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Background: Since severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was first reported in Wuhan, China, in December 2019, it has spread rapidly, and many coronavirus disease (COVID‐19) cases have occurred in Gwangju, South Korea. Viral mutations following the COVID‐19 epidemic have increased interest in the characteristics of epidemics in this region, and pathogen genetic analysis is required for infection control and prevention. Methods: In this study, SARS‐CoV‐2 whole‐genome analysis was performed on samples from patients with COVID‐19 in Gwangju from 2020 to 2022 to identify the trends in COVID‐19 prevalence and to analyze the phylogenetic relationships of dominant variants. B.41 and B.1.497 prevailed in 2020, the early stage of the COVID‐19 outbreak; then, B.1.619.1 mainly occurred until June 2021. B.1.617.2, classified as sublineages AY.69 and AY.122, occurred continuously from July to December 2021. Since strict measures to strengthen national quarantine management had been implemented in South Korea until this time, the analysis of mutations was also able to infer the epidemiological relationship between infection transmission routes. Since the first identification of the Omicron variant in late December 2021, the spread of infection has been very rapid, and weekly whole‐genome analysis of specimens has enabled us to monitor new Omicron sublineages occurring in Gwangju. Conclusions: Our study suggests that conducting regional surveillance in addition to nation‐level genomic surveillance will enable more rapid and detailed variant surveillance, which will be helpful in the overall prevention and management of infectious diseases. [ABSTRACT FROM AUTHOR]

Semiconductor manufacturing is performed through unit processes that use various chemicals and facilities. In particular, flammable gases, such as H2, NH3, and CH4, are used, and there is a risk of explosion when such gases leak. In this study, computational fluid dynamics (CFD) simulation and a "tracer gas test" according to the SEMI (Semiconductor Equipment and Materials International) S6 Environmental, Health, and Safety Guideline for Exhaust Ventilation of Semiconductor Manufacturing Equipment specification were performed during the leakage of hydrogen, a highly flammable gas used in the etching process of a gas box in the semiconductor industry. The CFD simulation was conducted to investigate the safety of semiconductor production facilities in relation to the explosion risk. Flow analysis was performed for the interior of a gas box used in the etching process. A steady-state analysis was performed to predict the concentration range of the explosion limit in the case of continuous hydrogen gas leakage. The interior of the gas box used in the simulation was modeled, and the ventilation flow rate, which has a significant impact on the leakage gas concentration distribution, obtained from experiments was used. The lower flammability limit (LFL) value of the leaked gas was 4% based on H2, and LFL/4 (25% of the LFL) was analyzed as the explosion limit concentration according to the acceptance criteria of the SEMI S6 tracer gas test. To validate the CFD simulation, a tracer gas test was performed according to SEMI S6. A mixture of hydrogen (5%) and nitrogen (95%) was used as the tracer gas. The flow rate was controlled by a gas regulator valve and measured using an Aalborg mass flow meter. The measured concentration of the tracer gas was calculated using the equivalent release concentration, which was calculated when 100% of the hydrogen was released, and the risk was assessed by comparing it with the LFL/4 of H2. [ABSTRACT FROM AUTHOR]

In the semiconductor industry, hydrogen is used with many other hazardous and dangerous substances with flammable, toxic, and corrosive properties. In order to safely handle them, convenient-to-use gas cabinets are often required. As known well, hydrogen is highly flammable and explosive, and risk analysis needs to safely use the gas in the cabinets. In this study, overpressure and impact according to various gas cabinet conditions were measured when hydrogen leaks in the gas cabinet, and the effect of overpressure on the protective wall was simulated. For the research, a demonstration experiment was conducted by custom manufacturing a gas cylinder cabinet identical to the standard used in the field, and the protection performance analysis was performed by reverse-engineering it through 3D scanning. As a result of the demonstration experiment, the maximum pressure at the time of hydrogen gas explosion in the gas cylinder cabinet was measured at 0.3 bar. After calculating the detonation pressure propagation profile using the TNT equivalence method, the protective performance of the protective wall was confirmed using AUTODYN. The maximum stress of the concrete and the maximum stress of the reinforcing bar due to the explosion in the gas cylinder cabinet were calculated to be 30.211 MPa and 112.88 MPa, respectively, which do not exceed the tensile strength of concrete and the yield strength of the reinforcing bar. This result is expected to be of great help to the development of the semiconductor industry by suggesting the rationale for mitigating the firewall when changing the semiconductor layout. [ABSTRACT FROM AUTHOR]

Recently, there has been social controversy regarding whether benzimidazole anthelmintic drugs can be used as anticancer drugs. On this note, we wish to address the use of current benzimidazole anthelmintic drugs for the treatment of cancer patients. We explored the anticancer efficacy of benzimidazole anthelmintic drugs in vitro and their mechanism of action. We also conducted pharmacokinetic studies of two benzimidazole anthelmintics and assessed the predictive systemic efficacy. Finally, we present the anticancer efficacy of benzimidazole anthelmintics' putative metabolites from hydrolysis. Our data suggest that benzimidazole anthelmintic drugs are not expected to show systemic anticancer efficacy in vivo due to poor pharmacokinetic parameters. Therefore, patients should not consider oxibendazole or fenbendazole as cancer treatment option. [ABSTRACT FROM AUTHOR]

• Consequence analysis for detecting indoor leak sources with the help of machine learning algorithm. • Generation of the gas leak dataset using CFD and pre-processing method. • Encoding-prediction network development for the spatiotemporal and layout-adaptive prediction of leak gas dispersion. Gas leak accident has been troublesome issues in the chemical industries. Predicting dispersion boundaries are important to make rapid and proper actions. Currently, computational fluid dynamics (CFD) are used to predict the dispersion boundaries. However, when the facility-layout of a workplace is often modified, using CFD is not desirable since it requires large computational expenses. This study proposes an encoding-prediction neural network to learn representations between dispersion of leak gas, velocity field, and facility-layouts. This network predict volume fraction field of leak gas in t + kΔt timestep by observing that data in t ∼ t + (k-1)Δt timestep. Training and test losses are decreased to 1.04 × 10−5 and 1.46 × 10−5, respectively. The network predicts dispersion of leak gas through recursive prediction scheme, the predicted results shows good agreement with ground truth. Methodology to generated various facility-layouts, and preprocessing methods to deal with skewed data are suggested. The methodology and results proposed in this study would be useful for developing the CFD surrogate model. [ABSTRACT FROM AUTHOR]

