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  1. Abstract

    Previous urinary tract infections (UTIs) can predispose one to future infections; however, the underlying mechanisms affecting recurrence are poorly understood. We previously found that UTIs in mice cause differential bladder epithelial (urothelial) remodelling, depending on disease outcome, that impacts susceptibility to recurrent UTI. Here we compared urothelial stem cell (USC) lines isolated from mice with a history of either resolved or chronic uropathogenicEscherichia coli(UPEC) infection, elucidating evidence of molecular imprinting that involved epigenetic changes, including differences in chromatin accessibility, DNA methylation and histone modification. Epigenetic marks in USCs from chronically infected mice enhanced caspase-1-mediated cell death upon UPEC infection, promoting bacterial clearance. IncreasedPtgs2os2expression also occurred, potentially contributing to sustained cyclooxygenase-2 expression, bladder inflammation and mucosal wounding—responses associated with severe recurrent cystitis. Thus, UPEC infection acts as an epi-mutagen reprogramming the urothelial epigenome, leading to urothelial-intrinsic remodelling and training of the innate response to subsequent infection.

  2. Web personalization, e.g., recommendation or relevance search, tailoring a service/product to accommodate specific online users, is becoming increasingly important. Inductive personalization aims to infer the relations between existing entities and unseen new ones, e.g., searching relevant authors for new papers or recommending new items to users. This problem, however, is challenging since most of recent studies focus on transductive problem for existing entities. In addition, despite some inductive learning approaches have been introduced recently, their performance is sub-optimal due to relatively simple and inflexible architectures for aggregating entity’s content. To this end, we propose the inductive contextual personalization (ICP) framework through contextual relation learning. Specifically, we first formulate the pairwise relations between entities with a ranking optimization scheme that employs neural aggregator to fuse entity’s heterogeneous contents. Next, we introduce a node embedding term to capture entity’s contextual relations, as a smoothness constraint over the prior ranking objective. Finally, the gradient descent procedure with adaptive negative sampling is employed to learn the model parameters. The learned model is capable of inferring the relations between existing entities and inductive ones. Thorough experiments demonstrate that ICP outperforms numerous baseline methods for two different applications, i.e., relevant author search and new item recommendation.
  3. Lack of long-term patency has hindered the clinical use of small-diameter prosthetic vascular grafts with the majority of these failures due to the development of neointimal hyperplasia. Previous studies by our laboratory revealed that small-diameter expanded polytetrafluoroethylene (ePTFE) grafts coated with antioxidant elastomers are a promising localized therapy to inhibit neointimal hyperplasia. This work is focused on the development of poly(diol- co -citrate- co -ascorbate) (POCA) elastomers with tunable properties for coating ePTFE vascular grafts. A bioactive POCA elastomer (@20 : 20 : 8, [citrate] : [diol] : [ascorbate]) coating was applied on a 1.5 mm diameter ePTFE vascular graft as the most promising therapeutic candidate for reducing neointimal hyperplasia. Surface ascorbate density on the POCA elastomer was increased to 67.5 ± 7.3 ng mg −1 cm −2 . The mechanical, antioxidant, biodegradable, and biocompatible properties of POCA demonstrated desirable performance for in vivo use, inhibiting human aortic smooth muscle cell proliferation, while supporting human aortic endothelial cells. POCA elastomer coating number was adjusted by a modified spin-coating method to prepare small-diameter ePTFE vascular grafts similar to natural vessels. A significant reduction in neointimal hyperplasia was observed after implanting POCA-coated ePTFE vascular grafts in a guinea pig aortic interposition bypass graft model. POCA elastomer thus offers a newmore »avenue that shows promise for use in vascular engineering to improve long-term patency rates by coating small-diameter ePTFE vascular grafts.« less
  4. Abstract Necroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.
  5. X.509 certificates underpin the security of the Internet economy, notably secure web servers, and they need to be revoked promptly and reliably once they are compromised. The original revocation method specified in the X.509 standard, to distribute certificate revocation lists (CRLs), is both old and untrustworthy. CRLs are susceptible to attacks such as Man-in-the-Middle and Denial of Service. The newer Online Certificate Status Protocol (OCSP) and OCSP-stapling approaches have well-known drawbacks as well. The primary contribution of this paper is Secure Revocation as a Peer Service (SCRaaPS). SCRaaPS is an alternative, reliable way to support X.509 certificate revocation via the Scrybe secure provenance system. The blockchain support of Scrybe enables the creation of a durable, reliable revocation service that can withstand Denial-of-Service attacks and ensures non-repudiation of certificates revoked. We provide cross-CA-revocation information and address the additional problem of intermediate-certificate revocation with the knock-on effects on certificates derived thereof. A Cuckoo filter provides quick, communication-free testing by servers and browsers against our current revocation list (with no false negatives). A further contribution of this work is that the revocation service can fit in as a drop-in replacement for OCSP-stapling with superior performance and coverage both for servers and browsers. Potentialmore »revocation indicated by our Cuckoo filter is backed up by rigorous service query to eliminate false positives. Cuckoo filter parameters are also stored in our blockchain to provide open access to this algorithmic option for detection. We describe the advantages of using a blockchain-based system and, in particular, the approach to distributed ledger technology and lightweight mining enabled by Scrybe, which was designed with secure provenance in mind.« less
  6. As data-intensive science becomes the norm in many fields of science, high-performance data transfer is rapidly becoming a core scientific infrastructure requirement. To meet such a requirement, there has been a rapid growth across university campus to deploy Science DMZs. However, it is challenging to efficiently monitor the traffic in Science DMZ because traditional intrusion detection systems (IDSes) are equipped with deep packet inspection (DPI), which is resource-consuming. We propose to develop a lightweight side-channel based anomaly detection system for traffic winnowing to reduce the volume of traffic finally monitored by the IDS. We evaluate our approach based on the experiments in a Science DMZ environment. Our evaluation demonstrates that our approach can significantly reduce the resource usage in traffic monitoring for Science DMZ.