Novel Mechanism-Based Descriptors for Extreme Ultraviolet-Induced Photoacid Generation: Key Factors Affecting Extreme Ultraviolet Sensitivity.

Predicting photolithography performance in silico for a given materials combination is essential for developing better patterning processes. However, it is still an extremely daunting task because of the entangled chemistry with multiple reactions among many material components. Herein, we investigated the EUV-induced photochemical reaction mechanism of a model photoacid generator (PAG), triphenylsulfonium cation, using atomiC-Scale materials modeling to elucidate that the acid generation yield strongly depends on two main factors: the lowest unoccupied molecular orbital (LUMO) of PAG cation associated with the electron-trap efficiency 'before C-S bond dissociation' and the overall oxidation energy change of rearranged PAG associated with the proton-generation efficiency 'after C-S bond dissociation'. Furthermore, by considering stepwise reactions accordingly, we developed a two-parameter-based prediction model predicting the exposure dose of the resist, which outperformed the traditional LUMO-based prediction model. Our model suggests that one should not focus only on the LUMO energies but also on the energy change during the rearrangement process of the activated triphenylsulfonium (TPS) species. We also believe that the model is well suited for computational materials screening and/or inverse design of novel PAG materials with high lithographic performances.

Dark background-surface enhanced Raman spectroscopic detection of nanoplastics: Thermofluidic strategy.

This study aims to develop a cost-effective and time-efficient method for detecting nanoplastics, which have recently garnered significant attention due to their potential harmful impact on the water environment (XiaoZhi, 2021; Gigault et al., 2021; Mitrano et al., 2021; Ferreira et al., 2019). Although several techniques are available to accumulate data on microplastics, there is currently no universally accepted analytical technique for detecting nanoplastics (Gigault et al., 2021; Mitrano et al., 2021; Mitrano et al., 2019; Cai et al., 2021a; Allen et al., 2022). In this study, we have developed a substrate that exhibits Surface-enhanced Raman scattering (SERS) (Zhou et al., 2021; Lv et al., 2020; Lê et al., 2021; Hu et al., 2022; Chang et al., 2022; Yang et al., 2022; Xu et al., 2020; Jeon et al., 2021; Lee and Fang, 2022; Vélez-Escamilla and Contreras-Torres, 2022; Liu et al., 2022; Xie et al., 2023) activity over a large area and a dark background in optical (darkfield mode) vision, enabling the detection of sparkling nanoplastics on the substrate. This darkfield-based strategy allows for the point-by-point detection of single nanoplastics, offering cost and time-saving advantages over other resource-intensive analytical techniques. Our findings reveal the presence of PP nanoplastics in commonly used laboratory equipment, individual PE nanoplastics from a hot water-contained commercial paper cup, and the first detection of natural nanoplastics in coastal seawater. We believe that this technique will have a universal application in establishing a global map of nanoplastics and advancing our understanding of the environmental life cycle of plastics.

Novel Single-Particle Analytical Technique for Submicron Atmospheric Aerosols: Combined Use of Dark-Field Scattering and Surface-Enhanced Raman Spectroscopy.

Raman microspectrometry (RMS) is a useful single particle analysis method that can provide information on the mixing states, molecular species, and chemical functional groups of individual aerosol particles, which are difficult to determine by bulk analysis techniques. On the other hand, drawbacks, such as low Raman cross-section, spatial resolution (∼1 µm), and optical diffraction limit, make the analysis of atmospheric particles in the submicron size range difficult using conventional RMS. This study developed a new strategy to detect individual submicron-size atmospheric particles by combining dark-field (DF) microscopy and surface-enhanced Raman spectroscopy (SERS). The DF technique overcomes optical spatial diffraction limit by contrast enhancement, allowing the visualization of submicron particles. SERS facilitates spectroscopic characterization (obtaining information on molecular fingerprints and mixing states) of trace amounts of analyte by increasing the Raman scattering cross-section at the hot spot. SERS-active silver substrates sputter-coated on a Si wafer efficiently provided a clear background in the dark-field image and uniform hot spots over a large area, which were suitable for single-particle analysis. Various functional groups in individual particles and their heterogeneous mixing states were investigated, demonstrating the potential of this method to provide improved information on submicron atmospheric particles of femtogram-level masses. DF-SERS may elucidate the detailed physicochemical characteristics of individual submicron particles, providing new information on the formation mechanisms and fates of atmospheric particles.

