Building C(sp3)-rich complexity by combining cycloaddition and C-C cross-coupling reactions.

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres1, cycloaddition reactions have featured in numerous total syntheses2 and are a key component in the education of chemistry students3. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability4. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp2 manner5. Despite the ability of cycloadditions to introduce multiple carbon sp3 centres in a single step, they are less used6. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

A comparative study using gastric ultrasound to evaluate the safety of shortening the fasting time before pediatric echocardiography: a randomized controlled non-inferiority study.

PURPOSE: The objective of this study was to demonstrate that the gastric cross-sectional area (CSA) in the right lateral decubitus position (RLDP) during a 2-h fasting period is not larger than that during a conventional 4-h fasting period prior to pediatric echocardiography. METHODS: 93 patients aged under 3 years scheduled for echocardiography under sedation were enrolled and randomly allocated into two groups; 2-h fasting vs 4-h fasting. For group 4 h (n = 46), the patients were asked to be fasted for all types of liquid for more than 4 h, while group 2 h (n = 47) were asked to be fasted for all types of liquid for 2 h before echocardiography. Gastric ultrasound was performed before echocardiography, and CSARLDP was measured. We compared CSARLDP, incidence of at-risk stomach, fasting duration, and the incidence of major (pulmonary aspiration, aspiration pneumonia) and minor complications (nausea, retching, and vomiting, apnea, and bradycardia) between two groups. RESULTS: The mean difference of CSARLDP (group 2 h-group 4 h) was 0.49 (- 0.18 to 1.17) cm2, and it was within the non-inferiority margin (Δ = 2.1 cm2). There was no difference in the incidence of at-risk stomach (P = 0.514). There was no significant difference in the incidence of major and minor complications between the two groups. CONCLUSION: Two-hour fasting in pediatric patients who need an echocardiography did not increase major and minor complications and CSA significantly.

The Protective Effects of Moisturizer Containing Potentilla anserina Extract in the Topical Treatment of Skin Damage Caused by Masks.

The use of face masks during the COVID-19 pandemic resulted in significant societal changes, particularly for individuals with sensitive skin. To address this issue, the researchers explored traditional medicine and identified Potentilla anserina extract as a potential solution due to its anti-inflammatory and moisturizing effects. This research investigated how this extract influences skin hydration, barrier function, and itching. The findings revealed that the extract had a hydrating effect by elevating Aquaporin-3 (AQP3) expression. Additionally, the study demonstrated that the extract improved skin barrier function, with Filaggrin (FLG) expression being approximately three times higher (p < 0.001) in the Potentilla-anserina-extract-treated group compared to the control group and the genes associated with itching being reduced. In this process, we researched and developed HPßCD (hydroxypropyl-ß-cyclodextrin)-Liposome containing Potentilla anserina extract, gradually and sustainably releasing the active components of the Potentilla anserina extract. During four weeks of clinical trials involving individuals wearing masks for over 6 h a day, a moisturizer containing Potentilla anserina extract demonstrated a notable reduction in skin redness. Hemoglobin values (A.U.), which serve as indicators of skin redness, showed decreases of 5.06% and 6.74% in the test area inside the mask after 2 and 4 weeks, respectively, compared to the baseline measurements. Additionally, the moisturizer containing Potentilla anserina extract notably decreased Trans Epidermal Water Loss (TEWL), with reductions of 5.23% and 9.13% observed in the test area inside the mask after 2 and 4 weeks, respectively. The moisturizer, especially in the test area treated with the extract-containing moisturizer, significantly enhanced skin hydration compared to the control group. The Corneometer values (A.U) exhibited notable increases of 11.51% and 15.14% in the test area inside the mask after 2 and 4 weeks, respectively. These discoveries emphasize the potential of Potentilla anserina extract and its utility in tackling skin issues caused by mask wearing, including enhancing moisture, fortifying the skin's barrier, and alleviating itching. These results indicate that moisturizers incorporating specific ingredients provide greater benefits compared to conventional moisturizers.

