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Abstract:In this article, I explore the concept of διαθήκη in Gal 3:15–18 in terms of "bequest and its execution." In this light, I argue that, in the context of a will, the verb κυρόω in 3:15 should be interpreted as referring to "execution" rather than "ratification," contrary to previous interpretations. I also examine the fact that in antiquity a bequest was irrevocable after its execution or the transfer of ownership. In accordance with a Jewish tradition, Paul may be alluding to the irrevocability of the bequest in 3:15–18, taking into account that God has already granted (κεχάρισται) an inheritance to Abraham (3:18b). Thus, Paul arguably envisaged that Abraham had already acquired a "bequeathed estate" (κληρονομία) from God (Gen 15), and so the Abrahamic covenant (διαθήκη) cannot be altered by adding stipulations (i.e., the law) because the διαθήκη has already come into effect (Gal 3:18b).

Noise reduction in low-dose positron emission tomography (PET) is a well-researched topic aimed at reducing patient radiation doses and improving diagnosis. Software-based noise reduction mainly improves the contrast between regions by reducing the variation of the acquired image. However, it should be performed under appropriate parameters to reduce discrimination. We propose a method that derives optimal noise-reduction parameters using the multi-scale structural similarity index measure and visual information fidelity, which are metrics for image quality assessment. Simulation and experimental studies demonstrated the viability of the proposed algorithm. The contrast-to-noise ratio value of the denoised reconstruction slice, which was used as the optimal parameter, increased approximately three times compared to that of the low-dose slice while preserving the resolution. The results indicate that the proposed method successfully predicted the parameters according to the noise-reduction algorithm and PET system conditions in the sinogram domain. The proposed algorithm should help prevent misdiagnosis and provide standardized medical images for clinical application by performing appropriate noise reduction.

Mitochondrial dysfunction is linked to degenerative diseases, resulting from cardiolipin (CL)-induced disruption of cristae structure in the inner mitochondrial membrane (IMM); therefore, preserving cristae and preventing CL remodeling offer effective strategies to maintain mitochondrial function. To identify reactive oxygen species (ROS)-blocking agents against mitochondrial dysfunction, a library of cyclohexylamine-containing cell-penetrating α-helical amphipathic “bundle” peptides were screened. Among these, CMP3013 is selectively bound to abnormal mitochondria, preserving the cristae structure impaired by mitochondria-damaging agents. With a stronger affinity for CL compared with other IMM lipid components, CMP3013 exhibited high selectivity. Consequently, it protected cristae, reduced ROS production, and enhanced adenosine triphosphate (ATP) generation. In mouse models of acute kidney injury, a 1 mg/kg dose of CMP3013 demonstrated remarkable efficacy, highlighting its potential as a therapeutic agent for mitochondrial dysfunction-related disorders. Overall, CMP3013 represents a promising agent for mitigating mitochondrial dysfunction and associated diseases.

Body odor is considered a diagnostic indicator of various infectious and chronic diseases. But, few studies have examined the odor markers for various toxic effects in the mammalian system. This study attempted to identify the novel diagnostic odor biomarkers for chemical-induced hepatotoxicity in animals. The changes in the concentration of odors were analyzed in the urine of Sprague Dawley (SD) rats treated with two dosages (100 or 200 mg/kg) of 1,2,3-trichloropropane (TCP) using gas chromatography-mass spectrometry (GC–MS). The TCP treatment induced significant toxicity, including a decrease in body weight, an increase in serum biochemical factors, and histopathological changes in the liver of SD rats. During this hepatotoxicity, the concentrations of six odors (ethyl alcohol, acrolein (2-propenal), methanesulfonyl chloride, methyl ethyl ketone, cyclotrisiloxane, and 2-heptanone) in urine changed significantly after the TCP treatment. Among them, acrolein, an acrid and pungent compound, showed the highest rate of increase in the TCP-treated group compared to the Vehicle-treated group. In addition, this increase in acrolein was accompanied by enhanced spermine oxidase (SMOX) expression, an acrolein metabolic enzyme, and the increased level of IL-6 transcription as a regulator factor that induces SMOX production. The correlation between acrolein and other parameters was conformed using correlagram analyses. These results provide scientific evidence that acrolein have potential as a novel diagnostic odor biomarker for TCP-induced hepatotoxicity.

Gallic acid (GA) is a phenolic compound known as 3,4,5-trihydroxybenzoic acid. GA is used as a hair dye ingredient. It is limited to be below 4.0% in Korea. Dermal absorption rate of GA has not been reported yet. In this study, an analytical method for GA was developed and validated using high-performance liquid chromatography (HPLC) in various matrices of swab, stratum corneum (SC), skin (dermis + epidermis), and receptor fluid (RF). HPLC analysis showed acceptable linearity (r2= 0.999–0.9998), accuracy (90.3–112.8%), and precision (0.7–13.6%) in accordance with validation guidelines by Korea Ministry of Food and Drug Safety (MFDS). The dermal absorption rate of GA was determined using Franz diffuse cells. GA (4.0%) was applied to mini pig skin of 10 μl/cm2. After 30 min application, the GA was wiped out and receptor fluid sampling was continued until 24 h. After 24 h, skin was wiped off with swab and SC was collected using tape stripping. All samples were extracted with ethanol and analyzed using the validated method. The total dermal absorption rate of GA was determined to be 2.6 ± 1.3% (24 h).