Discovery of Novel Small-Molecule Antiangiogenesis Agents to Treat Diabetic Retinopathy.

Diabetic retinopathy is the leading cause of blindness which is associated with excessive angiogenesis. Using the structure of wondonin marine natural products, we previously created a scaffold to develop a novel type of antiangiogenesis agent that possesses minimized cytotoxicity. To overcome its poor pharmaceutical properties, we further modified the structure. A new scaffold was derived in which the stereogenic carbon was changed to nitrogen and the 1,2,3-triazole ring was replaced by an alkyl chain. By comparing the bioactivity versus cytotoxicity, compound 31 was selected, which has improved aqueous solubility and an enhanced selectivity index. Mechanistically, 31 suppressed angiopoietin-2 (ANGPT2) expression induced by high glucose in retinal cells and exhibited in vivo antiangiogenic activity in choroidal neovascularization and oxygen-induced retinopathy mouse models. These results suggest the potential of 31 as a lead to develop antiangiogenic small-molecule drugs to treat diabetic retinopathy and as a chemical tool to elucidate new mechanisms of angiogenesis.

Protective effects of PARP1-inhibitory compound in dry age-related macular degeneration.

Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in the retinal pigment epithelium (RPE) is implicated in dry age-related macular degeneration (AMD). Although PARP1 inhibitors are available for treating dry AMD, their delivery route is not ideal for patients. The aim of this study was to test the efficacy of a novel PARP1-inhibitory compound (PIC) in vitro and in vivo. This study presents PIC, a novel small molecule, with superior efficacy to PARP1 inhibitors in the market. PIC demonstrated a distinctive inhibitory profile against PARP isotypes than the FDA-approved PARP1 inhibitors. PIC inhibited PARP1 activation at an IC50 of 0.41 ± 0.15 nM in an enzyme-based assay in vitro and at IC50 and EC50 in ARPE-19 cells of 0.11 ± 0.02 nM and 0.22 ± 0.02 nM, respectively, upon H2O2 insult. PIC also moderated mitochondrial fission and depolarization and maintained cellular energy levels under oxidative stress in ARPE-19 cells. Furthermore, PIC demonstrated good corneal penetration in a rat model, presenting PIC as a promising candidate for eye drop therapeutics for dry AMD. When PIC was administered as an eye drop formulation, RPE morphology was preserved, maintaining the thickness of the outer nuclear layers under sodium iodate (SI) treatment in rats. In SI-treated rabbits, eye drop administration of PIC also retained the structural and functional integrity when analyzed using funduscopy and electroretinogram. Collectively, our data portray PIC as an attractive treatment measure for dry AMD.

Automated technique for high-pressure water-based window cleaning and accompanying parametric study.

The maintenance of buildings has become an important issue with the construction of many high-rise buildings in recent years. However, the cleaning of the outer walls of buildings is performed in highly hazardous environments over long periods, and many accidents occur each year. Various robots are being studied and developed to reduce these incidents and to relieve workers from hazardous tasks. Herein, we propose a method of spraying high-pressure water using a pump and nozzle, which differs from conventional methods. The cleaning performance parameters, such as water pressure, spray angle, and spray distance, were optimized using the Taguchi method. Cleaning experiments were performed on window specimens that were contaminated artificially. The cleaning performance of the proposed method was evaluated using the image-evaluation method. The optimum condition was determined based on the results of a sensitive analysis performed on the image data. In addition, the reaction force due to high pressure and impact force on the specimens were investigated. These forces were not sufficient to affect the propeller thrust or cause damage to the building's surface. We expect to perform field tests in the near future based on the output of this research.

A novel mPGES-1 inhibitor alleviates inflammatory responses by downregulating PGE2 in experimental models.