Generation of waste personal protective equipment (PPE) related to COVID-19 using quantitative forecasting technique.

With the prolonged COVID-19 pandemic worldwide, lifestyles have totally changed and the characteristics of waste generation have also changed accordingly. Among the various wastes related to COVID-19, waste personal protective equipment (PPE), which was used to prevent infection of COVID-19, can be an indirect route for the infection of COVID-19. Hence, it requires proper management with estimating waste PPE generation. In this study, the estimation of generation amount of waste PPE in consideration of lifestyle and medical practice is proposed by quantitative forecasting technique. In the quantitative forecasting technique, the generation source of waste PPE consisted of household and test/treatment of COVID-19. For case study in Korea, the amount of waste PPE generated from household is evaluated by applying the quantitative forecasting technique reflecting the population and measures in lifestyle due to COVID-19. Also, the estimated amount of waste PPE generation from test and treatment of COVID-19 was evaluated to have a meaningful reliability compared with other observed values. This quantitative forecasting technique can estimate the amount of waste PPE generation related to COVID-19 and develop safe management measures for waste PPE in many other countries by modifying country-specific lifestyles and medical practices.

The Effect of Lactobacillus plantarum Extracellular Vesicles from Korean Women in Their 20s on Skin Aging.

Extracellular vesicles, which are highly conserved in most cells, contain biologically active substances. The vesicles and substances interact with cells and impact physiological mechanisms. The skin is the most external organ and is in direct contact with the external environment. Photoaging and skin damage are caused by extrinsic factors. The formation of wrinkles is a major indicator of skin aging and is caused by a decrease in collagen and hyaluronic acid. MMP-1 expression is also increased. Due to accruing damage, skin aging reduces the ability of the skin barrier, thereby lowering the skin's ability to contain water and increasing the amount of water loss. L. plantarum suppresses various harmful bacteria by secreting an antimicrobial substance. L. plantarum is also found in the skin, and research on the interactions between the bacteria and the skin is in progress. Although several studies have investigated L. plantarum, there are only a limited number of studies on extracellular vesicles (EV) derived from L. plantarum, especially in relation to skin aging. Herein, we isolated EVs that were secreted from L. plantarum of women in their 20s (LpEVs). We then investigated the effect of LpEVs on skin aging in CCD986sk. We showed that LpEVs modulated the mRNA expression of ECM related genes in vitro. Furthermore, LpEVs suppressed wrinkle formation and pigmentation in clinical trials. These results demonstrated that LpEVs have a great effect on skin aging by regulating ECM related genes. In addition, our study offers important evidence on the depigmentation effect of LpEVs.

Natural course of residual hearing preservation with a slim, modiolar cochlear implant electrode array.

PURPOSE: Understanding residual hearing preservation and its natural course following cochlear implantation is important for developing rehabilitation strategies for hearing loss. However, non-uniform evaluation criteria and varying surgical skills pose challenges in fair comparison of the effect of different electrodes on residual hearing preservation. We compared the effect of a slim modiolar electrode (SME) and a slim straight electrode (SSE), implanted by a single surgeon, on progression of residual hearing using different parameters, based on cross-sectional and longitudinal audiological analyses. METHODS: Patients with preoperative low-frequency pure-tone average (LFPTA) ≤85 dB at 250 and 500 Hz and who underwent minimally traumatic surgical techniques were included. The progression of residual hearing using threshold shifts, hearing preservation rate according to the HEARRING classification, and maintenance of functional low-frequency hearing potentially qualifying for a hybrid stimulation was analyzed up to five time points throughout the 1-year follow-up period. RESULTS: Threshold shifts and hearing preservation rates according to the HEARRING classification of the electrodes were comparable from 3 months through 12 months postoperatively. Maintenance of functional low-frequency hearing, required for the usage of a hybrid stimulation, was similar for both electrodes. A substantial proportion of implantees with SME use a hybrid stimulation, resulting in long-term use. However, a difference in the pattern of postoperative residual hearing preservation between the two electrodes is possible, probably due to differences in their physical characteristics and location. Specifically, correlation analysis exhibited that significantly less tight modiolar proximity negatively affect the residual hearing preservation, albeit only at 3 months postoperatively, among patients with the SME. CONCLUSION: Collectively, both SME and SSE implantation showed favorable residual hearing preservation. Our findings further refine the recently proposed hearing preservation with the SME and suggest that the physical characteristics and location of electrodes, in terms of electrode-to-modiolus distance, could affect loss of acoustic hearing in various ways.