Aircraft flap mechanisms require high safety standards because they must withstand large, complex forms of aerodynamic loads during flight. This paper proposes a computational analysis methodology for verifying the design of the aircraft flap-driving mechanism through MBD (Multi-Body Dynamics) and investigates the operating environment of the flap for analysis. Specifically, the aerodynamic loads obtained from CFD (Computational Fluid Dynamics) were applied using One-way and two-way Co-Simulation methods to analyze the MBD. From the analysis, the required actuator capacity to drive the flap and mechanical jamming between the rolle and the rail were investigated using the proposed flap mechanism analysis methodology. The analysis results indicated that the flap model under this study experienced mechanical jamming during flap deployment.

ObjectivesMalignant pericardial effusion (MPE) in patients with cancer is associated with poor prognosis. This study aimed to compare clinical outcomes in patients with cancer who underwent pericardiocentesis versus pericardial window formation.MethodsIn the present study, 765 consecutive patients with cancer (mean age 58.4 years, 395 men) who underwent pericardial drainage between 2003 and 2022 were retrospectively analysed. All-cause death and MPE recurrence were compared based on the drainage method (pericardiocentesis vs pericardial window formation) and time period (period 1: 2003–2012; period 2: 2013–2022).ResultsPericardiocentesis was performed in 639 (83.5%) patients and pericardial window formation in 126 (16.5%). There was no difference in age, sex distribution, proportion of metastatic or relapsed cancer, and chemotherapy status between the pericardiocentesis and pericardial window formation groups. Difference was not found in all-cause death between the two groups (log-rank p=0.226) regardless of the period. The pericardial window formation group was associated with lower MPE recurrence than the pericardiocentesis group (6.3% vs 18.0%, log-rank p=0.001). This advantage of pericardial window formation was more significant in period 2 (18.1% vs1.3%, log-rank p=0.005). In multivariate analysis, pericardial window formation was associated with lower MPE recurrence (HR: 0.31, 95% CI: 0.15 to 0.63, p=0.001); younger age, metastatic or relapsed cancer, and positive malignant cells in pericardial fluid were associated with increased recurrence.ConclusionIn patients undergoing pericardial drainage for MPE, pericardial window formation showed mortality outcomes comparable with pericardiocentesis and was associated with lower incidence of MPE recurrence.

Due to high consumption of cosmetics in modern society, people are always exposed to the risk of skin damage and complications. Para-phenylenediamine (P-PD), an ingredient of hair dye, has been reported to cause allergic contact dermatitis. However, the mechanism has not been well elucidated. Here, we identify that P-PD causes dermatitis by increasing thymic stromal lymphopoietin (TSLP) and inflammatory cytokines. Topical application of P-PD to mouse ear skin in consecutive 5 days resulted in dermatitis symptoms and increased ear thickness. TSLP production in skin was upregulated by P-PD treatment alone. In addition, P-PD-induced TSLP production was potentiated by MC903, which is an in vivo TSLP inducer. P-PD increased TSLP production in keratinocytes (KCMH-1 cells and phorbol 12-myristate 13-acetate-stimulated PAM212 cells). The production of proinflammatory cytokines such as IL-1β, IL-6, IFN-γ, and CCL2, was upregulated by P-PD treatment together with MC903. The results show that repeated exposure to P-PD causes acute contact dermatitis mediated by increasing the expression of TSLP and proinflammatory cytokines.

Placental site nodules (PSNs) are non-neoplastic remnants of chorionic-type intermediate trophoblastic cells from a previous gestation that form a well-defined single nodule or multiple nodules in the uterine and extrauterine sites. As the cases of PSNs transformed into gestational trophoblastic tumors were described in the literature, “atypical placental site nodules” (APSNs) have been considered as putative transitional lesions between PSNs and gestational trophoblastic tumors. Although histologic criteria and cutoff point of Ki-67 proliferation index for differentiating an APSN from a typical PSN have not been clearly defined, nodules larger than 5 mm with increased cellularity, a corded or nested appearance, marked nuclear atypia, increased mitotic activity, and an increased Ki-67 proliferation index (>5% or >8%) of intermediate trophoblastic cells seem to be accepted as diagnostic criteria for APSNs. However, some of the criteria, including lesion size and histologic features of the trophoblastic cells in the nodule are not only subjective but have features inherent of the intermediate trophoblastic cells of the fetal membrane and a typical PSN. We thought that it is not reasonable to consider them as diagnostic features of APSNs, if not associated with cellular proliferation. We present 2 cases of incidentally identified PSNs that were larger than 10 mm in size with a corded or nested arrangement of trophoblastic cells, which could have been categorized as APSNs according to the currently proposed criteria to discuss whether the currently proposed diagnostic criteria for APSNs are appropriate.

