Development of a novel, high-efficacy oncolytic herpes simplex virus type 1 platform equipped with two distinct retargeting modalities.

To retarget oncolytic herpes simplex virus (oHSV) to cancer-specific antigens, we designed a novel, double-retargeted oHSV platform that uses single-chain antibodies (scFvs) incorporated into both glycoprotein H and a bispecific adapter expressed from the viral genome to mediate infection predominantly via tumor-associated antigens. Successful retargeting was achieved using a nectin-1-detargeted HSV that remains capable of interacting with herpesvirus entry mediator (HVEM), the second canonical HSV entry receptor, and is, therefore, recognized by the adapter consisting of the virus-binding N-terminal 82 residues of HVEM fused to the target-specific scFv. We tested both an epithelial cell adhesion molecule (EpCAM)- and a human epidermal growth factor receptor 2-specific scFv separately and together to target cells expressing one, the other, or both receptors. Our results show not only dose-dependent, target receptor-specific infection in vitro, but also enhanced virus spread compared with single-retargeted virus. In addition, we observed effective infection and spreading of the EpCAM double-retargeted virus in vivo. Remarkably, a single intravenous dose of the EpCAM-specific virus eliminated all detectable tumors in a subcutaneous xenograft model, and the same intravenous dose seemed to be harmless in immunocompetent FVB/N mice. Our findings suggest that our double-retargeted oHSV platform can provide a potent, versatile, and systemically deliverable class of anti-cancer therapeutics that specifically target cancer cells while ensuring safety.

Mixing behavior of Ti-Al interface during the ultrasonic welding process and its welding strength: Molecular dynamics study.

In this study, we conducted molecular dynamics simulations to investigate the mechanical mixing and deformation behavior of hcp Ti/fcc Al bimetal formed by ultrasonic welding (UW). To analyze the effect of the interface shape, we considered sixteen sinusoidal interfaces of various heights and spatial periods along with the flat interface. Mechanical mixing between Ti and Al occurs mainly in the vibrational loading direction, while it is suppressed in the interface-normal direction, as the loading direction lies within the slip planes of both the hcp and fcc structures. The degree of mechanical mixing depended on the shape of the interface. According to the simulation results, mechanical mixing becomes active as the sinusoidal height increases, and the spatial period decreases because of the enlarged interface areas. During the bonding process, phase transformation is observed at the sinusoidal interface; hcp Ti is converted to fcc Ti as misfit dislocations formed at the interface glide as Shockley partials on the slip plane owing to the applied vibrational loading. A simple shear test was performed to analyze the welding strength. Although sinusoidal Ti/Al interfaces can have a welding strength that is higher than that of a flat interface, we found that the welding strength was not closely related to the degree of mechanical mixing. Rather, the welding strength was affected by the interaction between a wall of misfit dislocations, stacking fault tetrahedra, and lattice dislocations generated near the interface during the UW process.

Long-term neuropeptide modulation of female sexual drive via the TRP channel in Drosophila melanogaster.

Connectomics research has made it more feasible to explore how neural circuits can generate multiple outputs. Female sexual drive provides a good model for understanding reversible, long-term functional changes in motivational circuits. After emerging, female flies avoid male courtship, but they become sexually receptive over 2 d. Mating causes females to reject further mating for several days. Here, we report that pC1 neurons, which process male courtship and regulate copulation behavior, exhibit increased CREB (cAMP response element binding protein) activity during sexual maturation and decreased CREB activity after mating. This increased CREB activity requires the neuropeptide Dh44 (Diuretic hormone 44) and its receptors. A subset of the pC1 neurons secretes Dh44, which stimulates CREB activity and increases expression of the TRP channel Pyrexia (Pyx) in more pC1 neurons. This, in turn, increases pC1 excitability and sexual drive. Mating suppresses pyx expression and pC1 excitability. Dh44 is orthologous to the conserved corticotrophin-releasing hormone family, suggesting similar roles in other species.

Characteristics of Microcellular Foamed Ceramic Urethane.

Ceramics are non-metallic inorganic materials fabricated from natural or high-purity raw materials through heating and cooling processes. Urethane is a three-dimensional plastic with both elasticity and chemical resistance; moreover, it is used as a rubber substitute. The use of both materials in various applications is gradually increasing. However, as ceramics and urethane have distinctly different properties, this prompted questions regarding the properties of a material that is fabricated using both materials. Therefore, we studied the characteristics of a composite material fabricated through physical foaming using a batch process. The process was conducted with gas saturation, foaming, cooling, and curing. When a specimen of 2 mm thickness was saturated in 5 MPa of CO2 for 2 h, the solubility was 6.43%; when foaming was carried out at a temperature of 150 °C in boiled glycerin, the foaming ratio, cell size, cell density, and void fraction were found to be 43.62%, 24.40 µm, 9.1 × 107 cells/cm2, and 22.11%, respectively. Furthermore, the volume increased by 102.96%, color changed from dark to light gray, hardness decreased by 24%, thermal diffusivity increased by 0.046 mm2/s at 175 °C, and friction coefficient decreased to 0.203. Thus, the microcellular foamed ceramic urethane exhibits a larger volume, lighter weight, and improved thermal conductivity and friction coefficient.

The neuropeptide allatostatin C from clock-associated DN1p neurons generates the circadian rhythm for oogenesis.

