G-protein coupled receptors activation mechanism: from ligand binding to the transmission of the signal inside the cell

G-protein coupled receptors (GPCRs) are the largest family of pharmaceutical drug targets in the human genome and are modulated by a large variety of en- dogenous and synthetic ligands. GPCRs activation usually depends on agonist binding (except for receptors with basal activity), which stabilizes receptor con- formations and allow the requirement and activation of intracellular transducers. GPCRs are unique receptors and very well studied, since they play an important role in a great number of diseases. They interact with different type of ligands (such as light, peptides, proteins) and different partners in the intracellular part (such as G-proteins or β-arrestins). Based on homology and function GPCRs are divided in five classes: Class A or Rhodopsin, Class B1 or Secretin, Class B2 or Adhesion, Class C or Glutamate, Class F or Frizzled. What is still missing in the state of the art of these receptor, and in particular in Class A, is a global study on different binding cavities with divergent properties, with the aim to discover common binding characteristics, preserved during years of evolution. Gaining more knowledge on common features for ligand recognition shared among all the recep- tors may become crucial to deeply understand the mechanism used to transmit the signal into the cell. In the first step of this thesis we have used all the solved Class A receptors structures to analyze and find, if exist, a common way to transmit the signal inside the cell. We identified and validated ten positions shared between all the binding cavities and always involved in the interaction with ligands. We demonstrated that residues in these positions are conserved and have co-evolved together. In a second step, we used these positions to understand how ligands could be positioned in the binding cavities of three study cases: Muscarinic receptors, Kisspeptin receptors and the GPR3 receptor. We did not have any experimental information a priori. We used homology modeling and docking techniques for the first two cases, adding molecular dynamics simulations in the third case. All the predictions and suggestions from the computational point of view, turned out to be very successful. In particular for the GPR3 receptor we were able to identify and validate by alanine-scanning mutagenesis the role of three functionally relevant residues. The latter were correlated with the constitutive and agonist-stimulated adenylate cyclase activity of GPR3 receptor. Taken together, these results suggest an important role of computational structural biology and pave the way of strong collaborations between computational and experimental researches

FPGA-based range-limited molecular dynamics acceleration

Molecular Dynamics (MD) is a computer simulation technique that executes iteratively over discrete, infinitesimal time intervals. It has been a widely utilized application in the fields of material sciences and computer-aided drug design for many years, serving as a crucial benchmark in high-performance computing (HPC). Numerous MD packages have been developed and effectively accelerated using GPUs. However, as the limits of Moore's Law are reached, the performance of an individual computing node has reached its bottleneck, while the performance of multiple nodes is primarily hindered by scalability issues, particularly when dealing with small datasets. In this thesis, the acceleration with respect to small datasets is the main focus. With the recent COVID-19 pandemic, drug discovery has gained significant attention, and Molecular Dynamics (MD) has emerged as a crucial tool in this process. Particularly, in the critical domain of drug discovery, small simulations involving approximately ~50K particles are frequently employed. However, it is important to note that small simulations do not necessarily translate to faster results, as long-term simulations comprising billions of MD iterations and more are essential in this context. In addition to dataset size, the problem of interest is further constrained. Referred to as the most computationally demanding aspect of MD, the evaluation of range-limited (RL) forces not only accounts for 90% of the MD computation workload but also involves irregular mapping patterns of 3-D data onto 2-D processor networks. To emphasize, this thesis centers around the acceleration of RL MD specifically for small datasets. In order to address the single-node bottleneck and multi-node scaling challenges, the thesis is organized into two progressive stages of investigation. The first stage delves extensively into enhancing single-node efficiency by examining various factors such as workload mapping from 3-D to 2-D, data routing, and data locality. The second stage focuses on studying multi-node scalability, with a particular emphasis on strong scaling, bandwidth demands, and the synchronization mechanisms between nodes. Through our study, the results show our design on a Xilinx U280 FPGA achieves 51.72x and 4.17x speedups with respect to an Intel Xeon Gold 6226R CPU, and a Quadro RTX 8000 GPU. Our research towards strong scaling also demonstrates that 8 Xilinx U280 FPGAs connected to a switch achieves 4.67x speedup compared to an Nvidia V100 GP

Enabling Parallel Wireless Communication in Mobile Robot Teams

Wireless inter-robot communication enables robot teams to cooperatively solve complex problems that cannot be addressed by a single robot. Applications for cooperative robot teams include search and rescue, exploration and surveillance. Communication is one of the most important components in future autonomous robot systems and is essential for core functions such as inter-robot coordination, neighbour discovery and cooperative control algorithms. In environments where communication infrastructure does not exist, decentralised multi-hop networks can be constructed using only the radios on-board each robot. These are known as wireless mesh networks (WMNs). However existing WMNs have limited capacity to support even small robot teams. There is a need for WMNs where links act like dedicated point-to-point connections such as in wired networks. Addressing this problem requires a fundamentally new approach to WMN construction and this thesis is the first comprehensive study in the multi-robot literature to address these challenges. In this thesis, we propose a new class of communication systems called zero mutual interference (ZMI) networks that are able to emulate the point-to-point properties of a wired network over a WMN implementation. We instantiate the ZMI network using a multi-radio multi-channel architecture that autonomously adapts its topology and channel allocations such that all network edges communicate at the full capacity of the radio hardware. We implement the ZMI network on a 100-radio testbed with up to 20-individual nodes and verify its theoretical properties. Mobile robot experiments also demonstrate these properties are practically achievable. The results are an encouraging indication that the ZMI network approach can facilitate the communication demands of large cooperative robot teams deployed in practical problems such as data pipe-lining, decentralised optimisation, decentralised data fusion and sensor networks

