Schwannoma Gene Therapy via Adeno-Associated Viral Vector Delivery of Apoptosis-Associated Speck-like Protein Containing CARD (ASC): Preclinical Efficacy and Safety

Schwannomas are tumors derived from Schwann-lineage cells, cells that protect and support myelinated nerves in the peripheral nervous system. They are typically slow-growing, encapsulated and benign. These tumors develop along peripheral, spinal and cranial nerves causing pain, sensory-motor dysfunction and death. Primary treatment for schwannoma is operative resection which can be associated with significant morbidity. Pharmacotherapy is largely restricted to bevacizumab, which has minimal or no efficacy for many patients and can be associated with treatment-limiting adverse effects. Given the suffering and morbidity associated with schwannoma and the paucity of therapeutic options, there is an urgent need for safe and effective therapies for schwannomas. We previously demonstrated that adeno-associated virus serotype 1 (AAV1) vector mediated delivery of the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) under the control of the P0 promoter, produced a prolonged reduction in tumor volume and tumor-associated pain in human xenograft and mouse syngeneic schwannoma models. Here, we present data essential for the translation of our AAV1-P0-ASC schwannoma gene therapy to clinical trials. We determine the minimum effective dose of AAV1-P0-hASC required to induce an anti-tumor effect in the xenograft human-schwannoma model. We also show that the presence of preexisting AAV1 immunity does not alter the antitumor efficacy of AAV-P0-mASC in a syngeneic mouse schwannoma model. Furthermore, the maximum deliverable intratumoral dose of AAV1-P0-ASC was not associated with neuronal toxicity in immunocompetent mice. Taken together, these safety and efficacy data support the translation of the AAV1-P0-ASC schwannoma gene therapy strategy to clinical trials.     

A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application

Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.     

Decoupling of Confined Normal 3He

Anodic bonding was used to fabricate a 10 mm diameter × 640 nm tall annular geometry suitable for torsion pendulum studies of confined ³He. For pure ³He at saturated vapor pressure the inertia of the confined fluid was seen to be only partially coupled to the pendulum at 160 mK. Below 100 mK the liquid’s inertial contribution was negligible, indicating a complete decoupling of the ³He from the pendulum.     

Growth,ambient stability and electrical characterisation of MgO thin films on silicon surfaces

Magnesium oxide (MgO) thin films were deposited onto silicon substrates, from an MgO target, by electron beam evaporation. The ambient stability of the MgO films and the formation of the MgO/Si interface were analysed using standard X-ray photoelectron spectroscopy (XPS) and high resolution synchrotron radiation based photoemission. Ambient exposure of the deposited films results in the growth of magnesium hydroxide and magnesium carbide species which can be desorbed by annealing at 500 °C in an inert atmosphere. Electrical characterisation has been performed on nickel silicide/MgO/Si(1 0 0) MOS structures for different dielectric thicknesses. The C–V results show no evidence of a low-k layer at the MgO/Si interface.     

Epistatic Signaling and Minority Games,the Adversarial Dynamics in Social Technological Systems

We present a game theoretic framework that models strategic interactions among humans and things that are assumed to be interconnected by a social-technological network, as in an internet of humans and things (IOHT). Often a pair of agents in the network interacts in order for an informed sender-agent to signal an uninformed receiver-agent to take an action that benefits each of the players; the benefits to the pair of agents are modeled by two separate utility functions, both depending on the sender’s private information, the signal exchanged, and the receiver’s revealed (and also possibly unrevealed) action. In general, the two agents’ utilities may not be aligned and may encourage deceptive behavior. For example, a sender, aware of his/her own private “state of ignorance”, may seek useful information from a receiver who owns powerful computational resources to search a large corpus of webpages; the sender does so by sending a signal to the receiver in the form of a keyword. Obvious examples of deceptiveness here range from attempts to hide one’s intentions to auctioning the keywords on an ad exchange through real-time bidding. A rather troublesome situation occurs when deceptions are employed to breach the security of the system, thus making the entire social-technological network unreliable. Earlier, we proposed a signaling-game-theoretic framework to alleviate this problem. This paper further enhances that framework by reconfiguring signals to possess more complex structures (epistatic signals to represent attack and defense options over a given set of vulnerabilities). We explore two augmentations to the original evolutionary signaling game by first enhancing mutation bias toward strategies performing well in previous populations and second allowing the parameters of the utility functions to depend on population preferences giving rise to a minority game with epistatic signaling. The resulting game systems are empirically studied through extensive computer simulation.     

Properties of spin-on glass as an insulator for InP metal-insulator-semiconductor structures

The application of Futurrex IC1-200 spin-on glass as an insulator for InP metal-insu-lator-semiconductor (MIS) structures including InP MIS capacitors and InP MIS field-effect transistors (MISFET’s) was investigated. Preliminary measurements of the elec-trical properties of the spin-on glass were performed using Si MIS structures with the spin-on glass insulator layer. It was found that the spin-on glass which is subjected to a final curing treatment utilizing a rapid-thermal annealing at 600° C for 5 sec in a O₂ ambient exhibits the best electrical properties. However, it was demonstrated by sec-ondary ion mass spectroscopy that when done on InP, the 600° C rapid-thermal an-nealing resulted in the outdiffusion of indium and phosphorus into the spin-on glass. The change in the spin-on glass electrical characteristics due to this outdiffusion re-sulted in an instability in the InP MISFET operation.     