We previously reported the strong inhibitory potency of N-phenyl-N'-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production in macrophages. Herein, we characterized PBCH as a microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor and evaluated its anti-inflammatory effects using in vivo experimental models. PBCH inhibited PGE2 production in various activated cells in addition to inhibiting the mPGES-1 activity. In the ear edema and paw edema rat models, PBCH significantly reduced ear thickness and paw swelling, respectively. Besides, in adjuvant-induced arthritis (AIA) rat model, PBCH decreased paw swelling, plasma rheumatoid factor (RF), and receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. Furthermore, while PBCH reduced the plasma prostaglandin E metabolite (PGEM) levels, it did not affect the plasma levels of prostacyclin (PGI2) and thromboxane A2 (TXA2). Our data suggest that PBCH downregulates PGE2 production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.

C1q/TNF-α-Related Protein 1 (CTRP1) Maintains Blood Pressure Under Dehydration Conditions.

RATIONALE: Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation. OBJECTIVE: To investigate the physiological/pathophysiological role of CTRP1 in BP regulation. METHODS AND RESULTS: CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ΔCAG). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice. CONCLUSIONS: For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.

Effect of Korean Red Ginseng extracts on drug-drug interactions.

BACKGROUND: Ginseng has been the subject of many experimental and clinical studies to uncover the diverse biological activities of its constituent compounds. It is a traditional medicine that has been used for its immunostimulatory, antithrombotic, antioxidative, anti-inflammatory, and anticancer effects. Ginseng may interact with concomitant medications and alter metabolism and/or drug transport, which may alter the known efficacy and safety of a drug; thus, the role of ginseng may be controversial when taken with other medications. METHODS: We extensively assessed the effects of Korean Red Ginseng (KRG) in rats on the expression of enzymes responsible for drug metabolism [cytochrome p450 (CYP)] and transporters [multiple drug resistance (MDR) and organic anion transporter (OAT)] in vitro and on the pharmacokinetics of two probe drugs, midazolam and fexofenadine, after a 2-wk repeated administration of KRG at different doses. RESULTS: The results showed that 30 mg/kg KRG significantly increased the expression level of CYP3A11 protein in the liver and 100 mg/kg KRG increased both the mRNA and protein expression of OAT1 in the kidney. Additionally, KRG significantly increased the mRNA and protein expression of OAT1, OAT3, and MDR1 in the liver. Although there were no significant changes in the metabolism of midazolam to its major metabolite, 1'-hydroxymidazolam, KRG significantly decreased the systemic exposure of fexofenadine in a dose-dependent manner. CONCLUSION: Because KRG is used as a health supplement, there is a risk of KRG overdose; thus, a clinical trial of high doses would be useful. The use of KRG in combination with P-glycoprotein substrate drugs should also be carefully monitored.

HPLC-MS/MS analysis of mesupron and its application to a pharmacokinetic study in rats.

Mesupron, the first-in-class inhibitor of urokinase-type plasminogen activator (uPA) is known to regulate cell proliferation and migration, and is under investigation for the treatment of metastatic breast cancer. In this study, a quantification method was developed for the determination of mesupron in rat plasma using liquid chromatography with a tandem mass spectrometry (LC-MS/MS). After protein precipitation with acetonitrile including itraconazole (internal standard, IS), the analytes were chromatographed on a reversed phased column with a mobile phase of acetonitrile and water (7:3, v/v, including 0.1% formic acid). The ion transitions of the precursor to the product ion were principally protonated ion [M+H]+ at m/z 630.4→398.3 for mesupron and 705.2→392.1 for the IS. The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods This method was successfully applied to a pharmacokinetic study of mesupron after intravenous administration in rats.

Lung cancer risk among patients with combined pulmonary fibrosis and emphysema.

