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Familial Mediterranean Fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent and short attacks of fever with serosal inflammation that are caused by mutations in MEFV gene that encodes pyrin protein. To date, more than 70 disease-associated mutations have been identified, almost all of them representing missense nucleotide changes. FMF is very common among patients with Mediterranean ancestry, although the exact prevalence is not yet known, Greeks are considered to be at 'intermediate risk'. In the present study, we studied FMF patients in natives of Crete, a population sharing a common genetic and cultural background. The spectrum of MEFV gene mutations in 71 patients as well as 158 healthy controls was studied by performing a molecular analysis focused on the 12 most frequent FMF-associated mutations. We found that 59 of 71 (83.1%) FMF patients had at least one MEFV mutation, five patients were homozygotes and 54 heterozygotes for FMF-associated mutations. No mutations were detected in 12 patients (16.9%). As in high-risk populations, common MEFV mutations were found in Cretan FMF patients, with the M694V being the most penetrant. M694V and M694I mutations were associated with severe phenotypes, with many patients presenting with uncommon clinical manifestations such as erysipelas-like erythema or renal disturbances. Of interest, 20 (37%) of our heterozygous FMF patients presented with a severe phenotype. Population genetics analysis showed an FMF carrier frequency in healthy Cretan population of approximately 6% (1:17) and places Cretans closer to the Western rather than Eastern populations of the Mediterranean basin. Finally, we constructed a three-dimensional model showing the interaction of the PRYSPRY domain of pyrin with caspase-1 onto which we mapped MEFV mutations, classified according to disease severity. In this model, the 'flexible loops' of caspase-1 appear to have no access to some positions that have been previously associated with mild disease, suggesting that alternative pathogenic pathways leading to FMF need to be explored.

The realisation that the production of inflammatory cytokines in inflammatory rheumatic diseases may be induced by non-infectious endogenous signals has encouraged researchers to explore mechanisms of innate immunity and their contribution to the pathogenesis of these diseases. The nucleotide-binding and oligomerisation domain (NOD)-like receptors (NLRs) sense pathogens, products of damaged cells or endogenous metabolites and could potentially be involved in the initiation, amplification and progression of the inflammatory response in rheumatic diseases. NLRs are involved in the regulation of innate immune responses with some of them promoting the activation of inflammatory caspases within multiprotein complexes, called inflammasomes. A typical inflammasome consists of a sensor, an NLR protein, an adaptor protein such as ASC (for apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) and an effector protein that is a caspase that activates pro-inflammatory cytokines such as interleukin (IL)1beta and IL18. Recent data suggest a role of the inflammasome in the pathogenesis of autoinflammatory as well as inflammatory rheumatic diseases such as juvenile chronic arthritis, adult onset Still disease, rheumatoid arthritis and gout. Modulation of these pathways may be a potential therapeutic target for inflammatory rheumatic diseases.

This paper considers two emerging interdisciplinary, but related topics that are likely to create tipping points in advancing the engineering and science areas. Trusted Autonomy (TA) is a field of research that focuses on understanding and designing the interaction space between two entities each of which exhibits a level of autonomy. These entities can be humans, machines, or a mix of the two. Cognitive Cyber Symbiosis (CoCyS) is a cloud that uses humans and machines for decision-making. In CoCyS, human-machine teams are viewed as a network with each node comprising humans (as computational machines) or computers. CoCyS focuses on the architecture and interface of a Trusted Autonomous System. This paper examines these two concepts and seeks to remove ambiguity by introducing formal definitions for these concepts. It then discusses open challenges for TA and CoCyS, that is, whether a team made of humans and machines can work in fluid, seamless harmony.

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Great database systems performance relies heavily on index tuning, i.e., creating and utilizing the best indices depending on the workload. However, the complexity of the index tuning process has dramatically increased in recent years due to ad-hoc workloads and shortage of time and system resources to invest in tuning.This paper introduces holistic indexing, a new approach to automated index tuning in dynamic environments. Holistic indexing requires zero set-up and tuning effort, relying on adaptive index creation as a side-effect of query processing. Indices are created incrementally and partially; they are continuously refined as we process more and more queries. Holistic indexing takes the stateof-the-art adaptive indexing ideas a big step further by introducing the notion of a system which never stops refining the index space, taking educated decisions about which index we should incrementally refine next based on continuous knowledge acquisition about the running workload and resource utilization. When the system detects idle CPU cycles, it utilizes those extra cycles by refining the adaptive indices which are most likely to bring a benefit for future queries. Such idle CPU cycles occur when the system cannot exploit all available cores up to 100%, i.e., either because the workload is not enough to saturate the CPUs or because the current tasks performed for query processing are not easy to parallelize to the point where all available CPU power is exploited.In this paper, we present the design of holistic indexing for columnoriented database architectures and we discuss a detailed analysis against parallel versions of state-of-the-art indexing and adaptive indexing approaches. Holistic indexing is implemented in an opensource column-store DBMS. Our detailed experiments on both synthetic and standard benchmarks (TPC-H) and workloads (SkyServer) demonstrate that holistic indexing brings significant performance gains by being able to continuously refine the physical design in parallel to query processing, exploiting any idle CPU resources.