This Letter presents a synthesisable phase rotator (PR) which operates without switching glitches that are reported in conventional implementations. The proposed conditionally cascading PR (CCPR) is comprised of two multiplexers (MUXes) with logic gates, and a phase interpolator (PI). This composition enables the automatic design flow through hardware description language which shortens the design time. With the MUXes operating as a cascaded PI at transition points, the proposed CCPR outputs a clock without any transient anomaly. A remarkable reduction in power and area is achieved by sharing a common PI for every pair of input clocks and merging low pass filters into the MUXes. Simulated in a 40‐nm technology, the proposed CCPR consumes 1.9 mW at a 1.1 V supply with 5.4 GHz operation. [ABSTRACT FROM AUTHOR]

A novel concept for diesel fuel processing utilizing H 2 O 2 is suggested to obtain the high-purity H 2 required for air-independent propulsion using polymer electrolyte membrane fuel cells for use in submarines and unmanned underwater vehicles. The core components include 1) a diesel-H 2 O 2 autothermal reforming (ATR) reactor to produce H 2 -rich gas, 2) a water-gas shift (WGS) reactor to convert CO to H 2 , and 3) a H 2 separation membrane to separate only high-purity H 2 . Diesel and H 2 O 2 can easily be pressurized as they are liquids. The application of the H 2 separation membrane without a compressor in the middle of the process is thus advantageous. In this paper, the characteristics of pressurized ATR and WGS reactions are investigated according to the operating conditions. In both reactors, the methanation reaction is enhanced as the pressure increases. Then, permeation experiments with a H 2 separation membrane are performed while varying the temperature, pressure difference, and inlet gas composition. In particular, approximately 90% of the H 2 is recovered when the steam-separated rear gas of the WGS reactor is used in the H 2 separation membrane. Finally, based on the experimental results, design points are suggested for maximizing the efficiency of the diesel-H 2 O 2 fuel processor. [ABSTRACT FROM AUTHOR]

A novel technology of a diesel reformer that uses hydrogen peroxide is developed to obtain the hydrogen required for fuel cell air-independent propulsion for underwater applications, such as submarines and unmanned underwater vehicles. Diesel fuel could be a promising hydrogen source for underwater applications due to its high hydrogen density and its globally well-equipped infrastructure. An alternative oxidant, hydrogen peroxide (H 2 O 2 ), is applied to supply not only oxygen but also the water required for diesel autothermal (ATR) reforming. The proposed reformer does not require an additional heating device to supply heat for the vaporization of diesel or oxidant due to the exothermic nature of the ATR reaction and the heat of decomposition of H 2 O 2 . The effects of H 2 O 2 on diesel reforming were confirmed based on operating the engineering-scale (kW e -class) diesel-H 2 O 2 reformer. Undecomposed H 2 O 2 caused an excessively high temperature in the mixing zone and a corrosion effect in the reformer wall. To overcome these phenomena, we introduced a catalytic H 2 O 2 decomposer to fully decompose hydrogen peroxide into steam and oxygen. From this important step, we essentially eliminate side effects from undecomposed H 2 O 2 and retain a high reforming efficiency by utilizing the heat of decomposition of H 2 O 2 . [ABSTRACT FROM AUTHOR]

Background: Coil embolization is the mainstay treatment for carotid-cavernous fistulas (CCFs). However, few studies have reported entire occlusion of engorged veins to interrupt venous outflow. We report our experience with venous outflow-targeted coil embolization of direct CCFs. Methods: We retrospectively reviewed all the patients diagnosed with direct CCFs treated with venous outflow-targeted coil embolization between November 2013 and February 2020. Venous outflow-targeted coil embolization of the CCFs was performed as follows. First, transarterial stent-assisted coil embolization of CCFs was performed. If the venous outflow to the engorged veins persisted after transarterial stent-assisted coil embolization, entire occlusion of the engorged veins and additional coil packing within the cavernous sinus were performed to interrupt the venous outflow. Results: Ten patients had undergone venous outflow-targeted coil embolization, 6 women (60%) and 4 men (40%). Transfemoral cerebral angiography showed high-flow, direct CCFs in all the patients. Venous outflow occurred through the superior ophthalmic vein (SOV) in all the patients and was completely interrupted by the entire occlusion of the engorged veins with fibered coils. Three patients (30%) had undergone additional treatment in a supplementary manner because of recurrent symptoms (chemosis in 1 patient, faint tinnitus in 2 patients) in the early postprocedural period (1 to 4 weeks). All the symptoms were resolved on follow-up. No additional recurrence was found during follow-up (1–75 months). No peri-procedural complications were encountered. Conclusions: Venous outflow-targeted coil embolization of CCFs would be a safe and effective treatment method. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage with ruptured cerebral artery dissection caused by varicella zoster (VZ) vasculopathy is rare. We report a rare case of vertebral artery (VA) dissection induced by VZ virus, successfully treated with stent-assisted coil embolization and systemic anti viral medication, on six month follow-up cerebral angiography with the review of literatures. [ABSTRACT FROM AUTHOR]

Although interactions between superoxide (O2-) and nitric oxide underlie many physiologic and pathophysiologic processes, regulation of this crosstalk at the enzymatic level is poorly understood. Here, we demonstrate that xanthine oxidoreductase (XOR), a prototypic superoxide O2-producing enzyme, and neuronal nitric oxide synthase (NOS1) coimmunoprecipitate and colocalize in the sarcoplasmic reticulum of cardiac myocytes. Deficiency of NOS1 (but not endothelial NOS, NOS3) leads to profound increases in XOR-mediated or production, which in turn depresses myocardial excitation-contraction coupling in a manner reversible by XOR inhibition with allopurinol. These data demonstrate a unique interaction between a nitric oxide and an O2--generating enzyme that accounts for crosstalk between these signaling pathways; these findings demonstrate a direct antioxidant mechanism for NOS1 and have pathophysiologic implications for the growing number of disease states in which increased XOR activity plays a role. [ABSTRACT FROM AUTHOR]

