Graph database management systems: storage, management and query processing

The proliferation of graph data, generated from diverse sources, have given rise to many research efforts concerning graph analysis. Interactions in social networks, publication networks, protein networks, software code dependencies and transportation systems are all examples of graph-structured data originating from a variety of application domains and demonstrating different characteristics. In recent years, graph database management systems (GDBMS) have been introduced for the management and analysis of graph data. Motivated by the growing number of real-life applications making use of graph database systems, this thesis focuses on the effectiveness and efficiency aspects of such systems. Specifically, we study the following topics relevant to graph database systems: (i) modeling large-scale applications in GDBMS; (ii) storage and indexing issues in GDBMS, and (iii) efficient query processing in GDBMS. In this thesis, we adopt two different application scenarios to examine how graph database systems can model complex features and perform relevant queries on each of them. Motivated by the popular application of social network analytics, we selected Twitter, a microblogging platform, to conduct our detailed analysis. Addressing limitations of existing models, we pro- pose a data model for the Twittersphere that proactively captures Twitter-specific interactions. We examine the feasibility of running analytical queries on GDBMS and offer empirical analysis of the performance of the proposed approach. Next, we consider a use case of modeling software code dependencies in a graph database system, and investigate how these systems can support capturing the evolution of a codebase overtime. We study a code comprehension tool that extracts software dependencies and stores them in a graph database. On a versioned graph built using a very large codebase, we demonstrate how existing code comprehension queries can be efficiently processed and also show the benefit of running queries across multiple versions. Another important aspect of this thesis is the study of storage aspects of graph systems. Throughput of many graph queries can be significantly affected by disk I/O performance; therefore graph database systems need to focus on effective graph storage for optimising disk operations. We observe that the locality of edges plays an important role and we address the edge-labeling problem which aims to label both incoming and outgoing edges of a graph maximizing the ‘edge-consecutiveness’ metric. By achieving a better layout and locality of edges on disk, we show that our proposed algorithms result in significantly improved disk I/O performance leading to faster execution of neighbourhood queries. Some applications require the integrated processing of queries from graph and the textual domains within a graph database system. Aggregation of these dimensions facilitates gaining key insights in several application scenarios. For example, in a social network setting, one may want to find the closest k users in the network (graph traversal) who talk about a particular topic A (textual search). Motivated by such practical use cases, in this thesis we study the top-k social-textual ranking query that essentially requires efficient combination of a keyword search query with a graph traversal. We propose algorithms that leverage graph partitioning techniques, based on the premise that socially close users will be placed within the same partition, allowing more localised computations. We show that our proposed approaches are able to achieve significantly better results compared to standard baselines and demonstrating robust behaviour under changing parameters

The HIV-1 protective-35SNP effect in Caucasians is CD8 T cell mediated

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High-Entropy Metal–Organic Frameworks for Highly Reversible Sodium Storage

Prussian blue analogues (PBAs) are reported to be efficient sodium storage materials because of the unique advantages of their metal–organic framework structure. However, the issues of low specific capacity and poor reversibility, caused by phase transitions during charge/discharge cycling, have thus far limited the applicability of these materials. Herein, a new approach is presented to substantially improve the electrochemical properties of PBAs by introducing high entropy into the crystal structure. To achieve this, five different metal species are introduced, sharing the same nitrogen-coordinated site, thereby increasing the configurational entropy of the system beyond 1.5R. By careful selection of the elements, high-entropy PBA (HE-PBA) presents a quasi-zero-strain reaction mechanism, resulting in increased cycling stability and rate capability. The key to such improvement lies in the high entropy and associated effects as well as the presence of several active redox centers. The gassing behavior of PBAs is also reported. Evolution of dimeric cyanogen due to oxidation of the cyanide ligands is detected, which can be attributed to the structural degradation of HE-PBA during battery operation. By optimizing the electrochemical window, a Coulombic efficiency of nearly 100% is retained after cycling for more than 3000 cycles

An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposi’s sarcoma under ART

HIV-associated Kaposi’s sarcoma (KS), which is caused by Kaposi’s sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally occurs in individuals with durable HIV viral suppression and CD4 T cell recovery under antiretroviral therapy (ART). The underlying mechanisms associated with this phenomenon are unclear. Suppression of viral infections can be mediated by CD8 T cells, which detect infected cells via their T cell receptor and the CD8 coreceptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 (“CD8dim T cells”) was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial alterations (PGC-1α, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS disease under ART. CD8 coreceptor down-modulation may be symptomatic of ongoing disease

