The Role of T-Cell Leukemia Translocation-Associated Gene Protein in Human Tumorigenesis and Osteoclastogenesis

Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-κB ligand (RANKL), TNF-α, IL-6, IL-17, and IFN-γ. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in regulating bone resorption. In 2009, we demonstrated that novel peptides from T-cell leukemia translocation-associated gene (TCTA) protein expressed in synovial tissues from patients with RA inhibit human osteoclastogenesis, preventing cellular fusion via the interaction between TCTA protein and a putative counterpart molecule. Only a few studies on the role of TCTA protein have been reported. Genomic Southern blots demonstrated a reduced TCTA signal in three of four small cell lung cancer cell lines, suggesting the loss of one of the two copies of the gene. In the current paper, we reviewed the roles of TCTA protein in lung cancer cell lines and human osteoclastogenesis

4D topology optimization: Integrated optimization of the structure and self-actuation of soft bodies for dynamic motions

Topology optimization is a powerful tool utilized in various fields for structural design. However, its application has primarily been restricted to static or passively moving objects, mainly focusing on hard materials with limited deformations and contact capabilities. Designing soft and actively moving objects, such as soft robots equipped with actuators, poses challenges due to simulating dynamics problems involving large deformations and intricate contact interactions. Moreover, the optimal structure depends on the object's motion, necessitating a simultaneous design approach. To address these challenges, we propose "4D topology optimization," an extension of density-based topology optimization that incorporates the time dimension. This enables the simultaneous optimization of both the structure and self-actuation of soft bodies for specific dynamic tasks. Our method utilizes multi-indexed and hierarchized density variables distributed over the spatiotemporal design domain, representing the material layout, actuator layout, and time-varying actuation. These variables are efficiently optimized using gradient-based methods. Forward and backward simulations of soft bodies are done using the material point method, a Lagrangian-Eulerian hybrid approach, implemented on a recent automatic differentiation framework. We present several numerical examples of self-actuating soft body designs aimed at achieving locomotion, posture control, and rotation tasks. The results demonstrate the effectiveness of our method in successfully designing soft bodies with complex structures and biomimetic movements, benefiting from its high degree of design freedom.Comment: 36 pages, 27 figures; for supplementary video, see https://youtu.be/sPY2jcAsNY

Up-conversion glass-ceramic devices of individual emission of red, green and blue and their applications

ABSTRACT When rare earth-doped oxyfluoride glasses are heat-treated at the first crystallization temperatures, the glasses turn into glass-ceramics in which rare earth-containing nanocrystals uniformly precipitate in the glass matrices. These glass-ceramics are transparent to the naked eye as well no heat-treated glasses. Since rare earth ions exist as solidsolution ions in the precipitated fluoride crystals with low phonon energies, these glass-ceramics exhibit highly efficient up-conversion luminescence by laser light excitation. In the present work, rare earth-doped oxyfluoride glass-ceramics in the Si02-PbF2-ErF3-TmF3-GdF3, Si02-PbF2-HoF3-YbF3-GdF3, and Si02-PbF2-TmF3-YbF3-GdF3 systems were developed. Under 980nm LD excitation the respective glass-ceramics gave selectively red-, green-, and blue-upconversion luminescence with high efficiency. Emission wavelengths in the center of gravity are 666, 543,and 479 nm, respectively. Except for these selective emissions, however, other emissions at different wavelengths are also observed, though extremely weak. Removal of these extra emissions was possible by using appropriate filter-glasses, presenting the up-conversion devices of individual emission of red (R), green (G), and blue (B). On the other hand, laminas of the mixtures of resin and the glass-ceramic powders exhibited extremely high enhancement of upconversion emission intensities. The developed upconversion glass-ceramics in which RGB emissions are independently available by 980 nm laser irradiation offer a variety of applications. Some of the expected utilization as optics devices is proposed

Bilateral verses bilateral with tri-segmental endoscopic drainage using metal stents for high-grade malignant hilar biliary obstructions: A multicenter, randomized controlled trial: BRAVE study (BRAVE study)

Introduction: Bilateral endoscopic drainage with self-expanding metallic stent (SEMS) can be used to manage hilar malignant biliary obstruction (HMBO) more effectively in comparison to unilateral drainage. An increased drainage area is predicted to prolong stent patency and patient survival. However, few reports have described the utility of trisegmental drainage and the benefits of using trisegmental drainage remain unknown. Thus, we launched a randomized clinical trial (RCT) to compare the clinical outcomes between bilateral and trisegmental drainage using SEMSs in patients with high-grade HMBO. Methods and analysis: This study was conducted as a multicenter randomized control trial (RCT) in 8 high-volume medical centers in Japan, and will prove the non-inferiority of bilateral drainage to trisegmental drainage. Patients with unresectable HMBO with Bismuth type IIIa or IV who pass the inclusion and exclusion criteria will be randomized to receive bilateral or trisegmental drainage at a 1:1 ratio. At each center, the on-site study investigators will obtain informed consent from the candidates, and will use an electronic data capture system (REDCap) to input necessary information, and register candidates with the registration secretariat. The primary endpoint is the rate of non-recurrent biliary obstruction (RBO) at 180 days after SEMSs placement. A -10% non-inferiority margin is assumed in the statistical analysis of the primary endpoint. Secondary endpoints include the rate of technical and clinical success, time to recurrent biliary obstruction (TRBO), causes of RBO, procedure-related adverse events (AEs), procedure time, TRBO with or without endoscopic sphincterotomy, overall survival, and the technical and clinical success rates at reintervention. Discussion: If the non-inferiority of bilateral drainage is demonstrated, it is predicted that the procedure time will be shortened and the medical cost will be reduced, which will be beneficial to the patient and the medical economy

IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis

Acute bout of exercise downregulates thioredoxin-interacting protein expression in rat contracting skeletal muscles

We previously reported that in rat skeletal muscle, disuse (i.e., decreased muscle contractile activity) rapidly increases thioredoxin-interacting protein (TXNIP), which is implicated in the reduced glucose uptake. Accordingly, we sought herein to (a) determine the effect of exercise (i.e., increased muscle contractile activity) on muscle TXNIP protein expression, and (b) elucidate the mechanisms underlying the changes of TXNIP protein expression in response to exercise. Rat epitrochlearis and soleus muscles were dissected out after an acute bout of 3-hr swimming (without weight loading) or 3-hr treadmill running (15% grade at 9m/min). In a separate protocol, the isolated epitrochlearis and soleus muscles were incubated for 3 hr with AMP-dependent protein kinase activator AICAR. Immediately after the cessation of the 3-hr swimming, the TXNIP protein was decreased in epitrochlearis but not in soleus muscle. Conversely, 3-hr treadmill running decreased the TXNIP protein in soleus but not in epitrochlearis muscle. TXNIP protein was decreased concomitantly with reduced postexercise muscle glycogen, showing that a decrease in TXNIP protein expression occurs in muscles that are recruited during exercise. In addition, 3-hr incubation with AICAR decreased TXNIP protein in both isolated epitrochlearis and soleus muscles. Our results suggest that (a) an acute bout of exercise downregulates TXNIP protein expression in rat contracting skeletal muscles, and (b) the reduction in TXNIP protein expression in contracting muscles is probably mediated by AMPK activation, at least in part

Effect of high-fat diet on phosphorus absorption

Objective: Dietary carbohydrate/fat ratio may affect phosphorus metabolism because both calcium and phosphorus are regulated by similar metabolic mechanisms, and a high-fat diet (HF) induces deleterious effects on the absorption of dietary calcium. We hypothesized that the HF induces an increase in phosphorus absorption; therefore, this study aimed to evaluate the effects of differences in the quantity and quality of dietary fat on phosphorus metabolism over the short and long term. Research Methods & Procedures: Eighteen 8-week-old Sprague-Dawley male rats were fed an isocaloric diet containing varied carbohydrate/fat energy ratio and sources of fat (control diet [Control], HF, and high saturated-fat diet [HF-SFA]). At 3 days and 7 weeks after the allocation and initiation of the test diets, feces and urine were collected and used for phosphorus and calcium measurement. Results: The fecal phosphorous concentration (F-Pi) was lower in the HF-SFA group than in the other two groups; however, the urine phosphorus concentration (U-Pi) was significantly higher in the HF-SFA group than the other two groups when the rats were fed over the short (p<0.01) and long term (p<0.01 vs Control group, p<0.05 vs HF group). There were no significant differences in type-IIa sodium-phosphate cotransporter (NaPi-2a) and type-IIc sodium-phosphate cotransporter (NaPi-2c) mRNA expression, which are renal phosphate transport-related genes; however, the expression of type-IIb sodium-phosphate cotransporter (NaPi-2b) and type-III sodium-phosphate cotransporter (Pit-1) mRNA in the duodenum was higher in the HF and HF-SFA groups than in the Control group (p<0.05), although there were no significant differences in these in the jejunum. Conclusions: Our results indicated that HF, particularly HF-SFA, increases intestinal phosphate absorption compared with Control

Topology optimization of locomoting soft bodies using material point method

Topology optimization methods have widely been used in various industries, owing to their potential for providing promising design candidates for mechanical devices. However, their applications are usually limited to the objects which do not move significantly due to the difficulty in computationally efficient handling of the contact and interactions among multiple structures or with boundaries by conventionally used simulation techniques. In the present study, we propose a topology optimization method for moving objects incorporating the material point method, which is often used to simulate the motion of objects in the field of computer graphics. Several numerical experiments demonstrate the effectiveness and the utility of the proposed method

Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia

Ozaki T., Kawamoto T., Iimori Y., et al. Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia. Scientific Reports 10, 20915 (2020); https://doi.org/10.1038/s41598-020-77345-y.Achondroplasia is caused by gain-of-function mutations in FGFR3 gene and leads to short-limb dwarfism. A stabilized analogue of C-type natriuretic peptide (CNP) is known to elongate bone by interacting with FGFR3 signals and thus is a promising drug candidate. However, it needs daily administration by percutaneous injection. FGFR inhibitor compounds are other drug candidates for achondroplasia because they directly fix the mutant protein malfunction. Although FGFR inhibitors elongate the bone of model mice, their adverse effects are not well studied. In this study, we found that a new FGFR inhibitor, ASP5878, which was originally developed as an anti-cancer drug, elongated the bone of achondroplasia model male mice at the dose of 300 μg/kg, which confers an AUC of 275 ng·h/ml in juvenile mice. Although ASP5878 was less effective in bone elongation than a CNP analogue, it is advantageous in that ASP5878 can be administered orally. The AUC at which minimal adverse effects were observed (very slight atrophy of the corneal epithelium) was 459 ng·h/ml in juvenile rats. The positive discrepancy between AUCs that brought efficacy and minimal adverse effect suggests the applicability of ASP5878 to achondroplasia in the clinical setting. We also analyzed effects of ASP5878 in a patient-specific induced pluripotent stem cell (iPSC) model for achondroplasia and found the effects on patient chondrocyte equivalents. Nevertheless, cautious consideration is needed when referring to safety data obtained from its application to adult patients with cancer in clinical tests