Glutamine‐addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co‐occurring mutations. To identify more drug‐like GLS inhibitors, we report the amides in the wing macrocycles for GLS inhibition with unique SAR analysis. Although the amidotriazoles (amides in the wing) are in general less potent than those of acylaminothiadiazole analogs (reverse amides in the wing), macrocycle 4, 5, and 7 are selected as a potent macrocyclic GLS inhibitor in both biochemical and cell viability assays. Selected molecules result in partial reduction in intracellular glutamate levels in LR (LDK378‐resistant) cells which is consistent to their cells viability result. Finally, selected compounds reduce the growth of A549 and H460 cells which have co‐occurring mutations including KRAS and KEAP1. The putative binding mode of macrocycle 4 is also suggested using a molecular docking model. [ABSTRACT FROM AUTHOR]

Discusses a method for the preparation of beta-hydroxy (siloxy) or beta-N,N-dialkylamino-substituted, 1-tributylstannylated, and 1-trimethylsilylated cyclopropanes by Ti(II)-mediated coupling of esters or amides with tributyl(vinyl)tin or vinyl-trimethylsilane. Features of the cyclopropanations; Experimental procedures.

• Effectiveness of scrubbers to reduce explosion risk of ZrO 2 ALD by-product was evaluated. • Burn-wet scrubber makes the by-product more thermally stable. • Burn-wet scrubber treatment is to combust the organic residues remaining in the by-product. • Burn-wet scrubber was shown to be more effective at reducing the risk than dry scrubber. In processes of manufacturing semiconductors, reactive by-products (as a form of fine powder, i.e., dust) are deposited in pipes installed on post processing and exhaust systems, potentially involving a considerable explosion risk. In this study, the effectiveness of scrubber methods (e.g., dry scrubber and burn-wet scrubber) to mitigate the risk was evaluated. To this end, three by-products generated from a ZrO 2 atomic layer deposition (ALD) process were collected from semiconductor manufacturers, which were treated with different methods (i.e., no treatment, treatment using dry scrubber, and treatment using burn-wet scrubber), and their characteristics were analyzed and compared. Particle size measurements of the by-products proved that the burn-wet scrubber treatment less decreased their particle size than the dry scrubber treatment. The burn-wet scrubber treatment made the by-product thermally stable, confirmed by thermogravimetric analysis. Fourier-transform infrared spectroscopy of the by-products before and after the scrubber treatments showed that burn-wet scrubbing of the by-product decreases surface functionalities that play a role in explosion. Dust explosion testing proved that robustness of explosion of the untreated by-product is about 7 times higher than the by-product treated with the burn-wet scrubber. Based on the results of this study, it would be suggested that burn-wet scrubber is a useful treatment method to decrease the explosion risks caused by dust by-products generated from ALD in semiconductor manufacturing processes. [ABSTRACT FROM AUTHOR]

Memory streaming operations (i.e., memory-to-memory data transfer with or without simple arithmetic/logical operations) are one of the most important tasks in general embedded/mobile computer systems. In this paper, we propose a technique to accelerate memory streaming operations. The conventional way to accelerate memory streaming operations is employing direct memory access (DMA) with dedicated hardware accelerators for simple arithmetic/logical operations. In our technique, we utilize not only a hardware accelerator with DMA but also a central processing unit (CPU) to perform memory streaming operations, which improves the performance and energy efficiency of the system. We also implemented our prototype in a field-programmable gate array system-on-chip (FPGA-SoC) platform and evaluated our technique in real measurement from our prototype. From our experimental results, our technique improves memory streaming performance by 34.1–73.1% while reducing energy consumption by 29.0–45.5%. When we apply our technique to various real-world applications such as image processing, 1 × 1 convolution operations, and bias addition/scale, performances are improved by 1.1 × –2.4 ×. In addition, our technique reduces energy consumptions when performing image processing, 1 × 1 convolution, and bias addition/scale by 7.9–17.7%, 46.8–57.7%, and 41.7–58.5%, respectively. [ABSTRACT FROM AUTHOR]

Death‐associated protein kinase‐related apoptosis‐inducing protein kinase 2 (DRAK2) has become a promising target for drug development. In search of novel and selective DRAK2 inhibitor motif, in vitro screen kinase assay was established performed using in‐house chemical libraries. After through hit triage procedure, N2‐(3,5‐dichlorophenyl)‐5‐fluoro‐N4‐methylpyrimidine‐2,4‐diamine (1) was selected as initial hit with structural novelty and drug‐likeness. During hit validation, structure–activity relationship of 1 was thoroughly disclosed and TRD‐93 was finally validated as hit for DRAK2 inhibition. TRD‐93 is small (mw = 290) but selectively potent to DRAK2 (IC50 = 0.16 μM) over other kinases including DAPK family kinases. Molecular binding model study of TRD‐93 to DRAK2 is also discussed. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase ( ALK ) gene rearrangements invariably develop resistance to 2 nd -generation ALK inhibitors. Lorlatinib (PF-06463922) ( 6 ) is a 3 rd -generation macrocyclic ALK-TKI that demonstrates many advantages over 2 nd -generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings. [ABSTRACT FROM AUTHOR]

Abstract: It has been recognized that the friction coefficient decreases with decreasing viscosity of lubricant oil in lubrication. In general, as the viscosity of the lubricant decreases, the wear rate increases due to a decrease of load-carrying capacity of the lubricant. It has been proposed that nano particles in oil decrease the friction coefficient and wear rate. The purpose of this study is to apply oil, which has lower viscosity and is mixed with nano particles, to the compressor used in a refrigerator to decrease the friction coefficient with the same or superior load-carrying capacity. Mineral oil of 8mm2/s was used and mixed with fullerene nanoparticles of 0.1vol%. Friction coefficient was evaluated by a disk-on-disk tribotester. As a result, the friction coefficient of the nano-oil decreased by 90% in comparison with raw oil. These results lead us to the conclusion that nano-oil can contribute to improving the efficiency and reliability of the compressor. [Copyright &y& Elsevier]