Recombination-mediated escape from primary CD8+ T cells in acute HIV-1 infection

Abstract Background A major immune evasion mechanism of HIV-1 is the accumulation of non-synonymous mutations in and around T cell epitopes, resulting in loss of T cell recognition and virus escape. Results Here we analyze primary CD8+ T cell responses and virus escape in a HLA B*81 expressing subject who was infected with two T/F viruses from a single donor. In addition to classic escape through non-synonymous mutation/s, we also observed rapid selection of multiple recombinant viruses that conferred escape from T cells specific for two epitopes in Nef. Conclusions Our study shows that recombination between multiple T/F viruses provide greater options for acute escape from CD8+ T cell responses than seen in cases of single T/F virus infection. This process may contribute to the rapid disease progression in patients infected by multiple T/F viruses

Prevalence and occurrence of zoonotic bacterial pathogens in surface waters determined by quantitative PCR

The prevalence and concentrations of Campylobacter jejuni, Salmonella spp. and enterohaemorrhagic E. coli (EHEC) were investigated in surface waters in Brisbane, Australia using quantitative PCR (qPCR) based methodologies. Water samples were collected from Brisbane City Botanic Gardens (CBG) Pond, and two urban tidal creeks (i.e., Oxley Creek and Blunder Creek). Of the 32 water samples collected, 8 (25%), 1 (3%), 9 (28%), 14 (44%), and 15 (47%) were positive for C. jejuni mapA, Salmonella invA, EHEC O157 LPS, EHEC VT1, and EHEC VT2 genes, respectively. The presence/absence of the potential pathogens did not correlate with either E. coli or enterococci concentrations as determined by binary logistic regression. In conclusion, the high prevalence, and concentrations of potential zoonotic pathogens along with the concentrations of one or more fecal indicators in surface water samples indicate a poor level of microbial quality of surface water, and could represent a significant health risk to users. The results from the current study would provide valuable information to the water quality managers in terms of minimizing the risk from pathogens in surface waters

De novo mutations in EIF2B1 affecting eIF2 signaling cause neonatal/early onset diabetes and transient hepatic dysfunction

Permanent neonatal diabetes is caused by reduced β-cell number or impaired β-cell function. Understanding the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 permanent neonatal diabetes patients and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified 2 further patients with de novo EIF2B1 variants. In addition to diabetes, 4/5 patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation which occurs under stress conditions and triggers expression of stress-response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway.Includes NIHR and Wellcome Trust. Wellcome Trust 200848/Z/16/

Proteome-wide analysis of HIV-specific naive and memory CD4+ T cells in unexposed blood donors

The preexisting HIV-1–specific T cell repertoire must influence both the immunodominance of T cells after infection and immunogenicity of vaccines. We directly compared two methods for measuring the preexisting CD4+ T cell repertoire in healthy HIV-1–negative volunteers, the HLA-peptide tetramer enrichment and T cell library technique, and show high concordance (r = 0.989). Using the library technique, we examined whether naive, central memory, and/or effector memory CD4+ T cells specific for overlapping peptides spanning the entire HIV-1 proteome were detectable in 10 HLA diverse, HIV-1– unexposed, seronegative donors. HIV-1–specific cells were detected in all donors at a mean of 55 cells/million naive cells and 38.9 and 34.1 cells/million in central and effector memory subsets. Remarkably, peptide mapping showed most epitopes recognized by naive (88%) and memory (56%) CD4+ T cells had been previously reported in natural HIV-1 infection. Furthermore, 83% of epitopes identified in preexisting memory subsets shared epitope length matches (8–12 amino acids) with human microbiome proteins, suggestive of a possible cross-reactive mechanism. These results underline the power of a proteome-wide analysis of peptide recognition by human T cells for the identification of dominant antigens and provide a baseline for optimizing HIV-1–specific helper cell responses by vaccination

A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies

Background: Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral ftness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in ftness losses. Results: Strongly selected mutations were identifed by analyzing 5′-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131. The K43R mutation in the gag gene was frst detected at day 91 post screening and was fxed in the viral population at day 273 while the synonymous N323tc mutation was frst detected at day 177 and fxed at day 670. No conventional or cryptic T cell responses were detected against either mutation sites by ELISpot analysis. However, when ftness costs of both mutations were measured by introducing each mutation into their cognate transmitted/founder (T/F) viral genome, the K43R mutation caused a signifcant ftness loss while the N323tc mutation had little impact on viral ftness. Conclusions: The rapid fxation, the lack of detectable immune responses and the signifcant ftness cost of the K43R mutation suggests that it was strongly selected by host factors other than T cell responses and neutralizing antibodie