Cocamidopropyl betaine (CAPB) is a surfactant derived from coconut oil that is widely used in cosmetics and personal products for several purposes, such as a surfactant, foam booster, mildness, and viscosity control. Cocamidopropyl betaine is used at concentrations up to 30% in cosmetics. The acute toxicity, skin irritation, eye irritation, skin sensitization, repeated dose toxicity, genotoxicity, carcinogenicity, and phototoxicity of cocamidopropyl betaine were evaluated. Cocamidopropyl betaine was observed to induce mild skin irritation, eye irritation and skin sensitization. The NOAEL of cocamidopropyl betaine was determined to be 250 mg/kg/day based on the results of a 92-day repeated-dose oral toxicity study in rats. The systemic exposure dose of cocamidopropyl betaine was estimated to range from 0.00120 to 0.93195 mg/kg/day when used in cosmetic products. The margin of safety of cocamidopropyl betaine was calculated to be greater than 100 when used at a maximum concentration of 6% in leave-on products and 30% in rinse-off products, suggesting that its use in cosmetic products is safe under current usage conditions.

Dodecamethylcyclohexasiloxane (D6) is a siloxane substance mainly used in cosmetics and personal care products. While octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) were once commonly used in personal care products, their usage has been restricted due to the classification as persistent, bioaccumulative, and toxic (PBT)/very persistent and very bio-accumulative (vPvB) substances. While D6 has emerged as a substitute for D4 and D5, the risk assessment for D6 remains limited compared to the evaluations for D4 and D5. To address this gap, we conducted a comprehensive risk assessment of D6. In this study, we reviewed the toxicity information on D6 and calculated the exposure level to D6, considering the content of D6 in cosmetic products. No observed adverse effect level (NOAEL) of 1500 mg/kg bw/day was established in a repeated dose toxicity study after oral administration to rats. Negative results were found in tests on the ocular and skin irritation, skin sensitization, and genotoxicity of D6. According to the product content of up to 48% of D6 reported in 2012, the Systemic Exposure Dose (SED) was 5.4E-06 to 7.04 mg/kg bw/day for a 60 kg adult using the exposure factors from Korean cosmetic usage. The Margin of Safety was estimated to be between 35.5 and 4.63E+07, posing a potential health risk of D6 according to the maximum concentration and the product type. Further consideration of the potential of D6 as PBT or vPvB is also required.

This study aimed to compare the outcomes, according to percutaneous mitral valvuloplasty (PMV) vs mitral valve replacement (MVR), of severe mitral stenosis (MS) with the updated criteria (MVA ≤ 1.5 cm2).

IMPORTANCE: The NIFTY trial demonstrated the benefit of treatment with second-line liposomal irinotecan (nal-IRI) plus fluorouracil (FU) and leucovorin (LV) for patients with advanced biliary tract cancer (BTC). OBJECTIVE: To report the updated efficacy outcomes from the NIFTY trial with extended follow-up of 1.3 years with reperformed masked independent central review (MICR) with 3 newly invited radiologists. DESIGN, SETTING, AND PARTICIPANTS: The NIFTY trial was a randomized, multicenter, open-label, phase 2b clinical trial conducted between September 5, 2018, and December 31, 2021, at 5 tertiary referral centers in South Korea. Patients with advanced BTC whose disease progressed while receiving first-line gemcitabine plus cisplatin with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors, version 1.1, were eligible. Data analysis was completed on May 9, 2022. INTERVENTIONS: Patients were randomized 1:1 to receive LV, 400 mg/m2, bolus and FU, 2400 mg/m2, for a 46-hour infusion intravenously every 2 weeks with or without nal-IRI, 70 mg/m2, before LV intravenously. Patients were treated until disease progression or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: Primary end point was progression-free survival (PFS) as assessed by MICR. Secondary end points were PFS as assessed by the investigator, overall survival, and objective response rate. RESULTS: A total of 178 patients (75 women [42.1%]; median [IQR] age, 64 [38-84] years) were randomly assigned, and 174 patients were included in the full analysis set (88 patients [50.6%] in the nal-IRI plus FU/LV group vs 86 patients [49.4%] in the FU/LV alone group). In this updated analysis, the median MICR-assessed PFS was 4.2 months (95% CI, 2.8-5.3) for the nal-IRI plus FU/LV group and 1.7 months (95% CI, 1.4-2.6) for the FU/LV alone group (hazard ratio, 0.61; 95% CI, 0.44-0.86; P = .004), in contrast to the 7.1 and 1.4 months reported in the previous study, respectively. The discordance rate for tumor progression date between the MICR and investigators was 17.8% (vs 30% in the previous study). CONCLUSIONS AND RELEVANCE: The NIFTY randomized clinical trial demonstrated significant improvement in PFS with treatment with nal-IRI plus FU/LV compared with FU/LV alone for patients with advanced BTC after progression to gemcitabine plus cisplatin. The combination of nal-IRI plus FU/LV could be considered as a second-line treatment option for patients with previously treated advanced BTC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03524508

Muon tomography is a useful method for monitoring special nuclear materials (SNMs) such as spent nuclear fuel inside dry cask storage. Multiple Coulomb scattering of muons can be used to provide information about the 3-dimensional structure and atomic number(Z) of the inner materials. Tomography using muons is less affected by the shielding material and less harmful to health than other measurement methods.

