Sca-1+ progenitors derived from embryonic stem cells differentiate into endothelial cells capable of vascular repair after arterial injury

Embryonic stem cells possess the ability to differentiate into endothelium. The ability to produce large volumes of endothelium from embryonic stem cells could provide a potential therapeutic modality for vascular injury. We describe an approach that selects endothelial cells using magnetic beads that may be used therapeutically to treat arterial injury.

Evaluation of Random Delay Insertion against DPA on FPGAs

Side-channel attacks (SCA) threaten electronic cryptographic devices and can be carried out by monitoring the physical characteristics of security circuits. Differential Power Analysis (DPA) is one the most widely studied side-channel attacks. Numerous countermeasure techniques, such as Random Delay Insertion (RDI), have been proposed to reduce the risk of DPA attacks against cryptographic devices. The RDI technique was first proposed for microprocessors but it was shown to be unsuccessful when implemented on smartcards as it was vulnerable to a variant of the DPA attack known as the Sliding-Window DPA attack.Previous research by the authors investigated the use of the RDI countermeasure for Field Programmable Gate Array (FPGA) based cryptographic devices. A split-RDI technique wasproposed to improve the security of the RDI countermeasure. A set of critical parameters wasalso proposed that could be utilized in the design stage to optimize a security algorithm designwith RDI in terms of area, speed and power. The authors also showed that RDI is an efficientcountermeasure technique on FPGA in comparison to other countermeasures.In this article, a new RDI logic design is proposed that can be used to cost-efficiently implementRDI on FPGA devices. Sliding-Window DPA and realignment attacks, which were shown to beeffective against RDI implemented on smartcard devices, are performed on the improved RDIFPGA implementation. We demonstrate that these attacks are unsuccessful and we also proposea realignment technique that can be used to demonstrate the weakness of RDI implementations.

Using simulation to assess cardiac first-responder schemes exhibiting stochastic and spatial complexities

A Monte-Carlo simulation-based model has been constructed to assess a public health scheme involving mobile-volunteer cardiac First-Responders. The scheme being assessed aims to improve survival of Sudden-Cardiac-Arrest (SCA) patients, through reducing the time until administration of life-saving defibrillation treatment, with volunteers being paged to respond to possible SCA incidents alongside the Emergency Medical Services. The need for a model, for example, to assess the impact of the scheme in different geographical regions, was apparent upon collection of observational trial data (given it exhibited stochastic and spatial complexities). The simulation-based model developed has been validated and then used to assess the scheme's benefits in an alternative rural region (not a part of the original trial). These illustrative results conclude that the scheme may not be the most efficient use of National Health Service resources in this geographical region, thus demonstrating the importance and usefulness of simulation modelling in aiding decision making.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2sigma;2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2sigma;2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca<inf>o</inf>²⁺) homeostasis. To elucidate the role of AP2sigma;2 in Ca<inf>o</inf>²⁺ regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2sigma;2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2sigma;2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2sigma;2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2sigma;2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2sigma;2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

c-Kit+ progenitors generate vascular cells for tissue-engineered grafts through modulation of the Wnt/Klf4 pathway

The development of decellularised scaffolds for small diameter vascular grafts is hampered by their limited patency, due to the lack of luminal cell coverage by endothelial cells (EC) and to the low tone of the vessel due to absence of a contractile smooth muscle cells (SMC). In this study, we identify a population of vascular progenitor c-Kit+/Sca-1- cells available in large numbers and derived from immuno-privileged embryonic stem cells (ESCs). We also define an efficient and controlled differentiation protocol yielding fully to differentiated ECs and SMCs in sufficient numbers to allow the repopulation of a tissue engineered vascular graft. When seeded ex vivo on a decellularised vessel, c-Kit+/Sca-1-derived cells recapitulated the native vessel structure and upon in vivo implantation in the mouse, markedly reduced neointima formation and mortality, restoring functional vascularisation. We showed that Krüppel-like transcription factor 4 (Klf4) regulates the choice of differentiation pathway of these cells through β-catenin activation and was itself regulated by the canonical Wnt pathway activator lithium chloride. Our data show that ESC-derived c-Kit+/Sca-1-cells can be differentiated through a Klf4/β-catenin dependent pathway and are a suitable source of vascular progenitors for the creation of superior tissue-engineered vessels from decellularised scaffolds.

Time-Independent Discrete Gaussian Sampling for Post-Quantum Cryptography

As the development of a viable quantum computer nears, existing widely used public-key cryptosystems, such as RSA, will no longer be secure. Thus, significant effort is being invested into post-quantum cryptography (PQC). Lattice-based cryptography (LBC) is one such promising area of PQC, which offers versatile, efficient, and high performance security services. However, the vulnerabilities of these implementations against side-channel attacks (SCA) remain significantly understudied. Most, if not all, lattice-based cryptosystems require noise samples generated from a discrete Gaussian distribution, and a successful timing analysis attack can render the whole cryptosystem broken, making the discrete Gaussian sampler the most vulnerable module to SCA. This research proposes countermeasures against timing information leakage with FPGA-based designs of the CDT-based discrete Gaussian samplers with constant response time, targeting encryption and signature scheme parameters. The proposed designs are compared against the state-of-the-art and are shown to significantly outperform existing implementations. For encryption, the proposed sampler is 9x faster in comparison to the only other existing time-independent CDT sampler design. For signatures, the first time-independent CDT sampler in hardware is proposed.