Waterfall formation at a desert river–reservoir delta isolates endangered fishes

Unforeseen interactions of dams and declining water availability have formed new obstacles to recovering endemic and endangered big‐river fishes. During a recent trend of drying climate and declining reservoir water levels in the Southwestern United States, a large waterfall has formed on two separate occasions (1989–1995 and 2001–present) in the transition zone between the San Juan River and Lake Powell reservoir because of deposited sediments. Since recovery plans for two large‐bodied endangered fish species, razorback sucker (Xyrauchen texanus) and Colorado pikeminnow (Ptychocheilus lucius), include annual stockings in the San Juan River, this waterfall potentially blocks upstream movement of individuals that moved downstream from the river into the reservoir. To quantify the temporal variation in abundance of endangered fishes aggregating downstream of the waterfall and determine population demographics, we remotely monitored and sampled in spring 2015, 2016, and 2017 when these fish were thought to move upstream to spawn. Additionally, we used an open population model applied to tagged fish detected in 2017 to estimate population sizes. Colorado pikeminnow were so infrequently encountered (<30 individuals) that population estimates were not performed. Razorback sucker captures from sampling (335), and detections from remote monitoring (943) showed high abundance across all 3 years. The razorback sucker population estimate for 2017 alone was 755 individuals and, relative to recent population estimates ranging from ~2,000 to ~4,000 individuals, suggests that a substantial population exists seasonally downstream of this barrier. Barriers to fish movement in rivers above reservoirs are not unique; thus, the formation of this waterfall exemplifies how water development and hydrology can interact to cause unforeseen changes to a riverscape.     

Three closely related herpesviruses are associated with fibropapillomatosis in marine turtles

Green turtle fibropapillomatosis is a neoplastic disease of increasingly significant threat to the survivability of this species. Degenerate PCR primers that target highly conserved regions of genes encoding herpesvirus DNA polymerases were used to amplify a DNA sequence from fibropapillomas and fibromas from Hawaiian and Florida green turtles. All of the tumors tested (n = 23) were found to harbor viral DNA, whereas no viral DNA was detected in skin biopsies from tumor-negative turtles. The tissue distribution of the green turtle herpesvirus appears to be generally limited to tumors where viral DNA was found to accumulate at approximately two to five copies per cell and is occasionally detected, only by PCR, in some tissues normally associated with tumor development. In addition, herpesviral DNA was detected in fibropapillomas from two loggerhead and four olive ridley turtles. Nucleotide sequencing of a 483-bp fragment of the turtle herpesvirus DNA polymerase gene determined that the Florida green turtle and loggerhead turtle sequences are identical and differ from the Hawaiian green turtle sequence by five nucleotide changes, which results in two amino acid substitutions. The olive ridley sequence differs from the Florida and Hawaiian green turtle sequences by 15 and 16 nucleotide changes, respectively, resulting in four amino acid substitutions, three of which are unique to the olive ridley sequence. Our data suggest that these closely related turtle herpesviruses are intimately involved in the genesis of fibropapillomatosis.     

The electrocatalytic behaviour of palladium in acid and base

Anomalous oxidation of noble metals such as platinum is now an established feature of metal cluster/ oxygen gas reactions. The same type of process at polycrystalline metal electrodes in aqueous media is assumed to give rise to incipient hydrous oxide formation. This approach was used here to rationalize the electrocatalytic behaviour of palladium, with regard to both oxidations and reductions, in aqueous acid and base. The activity of palladium was not dramatically different to that of platinum, and the presence of an unusual peak at about 0.23 V vs RHE in the case of palladium in acid is rather similar in character to the so-called anomalous hydrogen peak previously described for platinum under similar conditions. For both metals (and a similar claim was made recently for gold) an adatom/incipient hydrous oxide transition is assumed to be involved, and it is interesting that the onset/termination potential for hydrazine oxidation under potential sweep conditions virtually coincided with the potential for this minor peak or transition.This paper is dedicated to Professor Brian E. Conway on the occasion of his 65th birthday, and in recognition of his outstanding contribution to electrochemistry.     

Morphological effects of variant carbonates in biomimetic hydroxyapatite

We prepared nano-carbonated hydroxyapatite (CHA) with different additions of carbonated contents at room temperature. The resulting materials were tested by X-ray diffraction (XRD), Fourier transform Infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) respectively. Results were shown that the materials were platelet-like CHA polycrystals that were similar to natural bone minerals, except for the material sample with the highest carbonated content. The presence of carbonated content in hydroxyapatite (HA) significantly decreased the crystallinity of synthesized CHA. Moreover, the morphological change of CHA was observed with the increase of carbonated content. The sequence of morphological change was from flat-like platelet, needle-arrayed platelet, particle-consisted platelet, smaller platelet, and finally spherical particle. This tendency is accordant to controllable solubility of biological HA with certain carbonated content.