Community mitigation measures taken owing to the COVID-19 pandemic have caused a decrease in the number of respiratory viruses, including the human parainfluenza virus type 3 (HPIV3), and a delay in their occurrence. HPIV3 was rarely detected as a consequence of monitoring respiratory viral pathogens in Gwangju, Korea, in 2020; however, it resurfaced as a delayed outbreak and peaked in September–October 2021. To understand the genetic characteristics of the reemerging virus, antigenic gene sequences and evolutionary analyses of the hemagglutinin-neuraminidase (HN) and fusion (F) genes were performed for 129 HPIV3 pathogens prevalent in Gwangju from 2018 to 2021. Unlike the prevalence of various HPIV3 strains in 2018-2019, the prevalence of HPIV3 by strains with reduced diversity was confirmed in 2021. It could be inferred that this decrease in genetic diversity was due to the restriction of inflow from other regions at home and abroad following the community mitigation measures and the spread within the region. The HPIV3 that emerged in 2021 consisted of HN coding regions that were 100% consistent with the sequence identified in Saitama, Japan, in 2018, and F coding regions exhibiting 99.6% homology to a sequence identified in India in 2017, among the ranks reported to the National Center for Biotechnology Information. The emergence of a new lineage in a community can lead to a mass outbreak by collapsing the collective immunity of the existing acquired area; therefore, continuous monitoring is necessary. [ABSTRACT FROM AUTHOR]

The building sector is one of the largest contributors to the world's total energy use and greenhouse gas emissions. Advancements in building energy technologies have played a critical role in enhancing the energy sustainability of the built environment. Extensive research and new techniques in energy and environmental systems for buildings have recently emerged to address the global challenges. This study reviews existing articles in the literature, mostly since 2000, to explore technological advancement in building energy and environmental systems that can be applied to smart homes and buildings. This review study focuses on an overview of the design and implementation of energy-related smart building technologies, including energy management systems, renewable energy applications, and current advanced smart technologies for optimal function and energy-efficient performance. To review the advancement in building energy-related technologies, a systematic review process is adopted based on available published reviews and research types of articles. Review-type articles are first assessed to explore the current literature on the relevant keywords and to capture major research scopes. Research-type papers are then examined to investigate associated keywords and work scopes, including objectives, focuses, limitations, and future needs. Throughout the comprehensive literature review, this study identifies various techniques of smart home/building applications that have provided detailed solutions or guidelines in different applications to enhance the quality of people's daily activities and the sustainability of the built environmental system. This paper shows trends in human activities and technology advancements in digital solutions with energy management systems and practical designs. Understanding the overall energy flow between a building and its environmentally connected systems is also important for future buildings and community levels. This paper assists in understanding the pathway toward future smart homes/buildings and their technologies for researchers in related research fields. [ABSTRACT FROM AUTHOR]

Synthesis of reusable biomimetic enzymes was generated with the goal of cost-effective production of the enzyme for the application in bioconversion of lignocellulosic biomass. The current report describes the preparation and characterization of a biomimetic magnetic nanoenzyme (BMNE), functionalized with a carboxylic acid group that hydrolyzes β-1,4-glycosidic bonds with high catalytic efficiency. The nanometer scale of a BMNE allows it to structurally mimic the active sites of biomass-degrading enzymes. The BMNE functioned optimally at pH 3. The combination of BMNE with natural enzymes had a synergistic action on rice straw, increasing sugar release by 29.7 % and reducing hydrolysis time relative to the natural enzyme alone. The BMNE retained significant activity after five consecutive reaction cycles. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The bromodomain and extraterminal domain (BET) family proteins recognize acetyl-lysine (K ac) at the histone tail through two tandem bromodomains, i.e., BD1 and BD2, to regulate gene expression. BET proteins are attractive therapeutic targets in cancer due to their involvement in oncogenic transcriptional activation, and bromodomains have defined K ac -binding pockets. Here, we present DW-71177 , a potent BET inhibitor that selectively interacts with BD1 and exhibits strong antileukemic activity. X-ray crystallography, isothermal titration calorimetry, and molecular dynamic studies have revealed the robust and specific binding of DW-71177 to the K ac -binding pocket of BD1. DW-71177 effectively inhibits oncogenes comparable to the pan-BET inhibitor OTX-015, but with a milder impact on housekeeping genes. It efficiently blocks cancer-associated transcriptional changes by targeting genes that are highly enriched with BRD4 and histone acetylation marks, suggesting that BD1-selective targeting could be an effective and safe therapeutic strategy against leukemia. [Display omitted] • [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives exhibited potent in vitro inhibitory activity for BET bromodomains. • DW-71177 exhibited a significantly greater binding affinity towards BD1 (bromodomain 1) compared to BD2 (bromodomain 2). • X-ray crystallography and molecular modeling studies elucidated the molecular-level basis of domain selectivity of DW-71177. • DW-71177 effectively reduced tumor growth in an AML xenograft model, comparable to the pan-BET inhibitor. • DW-71177 strongly suppressed oncogenes that are essential for cancer cell proliferation. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: We evaluated right atrial (RA) contractility and right ventricular (RV) diastolic function in adult patients with acquired chronic pulmonary hypertension (PH) by pulsed Tissue Doppler Imaging (TDI) and assessed their relationship with serum brain natriuretic peptide (BNP). Materials and methods: Systolic myocardial wave (Sa), early diastolic myocardial wave (Ea), and late diastolic myocardial wave (Aa) at the tricuspid annulus were recorded in 77 consecutive patients with acquired PH. Early (E) RV inflow waves were recorded from 4-chamber views. RV Aa was regarded as the parameter of RA contractility and RV E/Ea was taken as the parameter of RV diastolic function using TDI. Results: All subjects had elevated BNP (mean 188.9±244.0 pg/dl) and pulmonary arterial systolic pressure (PASP) estimated at 62.9±26.7 mm Hg. BNP levels were positively correlated with RV E/Ea, Aa and PASP (r =0.47, p <0.0001 and r =0.35, p <0.01, respectively) but negatively with Aa (r =−0.29, p <0.05). Next, all predictor variables were used in a multiple regression model with serum BNP values as dependent variables, refined to include 3 predictors: RV E/Ea, Aa, and PASP, which were all found to influence serum BNP values (p <0.0001) by the formula Y =34.1X1⁎⁎ −19.11X2⁎⁎ +2.95X3⁎ (⁎⁎ p <0.001, ⁎ p <0.01) where Y =BNP, X1=E/Ea of RV, X2=Aa, and X3=PASP (standard regression coefficients were 0.37, −0.34 and 0.34, respectively). Conclusion: Serum BNP correlates with RA contractility and RV diastolic dysfunction by RV TDI in adults with acquired PH. Increased BNP may be related to decreased RA systolic function and RV diastolic function in these patients. [Copyright &y& Elsevier]

