Nuno C. Santos

Vector-field consistency for ad-hoc gaming

Developing distributed multiplayer games for ad-hoc networks is challenging. Consistency of the replicated shared state is hard to ensure at a low cost. Current consistency models and middleware systems lack the required adaptability and efficiency when applied to ad-hoc gaming. Hence, developing such robust applications is still a daunting task. We propose i) Vector-Field Consistency (VFC), a new consistency model, and ii) the Mobihoc middleware to ease the programming effort of these games, while ensuring the consistency of replicated objects. VFC unifies i) several forms of consistency enforcement and a multi-dimensional criteria (time, sequence and value) to limit replica divergence, with ii) techniques based on locality-awareness (w.r.t. players position). Mobihoc adopts VFC and provides game programmers the abstractions to manage game state easily and efficiently. A Mobihoc prototype and a demonstrating game were developed and evaluated. The results obtained are very encouraging.

Peptide Drug Discovery and Development: Translational Research in Academia and Industry

The potential of peptides as drugs has been widely recognized in pharmaceutical industry and in academic communities. The WileyVCH book series has drawn special attention to this fact in the past years with at least seven volumes covering topics concerned with peptide and protein design as pharmaceutical agents, their delivery technologies and safety aspects. A new volume in this series has been dedicated to the translational implications and describes a wide spectrum of preclinical and clinical challenges. It covers many crucial questions starting with the technological basis of design and delivery of peptide drugs, gives multiple examples for lessons to be learned from viral protease inhibitors, antimicrobial peptides, human immunodeficiency virus (HIV)-derived peptides as viral fusion inhibitors and peptides useful as therapeutics in metabolic diseases or as immune modulators. A most useful and illuminating first chapter on peptides as leads for drug discovery describes the tedious steps and the advanced technology that is being employed to convert a peptide hit into a marketable drug. The development of inhibitors of the human cytomegalovirus (HCMV) and hepatitis C virus (HCV) proteases serve as instructive examples for such strategies. The mapping of essential elements of the peptide hit structure, the structural determination of the bound ligands, the derivation of peptide mimetics and the effects of dynamics and conformational changes provide lessons of general importance for drug design beyond the protease inhibitors detailed in the chapter. Since nature provides important examples of peptides with therapeutic potential, the special emphasis of the book on antimicrobial peptides (AMP) is not surprising. AMPs are antibiotic molecules, and the emergence of resistance to conventional antibiotics and the need to find new drugs with alternative modes of action constitute the basis for the wide attention. The chapters of the book describe in detail the molecular mechanisms employed by AMPs. They interact strongly with cell membranes and are able to translocate into the cytoplasm. In this capacity they have attracted attention as vector and possible drug transporters. AMPs are widely distributed in bacteria, plants, insects, amphibians and mammals and are able to kill pathogenic microorganisms, including bacteria, viruses, protozoa and fungi. Higher organisms express AMPs on epithelial surfaces and thus counteract colonization and infections. AMPs are active at micromolar concentrations and kill bacteria very rapidly. They disrupt bacterial membranes and interfere with metabolic processes. AMPs have also been implied in the pathology of chronic inflammatory and skin diseases, e.g. , atopic dermatitis, psoriasis and cystic fibrosis. This makes them potentially valuable for the treatment, not only of infectious diseases, but also for other indications. Starting with the scaffold structures of amphipathic a-helical and cyclic s-sheet antimicrobial peptides, it is becoming possible to design novel therapeutics and, thus, target multidrug-resistant, Gram-negative pathogens. A second indication in which peptides have played important roles in the progress of therapy is HIV/AIDS. The life cycle of the virus has been elucidated in great detail and several essential steps in this cycle have been described that offer themselves as favorable points of interference. The fusion of the viral envelope with the membrane of target cells serves as an example. Helical peptides have been shown to be able to inhibit this fusion process and thus show potent anti-HIV activity. The complex of the envelope proteins gp120/gp41 of HIV-1 mediates the viral entry. It binds to cellular receptor CD4 and its coreceptor (CCR5 or CXCR4), and initiates the fusion of the viral and cellular membranes. Receptor binding induces structural changes in gp120 and causes gp41 to insert its Nterminal hydrophobic fusion peptide into cell membranes. Viral and cellular membranes come into close contact and fuse. Synthetic peptides derived from the gp41 sequence can bind to the exposed Nor C-terminal heptad repeat (NHR or CHR) of gp41 and efficiently inhibit HIV-1 infection.&&ok?&& These fusion inhibitors are still being improved with respect to their stability and potency, for example, sifuvirtide (SFT). Drugs and their drug targets are fatefully intertwined. A bona fide target has to be amenable to modulation in vivo by an appropriate drug and suitable ligand binding sites depend upon specific physicochemical properties of the protein surface. Most drugs exploit ligand binding sites and act as competitive inhibitors by blocking the binding of a substrate. The expansion of the quality of drug targets and the inclusion of alternative inhibitory mechanisms for innovative drugs, not restricted to the exploitation of pre-existing binding pockets but also targeting protein–protein or protein–DNA interactions, will be a main task for drug designers and developers of the future. This book illustrates many of the technical prerequisites and describes model systems in which these objectives have been at least partially achieved. It convincingly shows that peptide-based drug discovery has become a mainstream activity in the drug discovery and development process.

Unifying divergence bounding and locality awareness in replicated systems with vector-field consistency

Data replication is a very relevant technique for improving performance, availability, and scalability. These are requirements of many applications such as multiplayer distributed games, cooperative software tools, etc. However, consistency of the replicated shared state is hard to ensure. Current consistency models and middleware systems lack the required adaptability and efficiency. Thus, developing such robust applications is still a daunting task.We propose a new consistency model, named Vector-Field Consistency (VFC) that unifies (i) several forms of consistency enforcement and a multidimensional criteria (time, sequence, and value) to limit replica divergence with (ii) techniques based on locality-awareness (w.r.t. players position).Based on the VFC model, we propose a generic meta-architecture that can be easily instantiated both to centralized and (dynamically) partitioned architectures: (i) a single central server in which the VFC algorithm runs or (ii) a set of servers in which each one is responsible for a slice of the data being shared. The first approach is clearly more adapted to ad hoc networks of resource-constrained devices, while the second, being more scalable, is well adapted to large-scale networks. We developed and evaluated two prototypes of VFC (for adxa0hoc and large-scale networks) with very good performance results.