In radiography, an antiscatter grid is a well-known device for eliminating unexpected x-ray scatter. We investigate a new stationary grid artifact suppression method based on a nonsubsampled contourlet transform (NSCT) incorporated with Gaussian band-pass filtering. The proposed method has an advantage that extracts the Moiré components while minimizing the loss of image information and apply the prior information of Moiré component positions in multi-decomposition sub-band images. We implemented the proposed algorithm and performed a simulation and an experiment to demonstrate its viability. We did this experiment using an x-ray tube (M-113T, Varian, focal spot size: 0.1 mm), a flat-panel detector (ROSE-M Sensor, Aspenstate, pixel dimension: 3032 × 3800 pixels, pixel size: 0.076 mm), and carbon graphite-interspaced grids (JPI Healthcare, 18 cm × 24 cm, line density: 103 LP/inch and 150 LP/inch, ratio: 5:1, focal distance: 65 cm). Our results indicate that the proposed method successfully suppressed grid artifacts by reducing them without either reducing the spatial resolution or causing negative side effects. Consequently, we anticipate that the proposed method can improve image acquisition in a stationary grid x-ray system as well as in extended x-ray imaging.

Bioactive sphingolipids and enzymes that metabolize sphingolipid-related substances have been considered as critical messengers in various signaling pathways. One such enzyme is the crucial lipid kinase, sphingosine kinase (SphK), which mediates the conversion of sphingosine to the potent signaling substance, sphingosine-1-phosphate. Several studies have demonstrated that SphK metabolism is strictly regulated to maintain the homeostatic balance of cells. Here, we summarize the role of SphK in the course of liver disease and illustrate its effects on both physiological and pathological conditions of the liver. SphK has been implicated in a variety of liver diseases, such as steatosis, liver fibrosis, hepatocellular carcinoma, and hepatic failure. This study may advance the understanding of the cellular and molecular foundations of liver disease and establish therapeutic approaches via SphK modulation.

The optimization of air-breathing hypersonic propulsion system designs is crucial for ensuring the viability of aircraft in extreme thermal environments. Integrating a reliable heat transfer model of regenerative cooling systems is important in this optimization process. This study focuses on enhancing the heat transfer model for the cooling channels of scramjet engines operating at Mach 5, with a combustor operating pressure of 3 MPa. The study investigates the thermal properties and phenomena associated with the supercritical state of n-dodecane, as well as heat transfer deterioration (HTD). By improving the modified Bae-Kim (m-BK) heat transfer model, we propose an efficient model to enhance the design of scramjet propulsion systems. Our enhanced one-dimensional heat transfer model successfully integrates the heat transfer phenomenon in the cooling channels. The model accurately represents the supercritical characteristics of n-dodecane considering the three-dimensional aspects of the cooling channel.

The diagnosis of vestibular neuritis is based on clinical and laboratory findings after exclusion of other disease. There are occasional discrepancies between clinical impressions and laboratory results. It could be the first vertigo episode caused by other recurrent vestibular disease, other than vestibular neuritis.

From a conversation-analytic perspective, this article describes how “creative” formulation of resonance is effectuated through dialogic engagement in Korean conversation. It examines various forms of word play and categorisation work accomplished from dialogically engaging a prior utterance, whose features are reproduced in the subsequent utterance, such that resonance arises in an array of “creative” co-construction of adjoined utterances (e.g. in creating playful word play, empathic uptake or a sonorous repetition indexing allusive stance and heightened affect). Syllabic matching figures saliently in this process, shaping resonant sound sequences whose patterning endows talk with “poetic” qualities, sometimes bearing on the organisation of sequence and topic. The findings indicate that the syllable-matching practice furnishes Korean speakers with the means to accomplish “doing being creative” in organising recognisable actions and an undercurrent of flow of talk, through having the dialogical potential of a prior utterance maximally tested, explored and expanded on in syllabic terms.

This study attempts to understand and elucidate the factors limiting/determining the external quantum efficiency (EQE) of light‐emitting diodes (LEDs) depending on material systems, i.e., III‐arsenide (GaAs), III‐phosphide (AlGaInP), and III‐nitride (GaInN), via the temperature measurements (30–500 K). The behaviors of EQEs are investigated carefully in terms of the thermal droop and efficiency droop, revealing that the thermal droop in the AlGaInP and GaAs LEDs, while the efficiency droop in the GaInN LEDs, is a critical factor limiting the EQE. To deepen the insight, the EQE is separated into internal quantum efficiency (IQE) and light‐extraction efficiency (LEE). Further, the IQE is separated into radiative efficiency (RE) and injection efficiency (IE). The analysis shows that the LEE plays a significant role in the thermal droop for the AlGaInP and GaAs LEDs. Meanwhile, the IE and RE play a significant role in the EQE reduction of the blue and red LEDs at high temperatures and high current injection. This study attempts to understand the factors limiting the external quantum efficiency of light‐emitting diodes (LEDs) depending on material systems, i.e., GaAs, AlGaInP, and GaInN, via temperature experiments. The analysis shows that the light‐extraction efficiency and injection efficiency play critical roles in the thermal droop for the AlGaInP and GaAs LEDs, and the efficiency droop for the GaInN LED, respectively.

