Search

Strategies for developing targeted covalent inhibitors (TCIs), which have the advantages of a prolonged duration of action and selectivity toward a drug target, have attracted great interest in drug discovery. Herein, we report chemoselective covalent inhibitors that specifically target lysine ε-amine groups that conjugate with an endogenous protein to prevent disease-causing protein misfolding and aggregation. These TCIs are unique because the benzoyl group is preferentially conjugated to Lys15 at the top of the T4binding site within transthyretin (TTR) while simultaneously releasing a potent noncovalent TTR kinetic stabilizer. The potency of these covalent inhibitors is superior to tafamidis, the only FDA-approved drug for the treatment of hereditary TTR amyloidosis. In addition to investigations into the covalent modification of TTR via reverse-phase high-performance liquid chromatography, direct methods are performed to confirm and visualize the presumed covalent interaction via mass spectrometry and X-ray crystallography.

BackgroundTumour-unrelated, virus-specific bystander CD8+T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet.MethodsWe studied the characteristics of bystander CD8+TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy.ResultsWe show that bystander CD8+TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8+TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8+TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8+TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment.ConclusionThus, the study demonstrates that bystander CD8+TILs can be repurposed by IL-15 for tumour immunotherapy.

In addition to the textile industry, unwinding of cable or fiber is used in various fields such as electronics, communication, and guided weapons. The cable released from the package exhibit a complicated behavior, entailing a combination of rotational and translational motion. This causes problems such as entangling and fracture. Therefore, it is necessary to study boundary and adhesion conditions to prevent unwinding failure. In this study, an experimental device for the analysis of cable unwinding was developed, and unwinding behavior was analyzed experimentally under various unwinding conditions. The experimental device comprises a jig for high-speed camera measurements, control device, and cable unwinding device. Cable behavior was analyzed according to the unwinding velocity and the distance between the fiber package and the point where the fiber was released. In addition, unwinding behavior with respect of the tension acting on the cable was analyzed experimentally by applying the adhesive.

Background: Low tibial valgization osteotomy with medial opening wedge (LTO) is generally indicated for ankle arthritis with a small talar tilt (TT). We addressed the following research questions: the efficacy of LTO for more significant varus ankle arthritis, the effect of additional inframalleolar correction followed by LTO, and the preoperative or operation-related factors influencing postoperative TT decrease.Methods: We retrospectively reviewed the radiographic and clinical findings of 31 patients with more significant varus ankle arthritis (≥8 degrees) who underwent LTO or LTO plus inframalleolar correction. We grouped the included patients according to combination with inframalleolar correction and postoperative decreased TT. Furthermore, a binary logistic regression analysis was performed to determine the factors influencing postoperative TT decrease.Results: Even though the mean TT was unchanged postoperatively (from 12.1 to 9.9 degrees, P= .052), clinical parameters were significantly increased. In the group with concomitant inframalleolar correction, we found that TT was more corrected (3.9 vs 1.8 degrees, P= .023) with a greater lateralization of the talar center and a greater correction of the hindfoot alignment to valgus. The results of the binary logistic regression analysis showed a significant relationship between postoperative decreased TT and preoperative talar center migration (P= .016), hindfoot alignment angle (P= .033), hindfoot moment arm (P= .041), and hindfoot alignment ratio (P= .016).Conclusion: LTO in more significant varus ankle arthritis could result in clinical improvement, although TT was not significantly changed. We recommend adding inframalleolar correction after LTO for the patients with more significant varus ankle arthritis.Level of Evidence: Level III, comparative series.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2007.06.040 Byline: Kun Woo Kim, Roberto Romero, Hyun Soo Park, Chan-Wook Park, Soon-Sup Shim, Jong Kwan Jun, Bo Hyun Yoon Keywords: bedside test; interleukin-6; intraamniotic infection/inflammation; MMP-8 PTD check; preterm premature rupture of membranes Abstract: To examine whether the MMP-8 PTD Check (SK Pharma Co, Ltd, Kyunggi-do, Korea), a rapid bedside test that can be performed in 15 minutes, is of value in the identification of intraamniotic infection and/or inflammation and in the assessment of the likelihood of adverse pregnancy outcome in patients with preterm premature rupture of membranes (PPROM). Author Affiliation: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea. Article Note: (footnote) Cite this article as: Kim KW, Romero R, Park HS, et al. A rapid matrix metalloproteinase-8 bedside test for the detection of intraamniotic inflammation in women with preterm premature rupture of membranes. Am J Obstet Gynecol 2007;197:292.e1-292.e5., Supported by grant A06-00043182 from the Korea Health 21 Research and Development Project, Ministry of Health and Welfare, Republic of Korea.

