A New Paradigm in Split Manufacturing: Lock the FEOL, Unlock at the BEOL

Split manufacturing was introduced as an effective countermeasure against hardware-level threats such as IP piracy, overbuilding, and insertion of hardware Trojans. Nevertheless, the security promise of split manufacturing has been challenged by various attacks, which exploit the well-known working principles of physical design tools to infer the missing BEOL interconnects. In this work, we advocate a new paradigm to enhance the security for split manufacturing. Based on Kerckhoff's principle, we protect the FEOL layout in a formal and secure manner, by embedding keys. These keys are purposefully implemented and routed through the BEOL in such a way that they become indecipherable to the state-of-the-art FEOL-centric attacks. We provide our secure physical design flow to the community. We also define the security of split manufacturing formally and provide the associated proofs. At the same time, our technique is competitive with current schemes in terms of layout overhead, especially for practical, large-scale designs (ITC'99 benchmarks).Comment: DATE 2019 (https://www.date-conference.com/conference/session/4.5

A Supervisory Control Algorithm Based on Property-Directed Reachability

We present an algorithm for synthesising a controller (supervisor) for a discrete event system (DES) based on the property-directed reachability (PDR) model checking algorithm. The discrete event systems framework is useful in both software, automation and manufacturing, as problems from those domains can be modelled as discrete supervisory control problems. As a formal framework, DES is also similar to domains for which the field of formal methods for computer science has developed techniques and tools. In this paper, we attempt to marry the two by adapting PDR to the problem of controller synthesis. The resulting algorithm takes as input a transition system with forbidden states and uncontrollable transitions, and synthesises a safe and minimally-restrictive controller, correct-by-design. We also present an implementation along with experimental results, showing that the algorithm has potential as a part of the solution to the greater effort of formal supervisory controller synthesis and verification.Comment: 16 pages; presented at Haifa Verification Conference 2017, the final publication is available at Springer via https://doi.org/10.1007/978-3-319-70389-3_

Efficient Symbolic Supervisory Synthesis and Guard Generation: Evaluating partitioning techniques for the state-space exploration

The supervisory control theory (SCT) is a model-based framework, which automatically synthesizes a supervisor that restricts a plant to be controlled based on specifications to be fulfilled. Two main problems, typically encountered in industrial applications, prevent SCT from having a major breakthrough. First, the supervisor which is synthesized automatically from the given plant and specification models might be incomprehensible to the users. To tackle this problem, an approach was recently presented to extract compact propositional formulae (guards) from the supervisor, represented symbolically by binary decision diagrams (BDD). These guards are then attached to the original models, which results in a modular and comprehensible representation of the supervisor. However, this approach, which computes the supervisor symbolically in the conjunctive way, might lead to another problem: the state-space explosion, because of the large number of intermediate BDD nodes during computation. To alleviate this problem, we introduce in this paper an alternative approach that is based on the disjunctive partitioning technique, including a set of selection heuristics. Then this approach is adapted to the guard generation procedure. Finally, the efficiency of the presented approach is demonstrated on a set of benchmark examples

A One Health overview, facilitating advances in comparative medicine and translational research.