South Korea imported nuclear fuel in the 1970s and 1980s when nuclear power plants were first introduced. Then, it established a nuclear fuel localization programme through which first generation fuel [...]

Background Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A ([mARD1A.sup.225]) acetylates HIF-1[alpha], triggering its degradation, and thus may play a role in decreased expression of VEGFA. Methods We generated [Apc.sup.Min/+]/[mARD1A.sup.225] transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing [mARD1A.sup.225] were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of [mARD1A.sup.225] acetylation of Lys532 in HIF-1[alpha], we injected B16F10-[mARD1A.sup.225] cell lines stably expressing mutant HIF-1[alpha]/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant. Results [Apc.sup.Min/+]/[mARD1A.sup.225] transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than [Apc.sup.Min/+] mice (n = 21) (number of intestinal polyps per mouse: [Apc.sup.Min/+] mice vs [Apc.sup.Min/+]/[mARD1A.sup.225] transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with [mARD1A.sup.225]- overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of [mARD1A.sup.225] decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and [Apc.sup.Min/+] intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1[alpha] in B16F10-[mARDIA.sup.225] cells prevented HIF-1[alpha] degradation and inhibited the antimetastatic effect of [mARD1A.sup.225] (P < .001). Conclusion mARD1A22s may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis. DOI: 10.1093/jnci/djq026

Purpose: This study aimed to investigate clinical pharmacokinetics (PKs) of choline after oral administration of choline alfoscerate capsule and newly developed syrup formulation using population pharmacokinetic modeling and simulation approach. Methods: Each subject received 1,200 mg single administration of choline alfoscerate capsule or syrup. Blood collection was performed 13 times each day before administration and on the day of administration. Baseline blood was collected to investigate the circadian rhythm of endogenous substance of choline. A PK model of choline was developed to describe baseline circadian wave and its absorption and disposition characteristics after oral administration of exogenous choline substances. Furthermore, the developed model was used to generate stochastic simulation data for investigating choline exposure with a regimen of clinical practice settings. Results: The one-compartment with circadian input, first-order absorption, and first-order elimination well described the plasma concentration of choline. Baseline circadian wave was described using cosine function with parameters of baseline concentration (C0), amplitude (Amp), and time shift to peak (Tshift). Intrinsic choline concentration followed a typical circadian rhythm. Exogenous choline substance increased the endogenous choline concentration. Furthermore, three times daily dosing of choline alfoscerate increased choline exposure than once a day administration with the same amount of choline alfoscerate. Conclusion: This is the first study investigating PKs of choline alfoscerate using pharmacokinetic modeling, including circadian input function to ameliorate physiological and pharmacological properties of choline. Results of this study provide meaningful information for evaluating clinical effectiveness of choline alfoscerate.

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize.

Background The molecular chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor l[alpha] (HIF-1[alpha]) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90. Method Human xenograft tumors were generated in mice from H1299 (n = 6 per group) and A549 (n = 4 per group) non-small-cell lung cancer cells, UMSCC38 (n = 5 per group) head and neck cancer cells, MKN45 (n = 5 per group) stomach cancer cells, and PC-3 (n = 3 per group) prostate cancer cells. Tumor-bearing mice were treated with deguelin at 4 or 8 mg/kg or with vehicle (as a control) twice a day by oral gavage for 15-28 days. Protein expression was assessed by western blot analysis. Akt and Hsp90 were assessed by use of adenoviral vectors expressing constitutively active Akt or Hsp90. Binding of deguelin to Hsp90 was examined by docking analysis and by competition binding experiments with ATP-Sepharose beads. The proteasome inhibitor MG132 was used to investigate deguelin's effect on the induction of ubiquitin-mediated proteasomal degradation of HIF-1[alpha]. All statistical tests were two-sided. Results Deguelin bound to the ATP-binding pocket of Hsp90 and disrupted Hsp90 function, leading to ubiquitinmediated degradation of HIF-1[alpha] Administration of deguelin to xenograft-bearing mice statistically significantly decreased tumor growth by inducing apoptosis and decreasing the expression of Hsp90 client proteins, without detectable toxic effects. For example, at 15 days after the start of deguelin treatment, the volume of untreated control H1299 xenograft tumors was 798 [mm.sup.3] and that of xenograft tumors treated with deguelin at 4 mg/kg was 115.9 [mm.sup.3] (difference = 682.1 [mm.sup.3], ,5% confidence interval = 480.4 to 883.9 [mm.sup.3]; P Conclusions The antitumor activities of deguelin appear to involve its binding to the ATP-binding pocket of Hsp90, hich suppresses Hsp90 function.