Guiding waves through a stable physical channel is essential for reliable information transport. However, energy transport in high-frequency mechanical systems, such as in signal-processing applications1, is particularly sensitive to defects and sharp turns because of back-scattering and losses2. Topological phenomena in condensed matter systems have shown immunity to defects and unidirectional energy propagation3. Topological mechanical metamaterials translate these properties into classical systems for efficient phononic energy transport. Acoustic and mechanical topological metamaterials have so far been realized only in large-scale systems, such as arrays of pendulums4, gyroscopic lattices5,6, structured plates7,8and arrays of rods, cans and other structures acting as acoustic scatterers9–12. To fulfil their potential in device applications, mechanical topological systems need to be scaled to the on-chip level for high-frequency transport13–15. Here we report the experimental realization of topological nanoelectromechanical metamaterials, consisting of two-dimensional arrays of free-standing silicon nitride nanomembranes that operate at high frequencies (10–20 megahertz). We experimentally demonstrate the presence of edge states, and characterize their localization and Dirac-cone-like frequency dispersion. Our topological waveguides are also robust to waveguide distortions and pseudospin-dependent transport. The on-chip integrated acoustic components realized here could be used in unidirectional waveguides and compact delay lines for high-frequency signal-processing applications.

This paper proposes an optimal button arrangement of a percussion drill bit and its operating condition to improve drilling efficiency. A new evaluation method is introduced for the button arrangement that utilizes the superimposed impact area, blank area, and drilling deviation moment as the quantitative indices to evaluate the impact of buttons on the rock surface. To determine the optimal button arrangement and its operating conditions, a progressive metamodel-based design optimization was conducted using the new evaluation indices as the analysis response, and then the optimal solution was determined through iteration. Consequently, all the button evaluation indices were reduced significantly and the impact areas were distributed uniformly under a specific operating condition. Additionally, the drilling performances of the optimal button arrangement were investigated according to the operating conditions to obtain the maximum drilling performance in terms of the drilling machine operation.

The transient-state unwinding equation of motion for a thin cable can be derived by using Hamilton’s principle for an open system, which can consider the mass change produced by the unwinding velocity in a control volume. In general, most engineering problems can be analyzed in Cartesian, cylindrical, and spherical coordinate systems. In the field of unwinding dynamics, until now, only Cartesian and cylindrical coordinate systems have been used. A spherical coordinate system has not been used because of the complexity of derivatives. Therefore, in this study, the unwinding motion of a thin cable was analyzed using a spherical coordinate system in both water and air, and the results were compared with the results in Cartesian and cylindrical coordinate systems. The unwinding motions in the spherical, Cartesian, and cylindrical coordinate systems were nearly same in both water and air. The error related to the total length was within 0.5% in water, and the error related to the maximum balloon radius was also within 0.5 % in air. Therefore, it can be concluded that it is possible to solve the transient-state unwinding equation of motion in a spherical coordinate system.

Absolute nodal-coordinate formulation is a technique that was developed in 1996 for expressing the large rotation and deformation of a flexible body. It utilizes global slopes without a finite rotation in order to define nodal coordinates. The method has a shortcoming in that the central processing unit time increases because of increases in the degrees of freedom. In particular, when considering the deformation of a cross section, the shortcoming due to the increase in the degrees of freedom becomes clear. Therefore, in the present research, the dimensional equation of motion concerning a two-dimensional shear deformable beam, developed by Omar and Shabana, is converted into a nondimensional equation of motion in order to reduce the central processing unit time. By utilizing an example of a cantilever beam, wherein an exact solution for the static deflection exists, the nondimensional equation of motion was verified. Moreover, by using an example of a free-falling flexible pendulum, the efficiency of the nondimensional equation of motion gained by increasing the number of elements was compared with that of the dimensional equation of motion.

A flexible hose that is unwound along with fiber-optic cables from a mother ship helps prevent interference with the mother ship during the unwinding of the fiber-optic cable. Because the density of fiber-optic cables is close to the fluid density, if there is no flexible hose, the fiber-optic cable is more likely to interfere with the mother ship because of the motion of underwater vehicles or mother ships. Hence, it is necessary to prevent the interference of fiber-optic cables by using flexible hoses made of stainless steel. Flexible hoses unwound as an underwater vehicle moves are coupled to the vehicle by shear pins, and once all flexible hoses are unwound, the underwater vehicle continues to move forward as the pins fracture. Here, a dynamic load applied on the shear pin for connection in the early stages of the unwinding of the flexible hose is an important factor that controls the position, which should be accurately predicted, prior to the motion of the underwater vehicle. Further, it is essential that the shear pin of the connection part be designed to fracture under the selected load so that underwater vehicle can continue to move forward as the pin breaks. In this study, analysis results based on loading information measured in real experiments were compared and verified, and based on the findings, an analytical model that can predict loads applied on the shear pin was developed.

