretic analyses, which are thoroughly studied in the literature, the research on the finite-SNR performance of multi-antenna CC techniques is not yet mature. In this paper, we try bridging this gap by breaking down, categorizing, and studying the effect of six crucial parameters affecting the finite-SNR performance of multi-antenna CC schemes. We also investigate the interaction of different parameters and clarify how they could affect the implementation complexity in terms of the necessary computation and subpacketization. Theoretical discussions are followed and verified by numerical analysis