Upgrade of BL-5C as a highly automated macromolecular crystallography beamline at Pohang Light Source II.

BL-5C is an in-vacuum undulator beamline dedicated to macromolecular crystallography (MX) at the 3 GeV Pohang Light Source II in Korea. The beamline delivers X-ray beams with a focal spot size of 200 µm × 40 µm (FWHM, H × V) over the energy range 6.5-16.5 keV. The measured flux is 7 × 1011 photons s-1 at 12.659 keV through an aperture size of 50 µm. The experimental station is newly equipped with the photon-counting detector EIGER 9M, the multi-axis micro-diffractometer MD2, and a robotic sample changer with a high-capacity dewar. These instruments enable the operation of this beamline as an automated MX beamline specialized in X-ray fragment screening. This beamline can collect more than 400 data sets a day without human intervention, and a difference map can be automatically calculated by using the data processing pipeline for ligand or fragment identification.

Cisplatin Plus Cetuximab Inhibits Cisplatin-Resistant Human Oral Squamous Cell Carcinoma Cell Migration and Proliferation but Does Not Enhance Apoptosis.

Cisplatin is among the most widely used anticancer drugs used in the treatment of several malignancies, including oral cancer. However, cisplatin treatment often promotes chemical resistance, subsequently causing treatment failure. Several studies have shown that epidermal growth factor receptors (EGFRs) play a variety of roles in cancer progression and overcoming cisplatin resistance. Therefore, this study focused on EGFR inhibitors used in novel targeted therapies as a method to overcome this resistance. We herein aimed to determine whether the combined effects of cisplatin and cetuximab could enhance cisplatin sensitivity by inhibiting the epithelial-to-mesenchymal transition (EMT) process in cisplatin-resistant cells. In vitro analyses of three cisplatin-resistant oral squamous cell carcinoma cells, which included cell proliferation assay, combination index calculation, cell cytotoxicity assay, live/dead cell count assay, Western blot assay, propidium iodide staining assay, scratch assay, and qRT-PCR assay were then conducted. Our results showed that a cisplatin/cetuximab combination treatment inhibited cell proliferation, cell motility, and N-cadherin protein expression but induced E-cadherin and claudin-1 protein expression. Although the combination of cisplatin and cetuximab did not induce apoptosis of cisplatin-resistant cells, it may be useful in treating oral cancer patients with cisplatin resistance given that it controls cell motility and EMT-related proteins.

Seeded Ising Model and Distributed Biometric Template Storage and Matching.

It is known that a variant of Ising model, called Seeded Ising Model, can be used to recover the information content of a biometric template from a fraction of information therein. The method consists in reconstructing the whole template, which is called the intruder template in this paper, using only a small portion of the given template, a partial template. This reconstruction method may pose a security threat to the integrity of a biometric identity management system. In this paper, based on the Seeded Ising Model, we present a systematic analysis of the possible security breach and its probability of accepting the intruder templates as genuine. Detailed statistical experiments on the intruder match rate are also conducted under various scenarios. In particular, we study (1) how best a template is divided into several small pieces called partial templates, each of which is to be stored in a separate silo; (2) how to do the matching by comparing partial templates in the locked-up silos, and letting only the results of these intra-silo comparisons be sent to the central tallying server for final scoring without requiring the whole templates in one location at any time.

Increased FOXM1 Expression by Cisplatin Inhibits Paclitaxel-Related Apoptosis in Cisplatin-Resistant Human Oral Squamous Cell Carcinoma (OSCC) Cell Lines.

