Distinguishing Attack and Second-Preimage Attack on the CBC-like MACs

In this paper, we first present a new distinguisher on the CBC-MAC based on a block cipher in Cipher Block Chaining (CBC) mode. It can also be used to distinguish other CBC-like MACs from random functions. The main results of this paper are on the second-preimage attack on CBC-MAC and CBC-like MACs include TMAC, OMAC, CMAC, PC-MAC and MACs based on three-key encipher CBC mode. Instead of exhaustive search, this attack can be performed with the birthday attack complexity

Key Hub and Bottleneck Genes Differentiate the Macrophage Response to Virulent and Attenuated Mycobacterium bovis

Mycobacterium bovis is an intracellular pathogen that causes tuberculosis in cattle. Following infection, the pathogen resides and persists inside host macrophages by subverting host immune responses via a diverse range of mechanisms. Here, a high-density bovine microarray platform was used to examine the bovine monocyte-derived macrophage transcriptome response to M. bovis infection relative to infection with the attenuated vaccine strain, M. bovis Bacille Calmette–Guérin. Differentially expressed genes were identified (adjusted P-value ≤0.01) and interaction networks generated across an infection time course of 2, 6, and 24 h. The largest number of biological interactions was observed in the 24-h network, which exhibited scale-free network properties. The 24-h network featured a small number of key hub and bottleneck gene nodes, including IKBKE, MYC, NFKB1, and EGR1 that differentiated the macrophage response to virulent and attenuated M. bovis strains, possibly via the modulation of host cell death mechanisms. These hub and bottleneck genes represent possible targets for immuno-modulation of host macrophages by virulent mycobacterial species that enable their survival within a hostile environment

Elastic-Tweak: A Framework for Short Tweak Tweakable Block Cipher

Tweakable block cipher (TBC), a stronger notion than standard block ciphers, has wide-scale applications in symmetric-key schemes. At a high level, it provides flexibility in design and (possibly) better security bounds. In multi-keyed applications, a TBC with short tweak values can be used to replace multiple keys. However, the existing TBC construction frameworks, including TWEAKEY and XEX, are designed for general purpose tweak sizes. Specifically, they are not optimized for short tweaks, which might render them inefficient for certain resource constrained applications. So a dedicated paradigm to construct short-tweak TBCs (tBC) is highly desirable. In this paper, we present a dedicated framework, called the Elastic-Tweak framework (ET in short), to convert any reasonably secure SPN block cipher into a secure tBC. We apply the ET framework on GIFT and AES to construct efficient tBCs, named TweGIFT and TweAES. We present hardware and software results to show that the performance overheads for these tBCs are minimal. We perform comprehensive security analysis and observe that TweGIFT and TweAES provide sufficient security without any increase in the number of block cipher rounds when compared to GIFT and AES. We also show some concrete applications of ET-based tBCs, which are better than their block cipher counterparts in terms of key size, state size, number of block cipher calls, and short message processing. Some notable applications include, Twe-FCBC (reduces the key size of FCBC and gives better security than CMAC), Twe-LightMAC Plus (better rate than LightMAC Plus), Twe-CLOC, and Twe-SILC (reduces the number of block cipher calls and simplifies the design of CLOC and SILC)

Stadium: A Distributed Metadata-Private Messaging System

Private communication over the Internet remains a challenging problem. Even if messages are encrypted, it is hard to deliver them without revealing metadata about which pairs of users are communicating. Scalable anonymity systems, such as Tor, are susceptible to traffic analysis attacks that leak metadata. In contrast, the largest-scale systems with metadata privacy require passing all messages through a small number of providers, requiring a high operational cost for each provider and limiting their deployability in practice. This paper presents Stadium, a point-to-point messaging system that provides metadata and data privacy while scaling its work efficiently across hundreds of low-cost providers operated by different organizations. Much like Vuvuzela, the current largest-scale metadata-private system, Stadium achieves its provable guarantees through differential privacy and the addition of noisy cover traffic. The key challenge in Stadium is limiting the information revealed from the many observable traffic links of a highly distributed system, without requiring an overwhelming amount of noise. To solve this challenge, Stadium introduces techniques for distributed noise generation and differentially private routing as well as a verifiable parallel mixnet design where the servers collaboratively check that others follow the protocol. We show that Stadium can scale to support 4X more users than Vuvuzela using servers that cost an order of magnitude less to operate than Vuvuzela nodes

The Identification of Genetic and Epigenetic Changes that Contribute to Type 1 Diabetes