Although combined pulmonary fibrosis and emphysema (CPFE) might be relevant to lung cancer, no comparison studies have been done. We evaluated the risk of lung cancer among CPFE patients compared to IPF and emphysema patients. We retrospectively reviewed the medical records of patients who were diagnosed as CPFE, IPF and emphysema using chest CT scans at Seoul National University Hospital from Jan 2000 to Dec 2011. Patients with CPFE were enrolled and matched (1:1:2) with IPF and emphysema patients based on the radiological criteria. The main outcome was time to diagnosis of lung cancer and evaluated with Cox-proportional hazard regression. Forty-eight CPFE, 48 IPF, and 96 emphysema patients were included in this study. Twenty-five cases of lung cancer occurred. The CPFE group had a higher risk of lung cancer (adjusted HR 4.62, 95% CI 1.58-13.55) than that of the emphysema group. Also, IPF group had a higher risk of lung cancer (adjusted HR 4.15, 95% CI 1.03-16.78) than that of emphysema group. However, there was no statistically significant difference in lung cancer risk between the CPFE and IPF group. Additionally, the CPFE group had a higher risk of lung cancer or death (adjusted HR 4.62, 95% CI 2.25-9.47) than that of the emphysema group. In conclusion, patients with CPFE and IPF had a higher risk of lung cancer than those with emphysema, although lung cancer risk was similar between CPFE and IPF.

Biologic fixation through bridge plating for comminuted shaft fracture of the clavicle: technical aspects and prospective clinical experience with a minimum of 12-month follow-up.

For comminuted shaft fracture of clavicle, the operative goal, aside from sound bone healing without complications of direct reduction, is maintenance of the original length in order to maintain the normal biomechanics of adjacent joint. Our bridge plating technique utilizing distraction through a lumbar spreader was expected to be effective for restoring clavicular length with soft tissue preservation. However, there are two disadvantages. First, there is more exposure to radiation compared to conventional plating; and second, it is difficult to control the rotational alignment. Despite these disadvantages, our technique has important benefits, in particular, the ability to preserve clavicular length without soft tissue injury around the fracture site.

Clinical analysis of femur shaft insufficiency fractures.

BACKGROUND: To characterize the recently issued femur shaft insufficiency fracture in terms of a patient's own epidemiological status. METHODS: Fourteen patients were treated for insufficiency fracture from July 2002 to June 2008, excluding cases including the risk factors of insufficiency fracture. All patients were female, and their mean age was 75.6 years (range, 65 to 89 years). The mean follow-up period was 50.6 months (range, 14 to 86 months). RESULTS: The mean body weight of the Koreans in the same age group was 58.1 ± 9.7 kg, and the mean height was 155.5 ± 8.8 cm. The mean body weight of our insufficiency fracture patients was 45.7 kg and it was statistically significantly lower than that of the Koreans in the same age group (p < 0.001). The mean height was 147.3 cm and it was significantly shorter than the mean height of the Koreans in the same age group (p = 0.002). In regard to menopausal time, the mean menopausal time of the Koreans was 48.0 ± 4.2 years, it was 44 years in our study, as menopause occurred statistically significantly earlier (p = 0.017). The patients with insufficiency fracture showed statistically lower weight, shorter stature and an earlier menopausal period than that of the general population. CONCLUSIONS: In early menopausal, underweight, and short patients prescribed osteoporosis medication for an extended period of time, if predromal symptom is present, it is necessary to suspect insufficiency fracture of the femur.

Functional outcomes and structural integrity after double-pulley suture bridge rotator cuff repair using serial ultrasonographic examination.

BACKGROUND: We evaluated the integrity and functional outcomes of rotator cuff tear after performing the double-pulley suture bridge (DPSB) repair technique according to the tear size by using serial ultrasonographic examinations. MATERIALS AND METHODS: The study included 41 consecutive arthroscopic rotator repairs using the DPSB technique. The average follow-up was 28 months. We completed the serial ultrasonographic examinations and compared the results with the functional outcome using the American Shoulder and Elbow Surgeons (ASES) score, the Constant score, the Korean Shoulder Scoring (KSS) system, and the University of California, Los Angeles (UCLA) score. RESULTS: The overall retear rate was 19.5% (8 of 41), comprising 50% (2 of 4) for massive tears, 18% (2 of 11) for large tears, 17% (4 of 23) for medium tears, and no failures for small tears (0 of 3). The retear rate was 17.6% (6 of 34) after complete repair and 28.6% (2 of 7) after repair with gap formation. Seventy-five percent (6 of 8) of retears were identified within 6 months after operation and 25% (2 of 8) were identified more than 1 year after repair. The functional outcomes of the intact group and the retear group according to the ASES score, the Constant score, the KSS, and the UCLA score were 96, 93, 94, and 33, and 90, 82, 87, and 31, respectively (P > .05). CONCLUSION: The overall retear rate after DPSB repair was 19.5% with 2 time periods of retear. The outcome improved independent of the tear size and the cuff integrity.