Vibrotactile rendering is a process of computing and generating haptic information in response to a user's interaction with virtual objects. The crucial procedure in the vibrotactile rendering is to transform the simulated behavior of a virtual object into vibrotactile information according to user's action. This paper presents a vibrotactile rendering method that expresses the reaction of a car on a road surface in a racing game using vibrotactile information. To this end, we first design a miniaturized vibrotactile rendering system with an eccentric vibration motor and a solenoid actuator, which generates vibrotactile information having a large bandwidth and amplitude. We also construct an interactive racing game as a test bed for the proposed vibration rendering method. We designed voltage input patterns that can be haptically discriminated by human for experiments. The proposed vibrotactile rendering based on these patterns generates control input to vibrotactile actuators to make users realistically feel the sensation of collision, driving on a bump, driving on a hard shoulder. To evaluate the proposed vibrotactile rendering method, nine persons experience two kind of racing games; one is the game with the proposed vibrotactile rendering, and the other is the game without the vibrotactile rendering. After the experiment, participants are asked to compare and appraise those two games based on suggested criteria. The experiment clearly shows the effectiveness and the feasibility of the proposed vibrotactile rendering method, which implies the sufficient applicability of the proposed vibrotactile rendering system to mobile devices (1). Index Terms--Game, vibrotactile information, haptic rendering.

Study objectives: Mycoplasma pneumoniae is a common cause of lower respiratory disease. Several studies have suggested that respiratory infection by M pneumoniae is associated with reactive airway disease and asthma. [...]

Smart phototheranostic nanomaterials are of significant interest for high-quality imaging and targeted therapy in the precision medicine field. Herein, a nanoscale photosensitizer (NanoPcM) is constructed through the self-assembly of morpholine-substituted silicon phthalocyanine (PcM) and albumin. NanoPcM displays a turn-on fluorescence depending on the acid-induced abolition of the photoinduced electron transfer effect (change in molecular structure) and disassembly of the nanostructure (change in supramolecular structure), which enables low-background and tumor-targeted fluorescence imaging. In addition, its efficient type I photoreaction endows NanoPcM with a superior immunogenic photodynamic therapy (PDT) effect against solid tumors. The combination of NanoPcM-based PDT and αPD-1-based immunotherapy can efficiently inhibit tumor growth, reduce spontaneous lung metastasis, and trigger abscopal effects. This study should provide a perspective for the future design of nanomaterials as promising phototheranostics for cancer imaging and therapy.

In the present report, we describe the synthesis and structure–activity relationships of novel “four-arm” dihydropyrazoline compounds designed as peripherally restricted antagonists of cannabinoid-1 receptor (CB1R). A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB1receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, showed high affinity for CB1R and potent in vitroCB1R antagonist activities. Promising compounds with potent CB1R activity were evaluated in tissue distribution studies. Compounds 6a, 6f, and 7cshowed limited brain penetrance attesting to its peripheral restriction. The 4S-enantiomer of these compounds further showed a stereoselective affinity for the CB1receptor and behaved as inverse agonists. In vivostudies on food intake and body weight reduction in diet-induced obese (DIO) mice showed that these compounds could serve as potential leads for the development of selective CB1R antagonists with improved potency and peripheral restriction.

Background: Transoral thyroidectomy has superior cosmesis and better postoperative voice outcomes than conventional thyroidectomy. However, it usually requires a steep learning curve and longer operative time. The transoral robotic thyroidectomy (TORT) learning curve has not been well investigated. This study aimed to evaluate the TORT learning curve and factors affecting operative time. Methods: We retrospectively studied 173 consecutive patients who underwent TORT with or without central neck dissection from July 2017 to August 2021. We assessed the TORT learning curve using operative time, complication rate, and surgical success (procedure conversion) rate. The operative time and surgical success rate learning curves were calculated using the cumulative summation (CUSUM) method. Additionally, we analyzed factors affecting operative time in TORT. Results: Total thyroidectomy operative time was significantly longer than those of lobectomy and isthmusectomy (p&lt; 0.001). In correlation analysis, a significantly positive correlation was observed between body mass index (BMI) and operative time (R2= 0.04, p= 0.025). The TORT learning curve was 52 cases in the CUSUM operative time analysis. In the CUSUM surgical success rate chart, the turning point was the 55th case. Complication and procedure conversion rates were significantly decreased after the learning curve. Conclusions: The CUSUM learning curve of TORT was about 52–55 cases, and the operative time, total complication rate, and procedure conversion decreased significantly after the learning curve. The operative time was associated with the extent of thyroidectomy and BMI. Graphical abstract:

Vehicle systems for safety and driver convenience are being installed worldwide. In particular, in the case of a large vehicle accident, various safety devices are applied to avoid risks to human life and property. Among these systems, the most basic are electric braking systems, lane departure warning systems, lane-keeping assistance systems, and drowsiness prevention devices. In particular, a device to improve the braking performance of large vehicles to prevent accidents is important. Auxiliary brakes are used to prevent the frequent use of the main brake and share the braking force in large vehicles. If the main brake is used excessively, braking power loss, such as vapor lock, may occur. Therefore, it is essential to install an auxiliary brake for large vehicles. There are several auxiliary brakes; however, structurally simple exhaust brakes are the most commonly used. Pneumatic actuators are used to operate the existing exhaust brakes and additional parts are used to create pressure; therefore, it is necessary to develop electric exhaust brakes. Electric exhaust brakes can reduce weight and cost by removing modules and additional parts. In this study, the electrified exhaust brake system was improved compared with the existing pneumatic actuator. A DC motor is applied to obtain this benefit, which is easy to control and inexpensive was designed. A high-ratio reducer was applied in consideration of the characteristics of the exhaust brake that requires high torque. To verify the performance, the module unit test, module test, and field test were performed.