Type 1 diabetes (T1D) results from an immune cell mediated destruction of insulin-producing pancreatic β cells. Currently there is no cure for T1D. The exact cause for T1D is unknown but growing evidence points to the contribution of both genetic and environmental factors, leading to a breakdown in immunological tolerance normally maintained by Regulatory T (Treg) cells. The exact environmental contributions to T1D progression are not well characterised but emerging studies suggest that they may alter the immune system via epigenetic modification. Recent data strongly link the breakdown in tolerance in T1D and other autoimmune diseases to alterations in the transcriptional program in CD4+ T cells, however, the molecular mechanisms are not well understood. This work proposes that in T1D causal genetic risk SNPs alter the gene expression patterns in CD4+ Treg and or T helper cells by either disrupting or creating new TF (transcription factor) binding sites in regulatory elements (enhancers) located in genetic susceptibility regions and this may combine with environmentally induced epigenetic change and alter chromatin accessibility. Current methods to identify the functional consequences and mechanisms of these changes are complex, time consuming and expensive as generally they can only examine one TF/binding site at a time, involve TF binding site prediction, which has a high degree of false positives/negatives and require large quantities of starting material making them challenging for application on limited clinical samples. To overcome these limitations, and to functionally annotate genetic risk of T1D, this study employs genome wide approaches including ATAC-seq and RNA-seq to compare the DNA accessibility and transcriptomes in CD4+ Treg and Th (Helper T)/Tconv (Conventional T) cells isolated from individuals with established T1D and sibling-matched healthy controls. By incorporating case-control ATAC-seq and TF footprints this study prioritises 111 and 96 T1D-associated SNPs in Treg and Tconv cells, respectively, that may play a role in mediating the disease susceptibility and subsequently contributing to the loss of tolerance in T1D. Using a bioinformatic pipeline to integrate case-control ATAC-seq differentially accessible peaks and RNA-seq differentially expressed genes with Hi-C 3D connectivity maps this study identifies 42 and 21 dysregulated gene targets in Treg and Tconv cells, respectively. Those targets include TIGIT, MAF and IL2 and the enhancers regulating those loci showed differential accessibility and are enriched for T1D SNPs and differential TF footprint signals. One theory to explain such observation is T1D SNPs and epigenetic alterations may alter or disrupt TF occupancy at these loci contributing to dysregulated target gene regulation. This study identifies changes in chromatin structure in T1D samples relative to healthy controls, enabling the identification of changes driven by both genetic and epigenetic variation that correlates with an altered transcriptional program in T1D. T1D associated SNPs at these regions can then be correlated with alterations in TF binding and putative epigenetically modified T1D regions can be validated in follow-up functional assays to demonstrate causality. This study captures chromatin and transcriptional changes between T1D and healthy individuals but it does not have the capability to distinguish if the changes are the driver or the consequence of the disease because the case cohort contains only established T1D from a single time point. In order to infer causality those changes would need to be tracked and validated over a timeline of disease progression in a longitudinal cohort. Nonetheless, this work provides a novel 3D genomic approach to functionally annotating the genetic risk and epigenetic changes that directly or indirectly result in altered gene expression, and promising preliminary data warranting further investigation on the causal functional role of the dysregulated gene targets in T1D.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 202