A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability.

Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.

Discovery of 3,4-dihydropyrimidin-2(1H)-ones with inhibitory activity against HIV-1 replication.

3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) were selected and derivatized through a HIV-1 replication assay based on GFP reporter cells. Compounds 14, 25, 31, and 36 exhibited significant inhibition of HIV-1 replication with a good safety profile. Chiral separation of each enantiomer by fractional crystallization showed that only the S enantiomer retained anti-HIV activity. Compound (S)-40, a novel and potent DHPM analog, could serve as an advanced lead for further development and the determination of the mechanism of action.

Comparison of efficacy of enucleation and pancreaticoduodenectomy for small (<3 cm) branch duct type intraductal papillary mucinous neoplasm located at the head of pancreas and the uncinate process.

PURPOSE: Accurate indications and the extent of surgery for branch duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas are still debatable. In particular, small tumor is located at the head portion of pancreas presents a dilemma. The purpose of this study is to compare the efficacy of enucleation (EN) with that of pancreaticoduodenectomy (PD) in patients with small (2 cm

Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors.

We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound 27, which possessed excellent potency against wild-type HIV-1 (EC50 = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development.

Fabrication of poly-silicon nano-wire transistors on plastic substrates.

We report the fabrication and characterization of poly-Si nanowire transistors on flexible substrates. The nanowire transistors are fabricated on a SiO2/Si substrate using conventional CMOS processes, and then they are transferred onto polyimide substrates. The transfer process is performed by spin-coating of polyimide, curing (annealing) of the polyimide layer, and removal of the SiO2 sacrificial layer. The optimized curing condition results in the maximum bending of 150 degrees with full recovery. The nanowire transistors exhibit transistor characteristics as a function of the backgate bias. Our new process can be applied to the fabrication of Si-nanowire transistors with larger mobilities.

Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways.

Glioblastoma is a severe type of primary brain tumor, and its highly invasive character is considered to be a major therapeutic obstacle. Several recent studies have reported that ionizing radiation (IR) enhances the invasion of tumor cells, but the mechanisms for this effect are not well understood. In this study, we investigated the possible signaling mechanisms involved in IR-induced invasion of glioma cells. IR increased the matrix metalloproteinase (MMP)-2 promoter activity, mRNA transcription, and protein secretion along with the invasiveness of glioma cells lacking functional PTEN (U87, U251, U373, and C6) but not those harboring wild-type (WT)-PTEN (LN18 and LN428). IR activated phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin, and blockade of these kinases by specific inhibitors (LY294002, Akt inhibitor IV, and rapamycin, respectively) and transfection of dominant-negative (DN) mutants (DN-p85 and DN-Akt) or WT-PTEN suppressed the IR-induced MMP-2 secretion in U251 and U373 cells. In addition, inhibitors of epidermal growth factor receptor (EGFR; AG490 and AG1478), Src (PP2), and p38 (SB203580), EGFR neutralizing antibody, and transfection of DN-Src and DN-p38 significantly blocked IR-induced Akt phosphorylation and MMP-2 secretion. IR-induced activation of EGFR was suppressed by PP2, whereas LY294002 and SB203580 did not affect the activations of p38 and PI3K, respectively. Finally, these kinase inhibitors significantly reduced the IR-induced invasiveness of these cells on Matrigel. Taken together, our findings suggest that IR induces Src-dependent EGFR activation, which triggers the p38/Akt and PI3K/Akt signaling pathways, leading to increased MMP-2 expression and heightened invasiveness of PTEN mutant glioma cells.