Ninjurin1 (Ninj1), an adhesion molecule, regulates macrophage function in hyaloid regression, multiple sclerosis, and atherosclerosis. However, its biological relevance and the mechanism underlying its function in vascular network integrity have not been studied. In this study, we investigated the role of Ninj1 in physiological (postnatal vessel formation) and pathological (endotoxin-mediated inflammation and diabetes) conditions and developed a strategy to regulate Ninj1 using specific micro (mi)RNAs under pathological conditions. Ninj1-deficient mice exhibited decreased hyaloid regression, tip cell formation, retinal vascularized area, recruitment of macrophages, and endothelial apoptosis during postnatal development, resulting in delayed formation of the vascular network. Five putative miRNAs targeting Ninj1 were selected using the miRanda algorithm and comparison of expression patterns. Among them, miR-125a-5p showed a profound inhibitory effect on Ninj1 expression, and miR-125a-5p mimic suppressed the cell-to-cell and cell-to-matrix adhesion of macrophages and expression of pro-inflammatory factors mediated by Ninj1. Furthermore, miR-125a-5p mimic inhibited the recruitment of macrophages into inflamed retinas in endotoxin-induced inflammation and streptozotocin-induced diabetes in vivo. In particular, miR-125a-5p mimic significantly attenuated vascular leakage in diabetic retinopathy. Taken together, these findings suggest that Ninj1 plays a pivotal role in macrophage-mediated vascular integrity and that miR-125a-5p acts as a novel regulator of Ninj1 in the management of inflammatory diseases and diabetic retinopathy.

Although 2-amino-5-nitrophenol (2A5NP) is one of the ingredients of hair dye, there has been no information on the dermal absorption rate of 2A5NP. 2A5NP is managed at less than 1.5% in Korea and Japan. In this study, analytical methods were developed and validated using high-performance liquid chromatography (HPLC) in various matrices of wash, swab, stratum corneum (SC), skin (dermis + epidermis), and receptor fluid (RF). Validation results were acceptable based on Korea Ministry of Food and Drug Safety (MFDS) guideline. The HPLC analysis showed a good linearity (r2= 0.9992–0.9999), a high accuracy (93.1–110.2%), and a good precision (1.1–8.1%) in accordance with the validation guideline. Franz diffusion cell was used to determine dermal absorption of 2A5NP using mini pig skin. 2A5NP (1.5%) was applied to skin at 10 μl/cm2. For certain cosmetic ingredients such as hair dye with short exposure time, an interim wash step (after 30 min) was added during the study. After application for 30 min and 24 h, skin was wiped off with swab and SC was collected using tape stripping. RF was sampled at 0, 1, 2, 4, 8, 12, and 24 h. Total dermal absorption rate of 2A5NP (1.5%) was determined to be 13.6 ± 2.9%.

Small-animal positron emission tomography (PET) systems are widely used for pathological and pharmacological studies. For good image quality, the timing resolution should be kept as low as possible, so we proposed a pulse reconstruction method based on curve fitting using a bi-exponential model for digital timing pickoff. To evaluate the proposed method, five different digital timing algorithms, leading edge discrimination (LED), digital constant fraction discrimination (DCFD), maximum rising interpolation (MRI), initial rising interpolation (IRI), and pulse reconstruction (PR) were established and compared. A single gamma pulse obtained from the silicon photomultiplier (SiPM) was simulated and the timing resolution was calculated according to the algorithms. Additionally, these methods were applied to the real PET dataset obtained from the AGPET detector and the timing resolution was derived. The simulation results proved that the PR method showed constant timing resolution independent from pulse rise time and sampling rate. In the experimental results, the PR method showed the best timing resolution of 0.9 ns to compare other digital methods. The results demonstrated that the proposed PR method can improve the performance of the small-animal PET with a relatively slow ADC.

This paper proposes a synthetic inertia control (SIC) scheme for a permanent-magnet synchronous generator-based wind turbine generator (WTG). The proposed SIC scheme uses only the frequency deviation loop operating in conjunction with the maximum power point tracking loop. To improve the frequency nadir while preventing over-deceleration of a WTG, the proposed scheme employs a variable control gain for the frequency deviation loop, which varies linearly with the rotor speed. In the high-rotor-speed region, the gain is set to be high so that the frequency nadir can be improved. In the low-rotor-speed region, the gain decreases with the rotor speed so that over-deceleration can be prevented while improving the frequency nadir. To investigate the efficacy of the proposed gain, simulation case studies are conducted in the modified IEEE 14-bus system under varying wind speeds and event sizes. Simulation results indicate that the proposed scheme successfully improves the frequency nadir while preventing over-deceleration of the rotor speed by varying the control gain in a linear manner with the rotor speed.

For tensile tests, Vickers hardness tests and microstructure tests, plate-type and box-type specimens of austenitic 316L stainless steels were produced by a conventional machining (CM) process as well as two additive manufacturing processes such as direct metal laser sintering (DMLS) and direct metal tooling (DMT). The specimens were irradiated up to a fast neutron fluence of 3.3 × 109n/cm2at a neutron irradiation facility. Mechanical performance of the unirradiated and irradiated specimens were investigated at room temperature and 300 °C, respectively. The tensile strengths of the DMLS, DMT and CM 316L specimens are in descending order but the elongations are in reverse order, regardless of irradiation and temperature. The ratio of Vickers hardness to ultimate tensile strength was derived to be between 3.21 and 4.01. The additive manufacturing processes exhibit suitable mechanical performance, comparing the tensile strengths and elongations of the conventional machining process.