Cisplatin and paclitaxel are commonly used to treat oral cancer, but their use is often limited because of acquired drug resistance. Here, we tested the effects of combined cisplatin and paclitaxel on three parental (YD-8, YD-9, and YD-38) and three cisplatin-resistant (YD-8/CIS, YD-9/CIS, and YD-38/CIS) oral squamous cell carcinoma (OSCC) cell lines using cell proliferation assays and combination index analysis. We detected forkhead box protein M1 (FOXM1) mRNA and protein expression via real-time qPCR and Western blot assays. Cell death of the cisplatin-resistant cell lines in response to these drugs with or without a FOXM1 inhibitor (forkhead domain inhibitory compound 6) was then measured by propidium iodide staining and TdT dUTP nick end labeling (TUNEL) assays. In all six OSCC cell lines, cell growth was more inhibited by paclitaxel alone than combination therapy. Cisplatin-induced overexpression of FOXM1 showed the same trend only in cisplatin-resistant cell lines, indicating that it was associated with inhibition of paclitaxel-related apoptosis. In summary, these results suggest that, in three cisplatin-resistant cell lines, the combination of cisplatin and paclitaxel had an antagonistic effect, likely because cisplatin blocks paclitaxel-induced apoptosis. Cisplatin-induced FOXM1 overexpression may explain the failure of this combination.

Estimation on migration characteristics of leachate using analysis of hydraulic conductivity at bioreactor landfill.

In bioreactor landfill, moisture content is one of the most important factors affecting the migration of leachate. The migration characteristics of leachate in the Sudokwon landfill site was estimated by examining relationships among self-loading weight of waste (waste weight load), bulk density, hydraulic conductivity and moisture content of the landfilled waste. Experimental zones in the Sudokwon landfill were divided into leachate recirculation zones (3-C and 4-C zone) and reference zone (3-D zone). The volume of the leachate recirculation was 207 m3 d-1 for 12 months in the 3-C zone and 190 m3 d-1 for 3 months in the 4-C zone. A logarithmic graph can describe the relationship between waste weight load and bulk density by moisture content. However, both the relationship between bulk density and hydraulic conductivity and the relationship between hydraulic conductivity and waste weight load can be expressed by an exponential graph. Through these relationships, generalised equations for hydraulic conductivity were established using moisture content and waste weight load. The hydraulic conductivity calculated from the generalised equation in the leachate recirculation zone was estimated to be 6.27 × 10-4 cm s-1 in the 3-C zone and 4.43 × 10-4 cm s-1 in the 4-C zone. The migration time of leachate in the leachate recirculation zone was estimated to be 64.2 days in the 3-C zone and 94.5 days in the 4-C zone, respectively.

Synthesis of a Polycyclic Halichondrin C1-C14 Fragment via Intermolecular Oxy-Michael/ Trans-Ketalization.

Syntheses of a crystalline polycyclic halichondrin C1-C14 building block starting from a d-gulono-1,4-lactone-derived intermediate in the current Halaven manufacturing process are described. Key features of the syntheses include an acid-catalyzed tandem intermolecular oxy-Michael/intramolecular trans-ketalization reaction and stereoselective Kishi reductions.

The role of p53 status on the synergistic effect of CKD-602 and cisplatin on oral squamous cell carcinoma cell lines.

The purpose of this study was to evaluate the synergistic apoptotic effect of CKD-602 in combination with cisplatin on different p53 statuses of oral squamous cell carcinoma (OSCC) cell lines, YD-8, YD-9, and YD-38. MTT assays were used to evaluate the inhibitory effect of the treatments modality on cell growth. The combination index was calculated using CompuSyn software. Detection of cell death was carried out using the propidium iodide (PI)/RNase staining assay, Annexin V/PI double staining assay, and Western blotting. Combination treatment using CKD-602 and cisplatin inhibited proliferation and increased the apoptotic effect on the three OSCC cell lines. Apoptotic cell death was detected in the cell lines, and significant synergistic effects of CKD-602 in combination with cisplatin were observed despite the differences in p53 status. From these results, it was suggested that the combination of CKD-602 with cisplatin might be a potential therapeutic strategy for OSCC. In particular, cell line-specific therapy is necessary because of the differences in treatment response based on p53 status.