The link between the biological clock and reproduction is evident in most metazoans. The fruit fly Drosophila melanogaster, a key model organism in the field of chronobiology because of its well-defined networks of molecular clock genes and pacemaker neurons in the brain, shows a pronounced diurnal rhythmicity in oogenesis. Still, it is unclear how the circadian clock generates this reproductive rhythm. A subset of the group of neurons designated "posterior dorsal neuron 1" (DN1p), which are among the ∼150 pacemaker neurons in the fly brain, produces the neuropeptide allatostatin C (AstC-DN1p). Here, we report that six pairs of AstC-DN1p send inhibitory inputs to the brain insulin-producing cells, which express two AstC receptors, star1 and AICR2. Consistent with the roles of insulin/insulin-like signaling in oogenesis, activation of AstC-DN1p suppresses oogenesis through the insulin-producing cells. We show evidence that AstC-DN1p activity plays a role in generating an oogenesis rhythm by regulating juvenile hormone and vitellogenesis indirectly via insulin/insulin-like signaling. AstC is orthologous to the vertebrate neuropeptide somatostatin (SST). Like AstC, SST inhibits gonadotrophin secretion indirectly through gonadotropin-releasing hormone neurons in the hypothalamus. The functional and structural conservation linking the AstC and SST systems suggest an ancient origin for the neural substrates that generate reproductive rhythms.

Linear Micro-patterned Drug Eluting Balloon (LMDEB) for Enhanced Endovascular Drug Delivery.

In-stent restenosis (ISR) often occurs after applying drug eluting stents to the blood vessels suffering from atherosclerosis or thrombosis. For treatment of ISR, drug eluting balloons (DEB) have been developed to deliver anti-proliferative drugs to the lesions with ISR. However, there are still limitations of DEB such as low drug delivery efficiency and drug loss to blood flow. Although most researches have focused on alteration of drug formulation for more efficient drug delivery, there are few studies that have attempted to understand and utilize the contact modality of DEB drug delivery. Here, we developed a linear micro-patterned DEB (LMDEB) that applied higher contact pressure to enhance drug stamping to vascular tissue. Ex vivo and in vivo studies confirmed that higher contact pressure from micro-patterns increased the amount of drug delivered to the deeper regions of vessel. Finite element method simulation also showed significant increase of contact pressure between endothelium and micro-patterns. Quantitative analysis by high performance liquid chromatography indicated that LMDEBs delivered 2.3 times higher amount of drug to vascular tissue in vivo than conventional DEBs. Finally, efficacy studies using both atherosclerotic and ISR models demonstrated superior patency of diseased vessels treated with LMDEB compared to those treated with DEB.

Female-specific myoinhibitory peptide neurons regulate mating receptivity in Drosophila melanogaster.

Upon mating, fruit fly females become refractory to further mating for several days. An ejaculate protein called sex peptide (SP) acts on uterine neurons to trigger this behavioural change, but it is still unclear how the SP signal modifies the mating decision. Here we describe two groups of female-specific local interneurons that are important for this process-the ventral abdominal lateral (vAL) and ventral abdominal medial (vAM) interneurons. Both vAL and vAM express myoinhibitory peptide (Mip)-GAL4. vAL is positive for Mip neuropeptides and the sex-determining transcriptional factor doublesex. Silencing the Mip neurons in females induces active rejection of male courtship attempts, whereas activation of the Mip neurons makes even mated females receptive to re-mating. vAL and vAM are located in the abdominal ganglion (AG) where they relay the SP signal to other AG neurons that project to the brain. Mip neuropeptides appear to promote mating receptivity both in virgins and mated females, although it is dispensable for normal mating in virgin females.

Identification of a Peptidergic Pathway Critical to Satiety Responses in Drosophila.

Although several neural pathways have been implicated in feeding behaviors in mammals [1-7], it remains unclear how the brain coordinates feeding motivations to maintain a constant body weight (BW). Here, we identified a neuropeptide pathway important for the satiety and BW control in Drosophila. Silencing of myoinhibitory peptide (MIP) neurons significantly increased BW through augmented food intake and fat storage. Likewise, the loss-of-function mutation of mip also increased feeding and BW. Suppressing the MIP pathway induced satiated flies to behave like starved ones, with elevated sensitivity toward food. Conversely, activating MIP neurons greatly decreased food intake and BW and markedly blunted the sensitivity of starved flies toward food. Upon terminating the activation protocol of MIP neurons, the decreased BW reverts rapidly to the normal level through a strong feeding rebound, indicating the switch-like role of MIP pathway in feeding. Surprisingly, the MIP-mediated BW decrease occurred independently of sex peptide receptor (SPR), the only known receptor for MIP, suggesting the presence of a yet-unknown MIP receptor. Together, our results reveal a novel anorexigenic pathway that controls satiety in Drosophila and provide a new avenue to study how the brain actively maintains a constant BW.

Conductive fiber-based ultrasensitive textile pressure sensor for wearable electronics.

A flexible and sensitive textile-based pressure sensor is developed using highly conductive fibers coated with dielectric rubber materials. The pressure sensor exhibits superior sensitivity, very fast response time, and high stability, compared with previous textile-based pressure sensors. By using a weaving method, the pressure sensor can be applied to make smart gloves and clothes that can control machines wirelessly as human-machine interfaces.