Acquired hemophilia A (AHA) occurs rarely in children. We report 2 cases of adolescent females with AHA. The first case underwent bone marrow aspiration/biopsy during workup, which was complicated by bleeding. Bleeding resolved after initiation of therapy with cyclophosphamide and glucocorticoid, but despite the addition of rituximab, she did not achieve complete remission until treatment with intravenous immunoglobulin. In the second case, we observed that a mixing study without incubation will not detect an acquired factor VIII inhibitor, but further workup based on suspicion for AHA led to the correct diagnosis. Both had significant medication toxicity which required treatment modification.

An efficient aerodynamic analysis was conducted for rapid prediction of the aerodynamic performance of air-breathing hypersonic vehicles in the early design phase. Surface pressure calculation on compression surfaces was performed using local surface inclination methods such as modified Newtonian, tangent cone, and tangent wedge methods. The Prandtl–Meyer expansion method was adopted for surface pressure calculation on expansion surfaces. Sharma’s three-dimensional correction is applied to the Prandtl–Meyer expansion if needed. The reference temperature method was used for the prediction of the local skin friction coefficient. An efficient approximate streamline tracing method was suggested to calculate the reference length for each local surface cell with just one percent of the CPU time required for the original naive stream tracing method. An internal flow passage for air-breathing propulsion was also considered under the isentropic assumption for prediction of aerodynamic performance of a whole vehicle. Comparisons are made for aerodynamic coefficients calculated by the present code and a high fidelity CFD code for a X-51A-like configuration at flight conditions of Mach 5 and 6, and good agreements were obtained. The developed code is very efficient and possesses enough accuracy for engineering prediction of the aerodynamic performance of hypersonic air-breathing vehicles.

The present study investigated the effect of as-built and post heat-treated microstructures of IN738LC alloy fabricated via selective laser melting process on high temperature oxidation behavior. The as-built microstructure showed fine cell and columnar structure due to high cooling rate. Ti element segregation was observed in inter-cell/inter-columnar area. After post heat-treatment, the initially-observed cell structure disappeared, instead bimodal Ni 3 (Al, Ti) particles formed. High temperature (1273 K and 1373 K) oxidation test results showed parabolic oxidation curves regardless of temperature and initial microstructure. The as-built IN738LC fabricated via the selective laser melting process displayed oxidation resistance similar to or slightly better than that of IN738LC fabricated via wrought or cast process. Heat-treated SLM IN738LC, although had similar oxidation weight-gain values to those of the SLM as-built material at 1273 K , showed relatively better oxidation resistance at 1373 K. Bimodal Ni 3 (Al, Ti) precipitate formed in the post heat treatment changed the local chemical composition, thereby led to changes in alumina former/chromia former location and fraction on the alloy surface. It was concluded that in heat-treated IN738LC increased alumina former fraction was found, and this resulted in excellent oxidation resistance and relatively low weight-gain. [ABSTRACT FROM AUTHOR]

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600mutant cells1–3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E-and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAFwithin the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAFmutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAFmutations as a driver of resistance to RAF dimer inhibitors.

Fecal calprotectin, an indicator of colonic inflammation, is associated with nonconstipated irritable bowel syndrome. Rifaximin is an antibiotic used to treat nonconstipated irritable bowel syndrome. We performed a retrospective review of patient charts to investigate the changes in fecal calprotectin levels and intestinal symptoms following treatment with rifaximin in patients with nonconstipated irritable bowel syndrome with elevated fecal calprotectin.

This study investigated the effect of multi-step heat treatment on the microstructure, mechanical properties and fracture behavior of thick 15Co-12Ni secondary hardening steel. As-quenched sample was found to have elongated prior austenite grain (PAG) and coarse lenticular martensitic structure. On the other hand, heat-treated sample was observed to have fine lenticular martensitic structure due to fine PAG size and a lot of nano-sized carbides. Also, after heat treatment, nano-scale reverted austenite film was formed at the martensite interfaces. The heat-treated sample showed 2.47 GPa superior tensile strength and superior elongation of about 12 %. The high strength was mainly due to fine block size and high number density of nano-sized carbides. The average value of plane strain fracture toughness (K IC) was 29.3 MPa m , which indicated a good fracture toughness even with the high tensile strength. The tensile fracture surface was observed to have ductile fracture mode (cup-and-cone) and the formation of about ∼1 μm ultra-fine dimples. In addition to this, nano-sized carbides were observed within the dimples. The findings suggested that the nano-sized carbide had a positive effect not only on the strength but also on the ductility of the alloy. The fractured surface after toughness test, also showed ductile fracture mode with a lot of dimples. Based on the above results, correlation among microstructural evolution, deformation and fracture mechanisms along the heat-treatment was also discussed. [ABSTRACT FROM AUTHOR]