Malarone® induced pancreatitis and alopecia in a dog: a case report.

BACKGROUND: Malarone® is a drug used for the treatment of malaria in humans. This drug is also particularly effective in the treatment of canine Babesia gibsoni infections. Malarone® is rarely used in dogs, and its adverse effects have not been widely reported. Its mechanism of action is related to the inhibition of cytochrome b and electron transport in the cell. This is the first known report of the development of acute pancreatitis and alopecia in a dog following the administration of Malarone®. CASE PRESENTATION: A 3-year-old, intact, female Maltese was referred to our clinic with intermittent vomiting and sudden, generalized alopecia. Two months previously, the dog had been prescribed Malarone® for the treatment of a suspected B. gibsoni infection. The dog was evaluated using hematology, radiography, ultrasonography, a PCR for Babesia detection, and a canine pancreatic lipase immunoreactivity (cPLI) assay. The result of the PCR test was negative, whereas the cPLI assay yielded a positive result. Dermatologic examination revealed bacterial infection with hair cycle arrest. CONCLUSIONS: Based on these findings, drug-induced acute pancreatitis and alopecia with superficial pyoderma were diagnosed. Malarone® may induce severe adverse reactions in dogs. Therefore, careful monitoring for adverse effects is required when using Malarone® in dogs.

Upregulation of MDR- and EMT-Related Molecules in Cisplatin-Resistant Human Oral Squamous Cell Carcinoma Cell Lines.

Cisplatin is one of the major drugs used in oral cancer treatments, but its usage can be limited by acquired drug resistance. In this study, we established three cisplatin-resistant oral squamous cell carcinoma (OSCC) cell lines and characterized them using cell viability assays, qPCR, Western blotting, FACS, immunofluorescence, and wound healing assays. Three OSCC cell lines (YD-8, YD-9, and YD-38) underwent long-term exposure to cisplatin, eventually acquiring resistance to the drug, which was confirmed by an MTT assay. In these three newly established cell lines (YD-8/CIS, YD-9/CIS, and YD-38/CIS), overexpression of multidrug resistance (MDR)-related genes was detected by qPCR and Western blotting. The cell lines displayed an increase in the functional activities of breast cancer resistance protein (BCRP) and multidrug resistance protein1 (MDR1) by rhodamine 123 and bodipy FL prazosin accumulation assays. Moreover, the cisplatin-resistant cells underwent morphological changes, from round to spindle-shaped, increased expression of epithelial-to-mesenchymal transition (EMT)-related molecules such as N-cadherin, and showed increased cell migration when compared with the parental cell lines. These results suggest that these newly established cell lines have acquired drug resistance and EMT induction.

A new concept of advanced management of hazardous waste in the Republic of Korea.

In order to activate the recycling of hazardous wastes, the hazardous characteristics of wastes should be removed or stabilized. However, most recyclers in recycling companies do not understand how to remove the hazardous characteristics in wastes with the proper technology. The aim of a new form of advanced management of hazardous waste is to inform recyclers and operators in industries about hazardous characteristics and the treatment methods required for all management processes, from waste generation to final treatment. In a new method of advanced management of hazardous wastes, chemicals in the waste should be initially examined at the generation source in each industry to create a chemical catalogue. Since hazardous characteristics can be determined by a chemical catalogue obtained from the waste, the hazardous characteristics of wastes can be established and considered when choosing the proper treatment method. Then, the categories of waste treatment methods for each hazardous characteristic can be introduced for generators to treat hazardous wastes properly. Therefore, it is possible to create a link between the source and the final treatment of hazardous wastes using a new concept of industry (In), waste (W), hazardous chemicals and their hazardous characteristics (Ha) and treatment methods (T). This new concept of the "InWhat" system, which includes all management processes in Korea, from waste generation to final treatment, will be proposed as a tool in the advanced management of hazardous wastes.

Electric Heating Performance of Pyrolyzed Photoresist Films Prepared by Proton Irradiation and Pyrolysis.

