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

Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4-NKX2-5 Interaction

Transcription factors are fundamental regulators of gene transcription, and many diseases, such as heart diseases, are associated with deregulation of transcriptional networks. In the adult heart, zinc-finger transcription factor GATA4 is a critical regulator of cardiac repair and remodelling. Previous studies also suggest that NKX2-5 plays function role as a cofactor of GATA4. We have recently reported the identification of small molecules that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy. Here, we examined the cardiac actions of a potent inhibitor (3i-1000) of GATA4-NKX2-5 interaction in experimental models of myocardial ischemic injury and pressure overload. In mice after myocardial infarction, 3i-1000 significantly improved left ventricular ejection fraction and fractional shortening, and attenuated myocardial structural changes. The compound also improved cardiac function in an experimental model of angiotensin II-mediated hypertension in rats. Furthermore, the up-regulation of cardiac gene expression induced by myocardial infarction and ischemia reduced with treatment of 3i-1000 or when micro-and nanoparticles loaded with 3i-1000 were injected intramyocardially or intravenously, respectively. The compound inhibited stretch- and phenylephrine-induced hypertrophic response in neonatal rat cardiomyocytes. These results indicate significant potential for small molecules targeting GATA4-NKX2-5 interaction to promote myocardial repair after myocardial infarction and other cardiac injuries

D3.2 First performance results for multi -node/multi -antenna transmission technologies

This deliverable describes the current results of the multi-node/multi-antenna technologies investigated within METIS and analyses the interactions within and outside Work Package 3. Furthermore, it identifies the most promising technologies based on the current state of obtained results. This document provides a brief overview of the results in its first part. The second part, namely the Appendix, further details the results, describes the simulation alignment efforts conducted in the Work Package and the interaction of the Test Cases. The results described here show that the investigations conducted in Work Package 3 are maturing resulting in valuable innovative solutions for future 5G systems.Fantini. R.; Santos, A.; De Carvalho, E.; Rajatheva, N.; Popovski, P.; Baracca, P.; Aziz, D.... (2014). D3.2 First performance results for multi -node/multi -antenna transmission technologies. http://hdl.handle.net/10251/7675

D 3. 3 Final performance results and consolidated view on the most promising multi -node/multi -antenna transmission technologies

This document provides the most recent updates on the technical contributions and research challenges focused in WP3. Each Technology Component (TeC) has been evaluated under possible uniform assessment framework of WP3 which is based on the simulation guidelines of WP6. The performance assessment is supported by the simulation results which are in their mature and stable state. An update on the Most Promising Technology Approaches (MPTAs) and their associated TeCs is the main focus of this document. Based on the input of all the TeCs in WP3, a consolidated view of WP3 on the role of multinode/multi-antenna transmission technologies in 5G systems has also been provided. This consolidated view is further supported in this document by the presentation of the impact of MPTAs on METIS scenarios and the addressed METIS goals.Aziz, D.; Baracca, P.; De Carvalho, E.; Fantini, R.; Rajatheva, N.; Popovski, P.; Sørensen, JH.... (2015). D 3. 3 Final performance results and consolidated view on the most promising multi -node/multi -antenna transmission technologies. http://hdl.handle.net/10251/7675

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