Abstract: Purpose: We evaluated whether right ventricular (RV) diastolic dysfunction assessed by pulsed tissue Doppler imaging (TDI) predicts cardiac events in patients with chronic pulmonary thromboembolism (CPTE). Materials and methods: In 63 consecutive patients with CPTE, early diastolic myocardial velocity (Ea) at the tricuspid annulus by TDI and early diastolic tricuspid inflow (E) by conventional pulsed Doppler were obtained, and E/Ea was calculated as an indicator of RV diastolic dysfunction. Brain natriuretic peptide (BNP) and other echo parameters were also obtained. A cardiac event (rehospitalization caused by congestive heart failure or cardiac death) was the study endpoint. Incidence of cardiac events was determined over a 374±451 day follow-up period. Results: In the follow-up period twelve patients had cardiac events. We divided patients into group A with cardiac events and group B without events. E/Ea was significantly increased in group A as compared with group B (8.3±4.1 vs. 5.7±2.6, p <0.01). BNP was higher in group A than group B (221±191 vs. 121±140 mg/dl, p <0.05), and in addition E/Ea was significantly positively correlated with BNP (r=0.48, p <0.001). A logistic regression model for predicting cardiac events was constructed and E/Ea was associated with an increased incidence of cardiac events (relative risk=1.33, 95% CI 1.00–1.75). Conclusion: Elevated values of E/Ea obtained by TDI may predict cardiac events in patients with CPTE. BNP may also be a significant predictor. [Copyright &y& Elsevier]

Abstract: Purpose: To assess the effects of the oral intake of flavonoid-rich dark chocolate on coronary circulation, we measured coronary flow velocity reserve (CFVR) by noninvasive transthoracic Doppler echocardiography (TTDE) in healthy adult subjects. Materials and methods: The study was a randomized, single-blind design conducted for 2 weeks in 39 healthy men (mean age 29.7±3.9 years, range 23–40 years). Subjects were randomly assigned a daily intake of either flavonoid-rich dark chocolate (Meiji Black Chocolate 45 g, Meiji Seika kaisya Ltd, including cacao polyphenol 550 mg/day, 200 kcal) or non-flavonoid white chocolate (Meiji White Chocolate 35 g, Meiji Seika kaisya Ltd, including cacao polyphenol 0 mg/day, 140 kcal) as a control. CFVR was recorded by TTDE, and assessed before and after 2 weeks of intake. At the same time, we also assessed serum asymmetric dimethylarginine, 8-isoprostanes, and malondialdehyde-modified low-density lipoprotein (MDA-LDL) as markers of oxidative stress. Results: Flavonoid-rich dark chocolate consumption significantly improved CFVR (3.38±0.49 before intake, 4.28±0.85 after intake; p <0.01), whereas non-flavonoid white chocolate consumption did not (3.28±0.49 before intake, 3.16±0.49 after intake; p =0.44). All predictor variables were used as dependent variables in a multiple regression model of the incremental change in CFVR after 2 weeks of chocolate intake. Intake of dark (but not white) chocolate, MDA-LDL, triglyceride (TG) and heart rate (HR) significantly influenced the change of CFVR after 2 weeks of intake (p <0.01) according to the multiple regression formula: Y =1.01X 1 −0.005X 2 −0.003X 3 −0.017X 4 (Y =change in CFVR after 2 weeks of chocolate intake, X 1 =intake of dark (but not white) chocolate, X 2 =MDA-LDL, X 3 =TG, X 4 =HR). Conclusion: Flavonoid-rich dark chocolate intake significantly improved coronary circulation in healthy adults, independent of changes in oxidative stress parameters, blood pressure and lipid profile, whereas non-flavonoid white chocolate had no such effects. [Copyright &y& Elsevier]

Abstract: Purpose: It has been reported that mental stress is an independent risk factor for cardiovascular events and impairs coronary circulation. Lavender aromatherapy, one of the most popular complementary treatments, is recognized as a beneficial mental relaxation therapy. However, no study has examined the effect of this therapy on coronary circulation. We aimed to assess the effect of lavender aromatherapy on coronary circulation by measuring coronary flow velocity reserve (CFVR) with noninvasive transthoracic Doppler echocardiography (TTDE). Material and methods: We enrolled 30 young healthy men (mean age 34±4.7 years, range 24–40 years). Coronary flow velocities in the left anterior descending coronary artery were recorded by TTDE at rest and during hyperemia induced with an intravenous infusion of adenosine triphosphate (ATP). CFVR was calculated as the ratio of hyperemic to basal mean diastolic flow velocity. CFVR was assessed at baseline and immediately after lavender aromatherapy (four drops of essential oil diluted with 20 ml of hot water and inhaled for 30 min). Simultaneously, serum cortisol was measured as a marker of stress hormones. To exclude the relaxation effects of rest, the same measurements were repeated in the same volunteers without aromatherapy as a control study. Results: CFVR measurements were obtained in all volunteers (100%). Blood pressure and heart rate responses to ATP infusion were not affected by lavender aromatherapy. Serum cortisol significantly decreased after lavender aromatherapy (8.4±3.6 to 6.3±3.3, p <0.05), but remained unchanged in controls (9.1±3.5 to 8.1±3.9, p =ns). In addition, CFVR significantly increased after lavender aromatherapy (3.8±0.87 to 4.7±0.90, p <0.001), but not in controls (3.9±0.8 to 3.9±0.8, p =ns). Conclusions: Lavender aromatherapy reduced serum cortisol and improved CFVR in healthy men. These findings suggest that lavender aromatherapy has relaxation effects and may have beneficial acute effects on coronary circulation. [Copyright &y& Elsevier]