Porous hematite clusters were prepared as anode materials for improved Li-ion batteries. First, poly-L-lysine (PLL)-linked Fe3O4was facilely prepared via cross-linking between the positive amine groups of PLL and carboxylate-bound Fe3O4. The subsequent calcination transformed the PLL-linked Fe3O4into porous hematite clusters (Fe2O3@PLL) consisting of spherical α-Fe2O3particles. Compared with standard Fe2O3, Fe3O4@PLL exhibited improved electrochemical performance as anode materials. The discharge capacity of Fe2O3@PLL was retained at 814.7 mAh g-1after 30 cycles, which is equivalent to 80.4% of the second discharge capacity, whereas standard Fe2O3exhibited a retention capacity of 352.3 mAh g-1. The improved electrochemical performance of Fe2O3@PLL was mainly attributed to the porous hematite clusters with mesoporosity (20–40 nm), which was beneficial for facilitating ion transport, suggesting a useful guideline for the design of porous architectures with higher retention capacity.

Abstract: In the field of ‘human vibration’, until now most frequency weighting functions have been derived from particular experiments whose subjects were only Western people. However, because of inherent differences (e.g., characteristic and shape of body parts, muscular and cellular tissue) between Western people and Asian people, frequency weighting function based on Asian people is required. An experiment was carried out to develop a frequency weighting function for the Korean people in vertical whole-body vibration, and to verify whether this weighting is acceptable in practical applications in comparison with ISO 2631-1. Ten male subjects of mean weight and height were tested for a posture similar to sitting in a passenger seat (footrest, upright and placement of the palms of hands on thighs, etc.) of a car. This experiment was performed using sinusoidal excitation in the range from 2 to 250 Hz, which was a combination of one-half and one-third octave bands at eight determined amplitudes. To guarantee the reliability and accuracy of the test, non-parametric statistics was adopted to resolve the fact that there was not enough of the sample. Furthermore, two methods were considered to make the frequency weighting function and equal sensation curves. The first method changes the amplitude at every fixed frequency, and the other assigns weighting values. Korean people showed the most sensitivity to vertical whole-body vibration at 6.3 Hz excitation, so much higher weighting factors than weighting factors of other frequencies must be assigned near that frequency.

ObjectiveTo determine by chest CT the proper compression landmark and depth for cardiopulmonary resuscitation in patients with pectus excavatum (PE).MethodsThe chest CT of 22 patients with PE (mean age=27 years; range 16–53 years, 10 male) from March 2002 to September 2011 were retrospectively evaluated as follows: length of sternum, external thickness/internal thickness (ET/IT) of the chest and the intrathoracic structures in the level of lower half (LH) of the sternum. In addition, Haller index (HI) and the degree of leftward displacement of the heart were measured. Finally, variables were also measured in an age/sex-matched control group (n=22) with no evidence of any chest wall deformity.ResultsThe sternal length was not different and LH of the sternum was adequate to compress left ventricle (LV) in both groups. Patients had a significant higher HI and showed a greater leftward displacement of LV centre with a mean difference of 11 mm. PE patients showed a lesser ET/IT with a mean difference of approximately 20 mm than controls (mean ET/IT=174±18/70±10 mm vs 199±23/93±15 mm, p<0.001).ConclusionsThe LH of the sternum is an appropriate chest compression landmark in PE patients to compress LV, although the centre of LV shows slightly leftward displacement. Since PE patients have sunken chest, a 3–4 cm may be the proper compression depth in the patients when considering the current compression guideline in normal subjects is 5–6 cm.

A lab-on-a-chip (LOC) magnetophoretic system for the remotely controllable transport of magnetic particles actuated by thin permalloy magnetic tracks has been developed as a novel architecture composed of radii and spiral tracks resembling a spider web network, where the network tracks have the asymmetric and anisotropic magnetic properties for the directional transportation of particles (cargos). A planar Hall resistance (PHR) sensor is integrated with the web networks, and the manipulation and detection are achieved via superparamagnetic particles with dual functions as a biomolecule cargo for transportation and labels for monitoring. The streptavidin protein-coated magnetic particles are precisely manipulated toward the PHR sensor surface via the radii and spiral tracks by applying an external rotating magnetic field. The stray field was analyzed in terms of the particle coverage on the sensor surface, where the sensor signal linearly varies with the number of particles on the sensor surface. This allows the effective collection of low-density biomolecule carriers to one specific point and monitors the accumulated carriers. The developed novel technology could affect multiple fields, including bioassays, cell manipulation and separation and biomechanics.