High Performance Large Graph Analytics by Enhancing Locality

Graphs are widely used in a variety of domains for representing entities and their relationship to each other. Graph analytics helps to understand, detect, extract and visualize insightful relationships between different entities. Graph analytics has a wide range of applications in various domains including computational biology, commerce, intelligence, health care and transportation. The breadth of problems that require large graph analytics is growing rapidly resulting in a need for fast and efficient graph processing. One of the major challenges in graph processing is poor locality of reference. Locality of reference refers to the phenomenon of frequently accessing the same memory location or adjacent memory locations. Applications with poor data locality reduce the effectiveness of the cache memory. They result in large number of cache misses, requiring access to high latency main memory. Therefore, it is essential to have good locality for good performance. Most graph processing applications have highly random memory access patterns. Coupled with the current large sizes of the graphs, they result in poor cache utilization. Additionally, the computation to data access ratio in many graph processing applications is very low, making it difficult to cover the memory latency using computation. It is also challenging to efficiently parallelize most graph applications. Many graphs in real world have unbalanced degree distribution. It is difficult to achieve a balanced workload for such graphs. The parallelism in graph applications is generally fine-grained in nature. This calls for efficient synchronization and communication between the processing units. Techniques for enhancing locality have been well studied in the context of regular applications like linear algebra. Those techniques are in most cases not applicable to the graph problems. In this dissertation, we propose two techniques for enhancing locality in graph algorithms: access transformation and task-set reduction. Access transformation can be applied to algorithms to improve the spatial locality by changing the random access pattern to sequential access. It is applicable to iterative algorithms that process random vertices/edges in each iteration. The task-set reduction technique can be applied to enhance the temporal locality. It is applicable to algorithms which repeatedly access the same data to perform certain task. Using the two techniques, we propose novel algorithms for three graph problems: k-core decomposition, maximal clique enumeration and triangle listing. We have implemented the algorithms. The results show that these algorithms provide significant improvement in performance and also scale well

Supercomputing Frontiers

This open access book constitutes the refereed proceedings of the 6th Asian Supercomputing Conference, SCFA 2020, which was planned to be held in February 2020, but unfortunately, the physical conference was cancelled due to the COVID-19 pandemic. The 8 full papers presented in this book were carefully reviewed and selected from 22 submissions. They cover a range of topics including file systems, memory hierarchy, HPC cloud platform, container image configuration workflow, large-scale applications, and scheduling

An improved MultiAnts-Aodv routing protocol for ad hoc wireless networks

Compared to the conventional table-driven and on-demand routing protocols, a hybrid routing protocol [71], which uses mobile agents and reactive route discovery, introduced a more realistic solution to this problem. However, the mobile agents were not fully exploited in this protocol. In this thesis research, we will propose an improved MultiAnts-AODV routing protocol based on ant-AODV The goal of our design is to reduce the end-to-end delay and route discovery latency. To achieve a better performance, the communication scheme among the agents is strengthened. We also present an improved navigation algorithm for mobile agents to update the routing tables more efficiently. We extend the routing table to reduce the latency of routing discovery in case of link failures. The simulation based comparisons among several navigation algorithms are also presented

Towards a Framework for DHT Distributed Computing

Distributed Hash Tables (DHTs) are protocols and frameworks used by peer-to-peer (P2P) systems. They are used as the organizational backbone for many P2P file-sharing systems due to their scalability, fault-tolerance, and load-balancing properties. These same properties are highly desirable in a distributed computing environment, especially one that wants to use heterogeneous components. We show that DHTs can be used not only as the framework to build a P2P file-sharing service, but as a P2P distributed computing platform. We propose creating a P2P distributed computing framework using distributed hash tables, based on our prototype system ChordReduce. This framework would make it simple and efficient for developers to create their own distributed computing applications. Unlike Hadoop and similar MapReduce frameworks, our framework can be used both in both the context of a datacenter or as part of a P2P computing platform. This opens up new possibilities for building platforms to distributed computing problems. One advantage our system will have is an autonomous load-balancing mechanism. Nodes will be able to independently acquire work from other nodes in the network, rather than sitting idle. More powerful nodes in the network will be able use the mechanism to acquire more work, exploiting the heterogeneity of the network. By utilizing the load-balancing algorithm, a datacenter could easily leverage additional P2P resources at runtime on an as needed basis. Our framework will allow MapReduce-like or distributed machine learning platforms to be easily deployed in a greater variety of contexts

Current Perspectives on Viral Disease Outbreaks

The COVID-19 pandemic has reminded the world that infectious diseases are still important. The last 40 years have experienced the emergence of new or resurging viral diseases such as AIDS, ebola, MERS, SARS, Zika, and others. These diseases display diverse epidemiologies ranging from sexual transmission to vector-borne transmission (or both, in the case of Zika). This book provides an overview of recent developments in the detection, monitoring, treatment, and control of several viral diseases that have caused recent epidemics or pandemics