An intermittently aerated membrane bioreactor (IAMBR) system has been developed to improve the efficiency of nutrient removal, and for the stable treatment of organic matter which is contained as suspended solid (SS) in the influent. The important operating factors of an intermittently aerated bioreactor (IABR) are sludge retention times (SRTs) and carbon/nitrogen (C/N) ratios. Because research on IAMBR is young, this paper explores the effect of SRTs and C/N ratios on these systems. For SRTs of 20, 25, 30, and 40 days, there was little difference in the removal of COD, T–N, and T–P. In comparing C/N ratios of 4.5, 7, and 10, the COD concentration in permeate with a C/N ratio of 10 was most stable, although the concentration of organic matter in the influent was high. The removal efficiencies of T–N and T–P in permeate with a C/N ratio of 10 were the highest at 92.9% and 88.9%, respectively. This implies that a C/N ratio above 10 should be maintained for a nutrient removal efficiency of approximately 90%. [Copyright &y& Elsevier]

This work proposes the data augmentation by molecular rotation, with consideration that the protein‐ligand binding events are rotation‐variant. As a proof‐of‐concept, known active (i. e., 1‐labeled) ligands to human β‐secretase 1 (BACE‐1) are rotated for the generation of 0‐labeled data, and the rotation‐dependent prediction accuracy of 3D graph convolutional network (3DGCN) is investigated after data augmentation. The data augmentation makes the orientation‐recognizing ability of 3DGCN improved significantly in the classification task for BACE‐1/ligand binding. Furthermore, the data‐augmented 3DGCN has a capability for predicting active ligands from a candidate dataset, via improved performance of orientation recognition, which would be applied to virtual drug screening and discovery. [ABSTRACT FROM AUTHOR]

Apoptosis signal‐regulating kinase 1 (ASK1) is a member of mitogen‐activated protein kinase kinase kinase (MAP3K) family that involves downstream phosphorylation of MAP kinases, c‐Jun N‐terminal kinases, and p38 MAP kinases. ASK1 inhibitors could possibly be beneficial for ameliorating the development and progression of diseases. Especially, ASK1 has been of interest as one of therapeutic targets for nonalcoholic fatty liver disease as the most common chronic liver diseases including simple steatosis and nonalcoholic steatohepatitis. In this manuscript, novel ASK1 inhibitor lead KTA‐29 which has an imidazo[1,2‐b]pyridazine core with novel C6‐bicycloheptaneimidazole is disclosed. With the novel imidazo[1,2‐b]pyridazine core, structure‐activity‐relationship study for ASK1 potency is described and KTA‐29 affinity toward ASK1 with molecular modeling study is explained. [ABSTRACT FROM AUTHOR]

The histidine-tagged protein binding capacity and purification efficiencies of TSMNPs (terpyridine receptor-immobilized silica-coated magnetic nanoparticles) is described. [ABSTRACT FROM AUTHOR]

The histidine-tagged protein binding capacity and purification efficiencies of TSMNPs (terpyridine receptor-immobilized silica-coated magnetic nanoparticles) is described. [ABSTRACT FROM AUTHOR]

This work describes the process by which a metabolically unstable TRT‐0002 compound exhibiting Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐sensitizing activity for Huh7 cells at a high working concentration (40 μM) is converted to more potent and metabolically improved analogues by modifying the 5‐amino group and the 1‐aryl moiety in the 1H‐indazole skeleton. The efforts enabled us to identify 5‐sulfonamido derivatives, TRT‐0029 and TRT‐0173 compounds, working at lower concentrations (10 and 20 μM, respectively) and with improved metabolic stabilities. As reported previously by us, co‐treating cultured Huh7 cells with either TRT‐0029 or TRT‐0173 and TRAIL resulted in TRAIL‐induced apoptosis due to the inhibition of the MKK7–TOR signaling pathway regulator‐like (TIPRL) interaction and subsequent phosphorylation of MKK7 and JNK. In addition, the injection of TRT‐0029 or TRT‐0173 compound suppressed tumor growth in combination with TRAIL in an in vivo hepatocellular carcinoma (HCC) mouse xenograft model. TRT‐0029 and TRT‐0173 compounds and the relevant structure–activity relationship can provide an insight into further study on optimization of potency and metabolic stability. [ABSTRACT FROM AUTHOR]

DAP kinase-related apoptosis-inducing protein kinase 2 (DRAK2) is a member of the death-associated protein kinase (DAPK) family[1] and originally identified as a proapoptotic protein with the ability to induce apoptosis when overexpressed in various cell types.[2] However, the apoptosis-inducing ability of DRAK2 seems to be controversial and influenced by cellular factors within a specific cell types.[[3]] Recently, it has been suggested that DRAK2 is closely involved in tumorigenesis; DRAK2 expression was found to be highly elevated in multiple tumor types such as basal-like and HER2-enriched breast cancers. B Vertex-3 b is a pyrimidine C5-methylated analog of B UC-3 b .[9] When B UC-3 b was assessed to ATP-binding site of 359 diverse kinases at 10 micromolar concentration, it bound to 337 kinases including CDK2, CDK5, JNK3, and others. We believe the nitrile of the B UC-3 b has hydrogen-bonding interaction to DRAK2 Lys62 and plays a key role for its kinase promiscuous activities. [Extracted from the article]

Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3- a ]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay. The substantial antiproliferative activities in human cancer cell lines, promising drug-like properties, and the selectivity for the BET family make the lead compound ( 13 ) as a novel BRD4 inhibitor motif for anti-cancer drug discovery. [ABSTRACT FROM AUTHOR]

[Display omitted] Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure − activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1. [ABSTRACT FROM AUTHOR]

DRAK2 is a serine/threonine kinase belonging to the death-associated protein kinase (DAPK) family and has emerged as a promising drug target for the treatment of autoimmune diseases and cancers. To identify small molecule inhibitors for DRAK2, we performed a high throughput screening campaign using in-house chemical library and identified indirubin-3′-monoximes as novel class of DRAK2 inhibitors. Among the compounds tested, compound 16 exhibited the most potent inhibitory activity against DRAK2 (IC 50 = 0.003 μM). We also propose that compound 16 may bind to the ATP-binding site of the enzyme based on enzyme kinetics and molecular docking studies. [ABSTRACT FROM AUTHOR]

The article focuses on a study which discussed the n-propyl tail effect to anaplastic lymphoma kinase (ALK) inhibition. Offered are information about nucleophosmin (NPM)-ALK fusion protein. Cited are several ALK inhibitors including the pyrimidine ALK inhibitors NVP-TAE684 and LDK378 or ceritinib. Also described is a general synthetic chemistry toward 2-anilino-4-(3,5-dicarboxamidespiperidine)-pyrimidines.

The article discusses the identification of tropomyosin receptor kinase A (TrkA) which encoded with the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene. It examines the anti-apoptotic event of TrKA in the nerve growth factor (NGF) function. It also stresses the synthetic chemistry of chemicals towards limited structure-activity relationship of TrkA .

Abstract: The synthesis of bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines is described and their structure–activity-relationship to anaplastic lymphoma kinase (ALK) is presented. KRCA-0008 is selective and potent to ALK and Ack1, and displays drug-like properties without hERG liability. KRCA-0008 demonstrates in vivo efficacy comparable to Crizotinib in xenograft mice model. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the efficiency of automated function imaging (AFI) on transthoracic echocardiogram (TTE) for detecting left ventricular (LV) wall motion (LVWM) abnormalities, we compared longitudinal peak systolic strain (LPSS) measurements using AFI with naked eye TTE evaluations by experienced cardiologists and non-experienced residents. Materials and methods: A total of 352 segments of LV myocardium from 22 consecutive subjects with LVWM abnormalities based on American Heart Association classifications (11 male, mean age 58±14years) on previous TTE (Vivid-7, GE) were evaluated. LPSS was measured using stored AFI data. Naked eye evaluation of LVWM was performed by 2 experienced cardiologists and 2 non-experienced residents. Results: AFI successfully tracked 342 (97%) of all segments (mean LPSS −14.8±8.1%). A significant strong negative correlation was observed between LV ejection fraction using method of disks and global LPSS (R=−0.8974). Temporary AFI criteria of LPSS were normal <−12; hypokinesis −12-2; and akinesis >2. Of 342 segments, 239, 87, and 16 segments were diagnosed as normal, hypokinesis, and akinesis, respectively. Level of agreement and kappa coefficients between qualitative evaluation of LVWM by AFI temporary criteria and qualitative evaluation of LVWM by experienced cardiologist 2 (0.784 and 0.479, respectively) were inferior to those comparing experienced cardiologists (0.845 and 0.595) but superior comparing experienced cardiologist with non-experienced resident (0.696 and 0.323), and between the 2 non-experienced-residents (0.682 and 0.347). Conclusion: Qualitative evaluation of LVWM using temporary AFI criteria had a 97% success rate and agreed well with findings of an experienced cardiologist. AFI can be a useful tool for training residents. [Copyright &y& Elsevier]

Abstract: Purpose: To distinguish focal fibrotic and non-fibrotic lesions in left-ventricular myocardium (LVM) in hypertrophic-cardiomyopathy (HCM)-subjects, we compared myocardial regional peak-strain values using two-dimensional speckle-tracking transthoracic-echocardiography (TTE) in multislice computed-tomography (CT)-detected fibrotic, non-fibrotic and normal control lesions. Methods: Twenty subjects (10 consecutive HCM-subjects (8-males, mean 63.4-years), 10 healthy controls (5-males, mean 51.5-years)) underwent speckle-tracking TTE (iE-33), and analysis of regional peak-longitudinal (LS) and radial-strain (RS), and corresponding strain rates in each of 17 LVM segments (American-Heart-Association classification). In HCM-subjects, fibrotic lesions were identified by early-phase defective enhancement and late-phase abnormal enhancement by CT (Light-Speed-Ultra-16). Regional peak LS and RS at basal, mid and apical levels were measured in MSCT-detected fibrotic and non-fibrotic LVM lesions. Results: In 10 HCM subjects, 143 lesions (84.1%) yielded good tracking on TTE. Twenty lesions showed fibrotic changes in 5 subjects by CT. Regional peak-LS and RS absolute values were significantly lower in both fibrotic and non-fibrotic lesions in HCM subjects than in controls at basal, mid, apical levels (all P<0.05). While peak-LS (%) absolute values were significantly lower in fibrotic than non-fibrotic lesions at basal, mid and apical levels (all P<0.05), regional peak-RS absolute values were significantly lower only at mid levels. LS was a more sensitive indicator than the corresponding rate, with better reproducibility. Conclusions: In HCM, regional peak-LS was significantly lower in fibrotic than non-fibrotic lesions in LVM by CT. Regional peak-LS by speckle-tracking provides useful information noninvasively to distinguish fibrotic from non-fibrotic lesions in LVM in HCM and normal LVM in healthy controls. [Copyright &y& Elsevier]

Abstract: A series of hydroxybenzoxazole derivatives was synthesized, and their c-Met kinase inhibitory activity was evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent benzoxazole scaffold, with particular focus on the hydroxyl substituent of the benzoxazole moiety. [Copyright &y& Elsevier]