Table of contentsA1 One health advances and successes in comparative medicine and translational researchCheryl StroudA2 Dendritic cell-targeted gorilla adenoviral vector for cancer vaccination for canine melanomaIgor Dmitriev, Elena Kashentseva, Jeffrey N. Bryan, David T. CurielA3 Viroimmunotherapy for malignant melanoma in the companion dog modelJeffrey N. Bryan, David Curiel, Igor Dmitriev, Elena Kashentseva, Hans Rindt, Carol Reinero, Carolyn J. HenryA4 Of mice and men (and dogs!): development of a commercially licensed xenogeneic DNA vaccine for companion animals with malignant melanomaPhilip J. BergmanA5 Successful immunotherapy with a recombinant HER2-expressing Listeria monocytogenes in dogs with spontaneous osteosarcoma paves the way for advances in pediatric osteosarcomaNicola J. Mason, Josephine S. Gnanandarajah, Julie B. Engiles, Falon Gray, Danielle Laughlin, Anita Gaurnier-Hausser, Anu Wallecha, Margie Huebner, Yvonne PatersonA6 Human clinical development of ADXS-HER2Daniel O'ConnorA7 Leveraging use of data for both human and veterinary benefitLaura S. TremlA8 Biologic replacement of the knee: innovations and early clinical resultsJames P. StannardA9 Mizzou BioJoint Center: a translational success storyJames L. CookA10 University and industry translational partnership: from the lab to commercializationMarc JacobsA11 Beyond docking: an evolutionarily guided OneHealth approach to drug discoveryGerald J. Wyckoff, Lee Likins, Ubadah Sabbagh, Andrew SkaffA12 Challenges and opportunities for data applications in animal health: from precision medicine to precision husbandryAmado S. GuloyA13 A cloud-based programmable platform for healthHarlen D. HaysA14 Comparative oncology: One Health in actionAmy K. LeBlancA15 Companion animal diseases bridge the translational gap for human neurodegenerative diseaseJoan R. Coates, Martin L. Katz, Leslie A. Lyons, Gayle C. Johnson, Gary S. Johnson, Dennis P. O'BrienA16 Duchenne muscular dystrophy gene therapyDongsheng DuanA17 Polycystic kidney disease: cellular mechanisms to emerging therapiesJames P. CalvetA18 The domestic cat as a large animal model for polycystic kidney diseaseLeslie A. Lyons, Barbara GandolfiA19 The support of basic and clinical research by the Polycystic Kidney Disease FoundationDavid A. BaronA20 Using naturally occurring large animal models of human disease to enable clinical translation: treatment of arthritis using autologous stromal vascular fraction in dogsMark L. WeissA21 Regulatory requirements regarding clinical use of human cells, tissues, and tissue-based productsDebra A. WebsterA22 Regenerative medicine approaches to Type 1 diabetes treatmentFrancis N. KaranuA23 The zoobiquity of canine diabetes mellitus, man's best friend is a friend indeed-islet transplantationEdward J. RobbA24 One Medicine: a development model for cellular therapy of diabetesRobert J. Harman

A Scalable System for Production of Functional Pancreatic Progenitors from Human Embryonic Stem Cells

Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process. We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo. In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors. This system has been optimized for the CyT49 cell line. Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing. Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50–100 fold expansion per week. Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol. Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population. Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice. By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia. In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry

Vitamin H-regulated transgene expression in mammalian cells

Although adjustable transgene expression systems are considered essential for future therapeutic and biopharmaceutical manufacturing applications, the currently available transcription control modalities all require side-effect-prone inducers such as immunosupressants, hormones and antibiotics for fine-tuning. We have designed a novel mammalian transcription-control system, which is reversibly fine-tuned by non-toxic vitamin H (also referred to as biotin). Ligation of vitamin H, by engineered Escherichia coli biotin ligase (BirA), to a synthetic biotinylation signal fused to the tetracycline-dependent transactivator (tTA), enables heterodimerization of tTA to a streptavidin-linked transrepressor domain (KRAB), thereby abolishing tTA-mediated transactivation of specific target promoters. As heterodimerization of tTA to KRAB is ultimately conditional upon the presence of vitamin H, the system is vitamin H responsive. Transgenic Chinese hamster ovary cells, engineered for vitamin H-responsive gene expression, showed high-level, adjustable and reversible production of a human model glycoprotein in bench-scale culture systems, bioreactor-based biopharmaceutical manufacturing scenarios, and after implantation into mice. The vitamin H-responsive expression systems showed unique band pass filter-like regulation features characterized by high-level expression at low (0–2 nM biotin), maximum repression at intermediate (100–1000 nM biotin), and high-level expression at increased (>100 000 nM biotin) biotin concentrations. Sequential ON-to-OFF-to-ON, ON-to-OFF and OFF-to-ON expression profiles with graded expression transitions can all be achieved by simply increasing the level of a single inducer molecule without exchanging the culture medium. These novel expression characteristics mediated by an FDA-licensed inducer may foster advances in therapeutic cell engineering and manufacturing of difficult-to-produce protein therapeutics