A Novel Role for ZEB2 as a Lineage Fidelity Checkpoint in Human Cd4+ T Cells

Autoimmune diseases are a broad range of more than eighty related disorders, affecting up to 5% of the population. The incidence of autoimmune disease is increasing worldwide. It is a disease where the body's immune system fails to recognize its own cells and tissues as “self”. Instead, immune cells attack these healthy cells and tissues as if they were foreign or invading pathogens. One of the key immune cell populations implicated in this immune attack is CD4+ T cells. The CD4+ T cell lineage consists of a number of phenotypically and functionally distinct subsets. In particular there are two functionally distinct compartments in CD4, namely T regulatory cells (Treg) and T conventional cells (Tconv), and the function of each is potentially altered in autoimmune disease. My PhD project has investigated the role of a transcription factor, ZEB2 in shaping the function of human CD4+ T cells. Little is known about the role of ZEB2 in CD4+ T cells and therefore elucidating its role in CD4+ T cells and identifying the transcriptional landscape controlled by ZEB2 has the potential to highlight novel targets for autoimmune disease diagnosis and therapy. ZEB2 is a zinc-finger transcription factor known to play a major role in early embryogenesis and in tumour metastasis. ZEB2 has an established role in the cancer metastasis of several cancers but its role in the immune system has only fairly recently been explored. Interestingly, ZEB2, is directly induced by T-bet (T helper 1 master transcription factor) in mouse NK cells and CD8+ T cells, and therefore I speculated that T-bet may be implicated in the regulation of ZEB2 in CD4+ T cells where T-bet is the defining transcription factor for Th1 cells. My PhD project identifies which CD4+ T cell subsets ZEB2 is expressed in. I show that ZEB2 is expressed highly in Tconv effector memory subsets, indicating its role in the effector compartment of CD4+ T cells. Further investigation indicated that ZEB2 was found predominantly in Th1 effector memory (EM) cells. ZEB2 was expressed at very low levels in the other Tconv helper lineages, suggesting a unique effector role of ZEB2 in Th1 where T-bet is highly expressed and FOXP3 is absent. However, the regulation of ZEB2 is clearly more complex, since in some CD4+ T cell subsets with high T-bet, for instance Th1/17, there is not necessarily high ZEB2, suggesting ZEB2 is not regulated by T-bet alone. In order to specifically define the role of ZEB2 in Th1 EM cells, I deleted ZEB2 and analysed global changes in gene expression by RNA-seq. RNA-seq analysis showed that 222 genes were differentially expressed between WT and ZEB2-deleted Th1 EM, and pathway analysis of the gene profile indicates a potential role for ZEB2 in regulating inflammatory cytokines, repressing cytotoxic responses, enhancing motility and increasing survival in high stress environments. ZEB2 is also shown to regulate effector memory and central memory genes important for Th1 effector memory differentiation. Hence, ZEB2 is important in maintaining the function and fidelity of a Th1 effector memory cell in the steady state, and indirectly or directly maintaining IFNγ expression. Th1 cells preferentially produce IFNγ and IL-2 and are the principal regulators of type 1 immunity (Th1 response), which eradicates intracellular pathogens including viruses. Unravelling the role of ZEB2 in the complex relationships between the Th1 and Treg lineages and subsets may provide critical insight into the disruption of immune homeostasis that leads to autoimmune disease including inflammatory bowel disease (IBD), and may suggest novel therapeutic targets for autoimmune diseases.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 202

Reference Transcriptomes of Porcine Peripheral Immune Cells Created Through Bulk and Single-Cell RNA Sequencing

Pigs are a valuable human biomedical model and an important protein source supporting global food security. The transcriptomes of peripheral blood immune cells in pigs were defined at the bulk cell-type and single cell levels. First, eight cell types were isolated in bulk from peripheral blood mononuclear cells (PBMCs) by cell sorting, representing Myeloid, NK cells and specific populations of T and B-cells. Transcriptomes for each bulk population of cells were generated by RNA-seq with 10,974 expressed genes detected. Pairwise comparisons between cell types revealed specific expression, while enrichment analysis identified 1,885 to 3,591 significantly enriched genes across all 8 cell types. Gene Ontology analysis for the top 25% of significantly enriched genes (SEG) showed high enrichment of biological processes related to the nature of each cell type. Comparison of gene expression indicated highly significant correlations between pig cells and corresponding human PBMC bulk RNA-seq data available in Haemopedia. Second, higher resolution of distinct cell populations was obtained by single-cell RNA-sequencing (scRNA-seq) of PBMC. Seven PBMC samples were partitioned and sequenced that produced 28,810 single cell transcriptomes distributed across 36 clusters and classified into 13 general cell types including plasmacytoid dendritic cells (DC), conventional DCs, monocytes, B-cell, conventional CD4 and CD8 αβ T-cells, NK cells, and γδ T-cells. Signature gene sets from the human Haemopedia data were assessed for relative enrichment in genes expressed in pig cells and integration of pig scRNA-seq with a public human scRNA-seq dataset provided further validation for similarity between human and pig data. The sorted porcine bulk RNAseq dataset informed classification of scRNA-seq PBMC populations; specifically, an integration of the datasets showed that the pig bulk RNAseq data helped define the CD4CD8 double-positive T-cell populations in the scRNA-seq data. Overall, the data provides deep and well-validated transcriptomic data from sorted PBMC populations and the first single-cell transcriptomic data for porcine PBMCs. This resource will be invaluable for annotation of pig genes controlling immunogenetic traits as part of the porcine Functional Annotation of Animal Genomes (FAANG) project, as well as further study of, and development of new reagents for, porcine immunology