Abstract: A series of 3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-quinolin-2-ones have been identified as a new class of VEGFR-2 kinase inhibitors. A variety of (4,5,6,7-tetrahydro-imidazo[5,4-c]pyridin-2-yl)-acetic acid ethyl esters were synthesized, and their VEGFR-2 inhibitory activity was evaluated. Described herein are the preparation of the series and the effects of the compounds on VEGFR-2 kinase activity. [Copyright &y& Elsevier]

Clostridium difficile(C. difficile) is a Gram positive, anaerobic bacterium that infects the lumenof the large intestine and produces toxins. This results in a rangeof syndromes from mild diarrhea to severe toxic megacolon and death.Alarmingly, the prevalence and severity of C. difficileinfection are increasing; thus, associated morbidity and mortalityrates are rising. 4-Aminothiazolyl analogues of the antibiotic naturalproduct GE2270 A (1) were designed, synthesized, andoptimized for the treatment of C. difficileinfection.The medicinal chemistry effort focused on enhancing aqueous solubilityrelative to that of the natural product and previous development candidates(2, 3) and improving antibacterial activity.Structure–activity relationships, cocrystallographic interactions,pharmacokinetics, and efficacy in animal models of infection werecharacterized. These studies identified a series of dicarboxylic acidderivatives, which enhanced solubility/efficacy profile by severalorders of magnitude compared to previously studied compounds and ledto the selection of LFF571 (4) as an investigationalnew drug for treating C. difficileinfection. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate efficacy and reproducibility of 320-slice computed tomography (CT) for measuring left atrial (LA) maximum (LAVmax) and minimum volume (LAVmin) during the cardiac cycle, we compared CT with three- and two-dimensional (3D and 2D) transthoracic echocardiogram (TTE). Materials and methods: LAVmax and LAVmin (ml), and LA ejection fraction (LAEF) (%) were assessed in 22 consecutive subjects (15 males, 59.5±15.1years) using retrospective electrocardiogram gated 320-slice CT (Aquilion One, Toshiba Medical) and 3D-TTE (IE-33, Phillips). LAVmax and LAVmin were selected from the time volume curve. LAEF was calculated as (LAVmax−LAVmin)/LAVmax×100(%). Results: Mean±standard deviation (SD) of LAVmax and LAV min were significantly larger by CT than 3D-TTE or 2D-TTE (both P<0.01). LAEF was 25.3±13.1% by CT, 30.2±6.8% by 3D-TTE (P=NS) and 33.9±8.9% by 2D-TTE (P<0.05). The correlation coefficients (CCs) between CT and 3D-TTE in LAVmax, LAmin, and LAEF were 0.64, 0.68 and 0.57, respectively. Mean difference±1.96SD of LAVmax, LAVmin and LAEF by Bland and Altman analysis calculated from CT minus 3D-TTE were 48.8±59.1ml, 41.1±63.2ml, and −4.9±21.1%, respectively. The CCs and mean difference±1.96SD between CT and 2D-TTE had similar tendencies. The CCs of interobserver variation were (for CT, 3D-TTE, 2D-TTE, respectively): 0.90, 0.95 and 0.94 (LAVmax), 0.97 and 0.97 and 0.93 (LAVmin), and 0.64, 0.77 and 0.34 (LAEF). Conclusions: 320-slice CT enables direct LAV measurements and has high reproducibility and positive correlation with 3D and 2D TTE. Absolute value of LAV by CT was larger than that by 3D and 2D TTE. [Copyright &y& Elsevier]

Abstract: Purpose: To differentiate pseudodyskinesis (PD) of the inferior left ventricular (LV) wall from inferior myocardial infarction (IMI) noninvasively, we performed focal site evaluation using two-dimensional speckle tracking transthoracic echocardiography (TTE). Materials and methods: Speckle tracking TTE was carried out in 57 patients, with 19 subjects in each of three groups (Group A, suspected PD; Group B, LV IMI; and Group C, controls). Inferior wall PD was defined as follows: compression of the inferior LV wall by the diaphragm in the LV short axis view with a normal electrocardiogram and no evidence of previous ischemic events. Results: Respective values in Groups A–C for LV ejection fraction (EF) were 63.6±4.2%, 52.3±7.6%, and 61.5±3.8%, for inferior wall speckle tracking focal site evaluation peak radial strain of 30.0±14.3%, 7.5±7.1%, and 42.1±22.9%, for peak circumferential strain of 23.1±6.0%, 16.8±8.4%, and 22.7±7.1%, and for longitudinal strain in the mid-inferior wall of 18.4±3.4%, 11.4±4.0% and 15.8±5.9%. LVEF values were significantly lower in Group B than Groups A and C (P<0.001), as were those of radial, circumferential, and longitudinal strains (P<0.05). In receiver-operating characteristic analysis the optimal cut-off values with corresponding sensitivities and specificities for differentiation of PD from IMI were >19% with 84.2% and 94.7% for radial, >15% with 89.4% and 52.6% for circumferential, and >15% with 73.6% and 100% for longitudinal strain, respectively. Conclusions: Determination of regional strain from speckle tracking TTE, especially radial and longitudinal strains, can provide focal and quantitative noninvasive evaluation for distinguishing PD of the inferior wall from IMI. [Copyright &y& Elsevier]

Patients with left unilateral neglect misbisect lines toward the right. To discriminate between contralesional unawareness and ipsilesional hyperattention hypotheses for this ipsilesional bias, we performed the line quadrisection test on 18 patients with and 25 without neglect, and 24 normal controls. Overall the patients with neglect were unbiased when performing the left quadrisection task, but erred rightward on the right quadrisection task. These results suggest that the ipsilesional bisection errors produced by patients with neglect are primarily influenced by ipsilesional hyperattention rather than contralesional unawareness. However, further analyses showed heterogeneity of performance in left quadrisection, which can be explained by multiple factors that include the top down attention to left space associated with left quadrisection, the orienting to the salience of the line's left end, and distorted mental representation, in addition to ipsilesional hyperattention. [ABSTRACT FROM AUTHOR]