In this study, pyrolyzed photoresist films (PPFs) were prepared using commercial SU8 photoresist by proton irradiation and pyrolysis. SU8 thin films were irradiated with high-energy proton ions and then pyrolyzed in a tube furnace at 1000 °C under inert atmosphere. The carbonization yield of the PPFs increased with an increasing fluence due to the formation of more crosslinked network structures at a higher fluence. The electrical resistance decreased with an increasing fluence due to the higher remaining thickness and carbonization yield at a higher fluence. Therefore, the PPFs prepared at 1 × 1016 ions/cm2 showed the maximum temperature of 150 °C at 20 V and a high electric power efficiency of 1.57 mW/°C.

SH003 enhances paclitaxel chemosensitivity in MCF-7/PAX breast cancer cells through inhibition of MDR1 activity.

Paclitaxel is an anti-cancer drug for treating cancer, but paclitaxel resistance is reported in cancer cells. Multidrug resistance (MDR) is related with the epithelial-to-mesenchymal transition (EMT) mechanism, which plays a key role in cancer metastasis. Moreover, EMT mechanism is connected to tamoxifen resistance in breast cancer cells. Consequently, oncologists are interested in finding new MDR1 inhibitors originating from herbal medicines to have less side-effect. Here, we investigated an inhibition effect of SH003 on MDR1 activity in paclitaxel-resistant MCF-7/PAX breast cancer cells. Our results showed that paclitaxel did not inhibit a proliferation in paclitaxel-resistant MCF-7 breast cancer cells. Paclitaxel-resistant MCF-7 cells showed an increase of MDR1 activity, which was confirmed by measuring an amount of accumulated rhodamine 123 in the cells. Also, qRT-PCR and Western blot assays confirmed that paclitaxel-resistant MCF-7 cells exhibited high MDR1 expression level. Furthermore, paclitaxel-resistant MCF-7 cells showed mesenchymal morphology with alterations of EMT markers, and acquired tamoxifen resistance with a decrease of ERα expression. We also found that a combinatorial treatment of SH003 and paclitaxel in paclitaxel-resistant MCF-7 cells caused apoptosis in synergistic manner, which was due to SH003 inhibition of MDR1 expression. Therefore, SH003 could be a potential agent for overcoming MDR in drug-resistant cancer cells.

Rhus verniciflua Stokes (RVS) and butein induce apoptosis of paclitaxel-resistant SKOV-3/PAX ovarian cancer cells through inhibition of AKT phosphorylation.

BACKGROUND: Rhus verniciflua Stokes (RVS) belongs to the Anacardiaceae family and traditionally used for cancer treatment. RVS and butein, a major compound of RVS, were known to induce apoptosis via AKT inhibition in cancer cells. Thus, in this study, we investigated the effect of RVS and its derivative compounds (fisetin, quercetin, butein) on cell death in SKOV-3/PAX cells. METHODS: The 80 % ethanol extract of RVS and its derivative compounds (fisetin, quercetin, butein) were prepared. The cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Apoptotic cells were detected by staining with propidium iodide (PI) and Annexin V-fluorescein isothiocyanate/7-aminoactinomycin D (Annexin V-FITC/7-AAD). The expression level of intracellular signaling related-proteins in apoptosis and growth were measured by western blot assay. RESULTS: We found that RVS and butein suppressed the growth of SKOV-3/PAX cells in a dose-dependent manner. We also found that RVS and butein produced the cleavage of caspase-9, -8, -3, and PARP. Similarly, sub-G1 phase and Annexin V-FITC positive cells were increased by RVS and butein. Moreover, RVS and butein significantly reduced AKT phosphorylation in SKOV-3/PAX cells. PI3K inhibitor LY294002 caused PARP cleavage supporting our finding. CONCLUSION: Our data clearly indicate that RVS and butein induce apoptosis of SKOV-3/PAX cells through inhibition of AKT activation. RVS and butein could be useful compounds for the treatment for paclitaxel resistant-ovarian cancer.