Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19.

BACKGROUND: Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. RESULTS: Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. CONCLUSION: Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

Effects of Antisolvent Treatment on Copper(I) Thiocyanate Hole Transport Layer in n-i-p Perovskite Solar Cells.

Copper(I) thiocyanate (CuSCN) is considered an efficient HTL of low cost and with high stability in perovskite solar cells (PSCs). However, the diethyl sulfide solvent used for CuSCN preparation is known to cause damage to the underlying perovskite layer in n-i-p PSCs. Antisolvent treatment of CuSCN during spin-coating can effectively minimize interfacial interactions. However, the effects of antisolvent treatment are not sufficiently understood. In this study, the effects of five different antisolvents were investigated. Scanning electron microscopy and X-ray diffraction analyses showed that the antisolvent treatment improved the crystallinity of the CuSCN layer on the perovskite layer and reduced damage to the perovskite layer. However, X-ray and ultraviolet photoelectron spectroscopy analyses showed that antisolvent treatment did not affect the chemical bonds or electronic structures of CuSCN. As a result, the power conversion efficiency of the PSCs was increased from 14.72% for untreated CuSCN to 15.86% for ethyl-acetate-treated CuSCN.

Configurational Isomerization-Induced Orientation Switching: Non-Fused Ring Dipodal Phosphonic Acids as Hole-Extraction Layers for Efficient Organic Solar Cells.

Phosphonic acid (PA) self-assembled molecules have recently emerged as efficient hole-extraction layers (HELs) for organic solar cells (OSCs). However, the structural effects of PAs on their self-assembly behaviors on indium tin oxide (ITO) and thus photovoltaic performance remain obscure. Herein, we present a novel class of PAs, namely "non-fused ring dipodal phosphonic acids" (NFR-DPAs), featuring simple and malleable non-fused ring backbones and dipodal phosphonic acid anchoring groups. The efficacy of configurational isomerism in modulating the photoelectronic properties and switching molecular orientation of PAs atop electrodes results in distinct substrate surface energy and electronic characteristics. The NFR-DPA with linear (C2h symmetry) and brominated backbone exhibits favorable face-on orientation and enhanced work function modification capability compared to its angular (C2v symmetry) and non-brominated counterparts. This makes it versatile HELs in mitigating interfacial resistance for energy barrier-free hole collection, and affording optimal active layer morphology, which results in an impressive efficiency of 19.11% with a low voltage loss of 0.52 V for binary OSC devices and an excellent efficiency of 19.66% for ternary OSC devices. This study presents a new dimension to design PA-based HELs for high-performance OSCs.

Effect of intensive seasonal pumping and recharge on sulfur biogeochemistry in groundwater of agricultural riparian zones.

Physico-chemical characteristics of groundwater are often impacted by agricultural practices such as land use, fertilizer types, and groundwater pumping. This study aimed to identify contaminant sources and redox processes controlling the hydrogeochemistry of groundwater in riparian zones influenced by intensive agricultural activities, focusing on sulfur species. Groundwater samples were collected bimonthly from March 2014 to March 2015 from groundwater wells in two zones in South Korea with different agricultural systems. The water isotopic compositions of the groundwater indicated that all groundwater originated from the same meteoric water. Groundwater samples affected by periodic groundwater pumping exhibited wide variations in Mn2+ (47.8 ± 18.2 µM) and Fe2+ (123 ± 61.0 µM) and elevated SO42-, while NO3- was below the detection limit. Groundwater chemistry was affected by fertilizer and manure, and denitrification. The oxidation of reduced sulfur compounds by oxygen and nitrate did not fully account for the elevated SO42- concentrations and isotopic composition of sulfate (δ34S and δ18O) in the investigated aquifers. Therefore, we postulate that water level change due to periodic groundwater pumping and recharge enabled oxidants (MnO2 and Fe3+) to also contribute to oxidation of reduced sulfur. Additionally, fertilizers with distinct δ34S values and bacterial sulfate reduction (BSR) affected groundwater chemistry and its sulfur species, including δ34SSO4 and δ18OSO4. Removal of sulfate from the aquifer during pumping limited BSR. Consequently, the agricultural practices may further increase sulfate concentrations in the groundwater. This environmental impact should be thoroughly managed because high sulfate concentrations in drinking water cause ingestion problems in humans.

Cross-sectional and skeletal anatomy of long-tailed gorals (Naemorhedus caudatus) using imaging evaluations.

BACKGROUND: Accurate diagnosis of diseases in animals is crucial for their treatment, and imaging evaluations such as radiographs, computed tomography (CT), and magnetic resonance imaging (MRI) are important tools for this purpose. However, a cross-sectional anatomical atlas of normal skeletal and internal organs of long-tailed gorals (Naemorhedus caudatus) has not yet been prepared for diagnosing their diseases. OBJECTIVES: The objective of this study was to create an anatomical atlas of gorals using CT and MRI, which are imaging techniques that have not been extensively studied in this type of wild animal in Korea. METHODS: The researchers used CT and MRI to create an anatomical atlas of gorals, and selected 37 cross-sections from the head, thoracic, lumbar, and sacrum parts of gorals to produce an average cross-sectional anatomy atlas. RESULTS: This study successfully created an anatomical atlas of gorals using CT and MRI. CONCLUSIONS: The atlas provides valuable information for the diagnosis of diseases in gorals, which can improve their treatment and welfare. The study highlights the importance of developing cross-sectional anatomical atlases of gorals to diagnose and treat their diseases effectively.

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication.

Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound 1c strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3'-to-5' exoribonuclease (ExoN). While 1c inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound 1c in the catalytic pocket of the ExoN domain of nsp14. Finally, 1c inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that 1c might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases.

GRP78 Inhibitor YUM70 Suppresses SARS-CoV-2 Viral Entry, Spike Protein Production and Ameliorates Lung Damage.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone that has been recently implicated as an essential host factor for SARS-CoV-2 entry and infection. In this study, we investigated the efficacy of YUM70, a small molecule inhibitor of GRP78, to block SARS-CoV-2 viral entry and infection in vitro and in vivo. Using human lung epithelial cells and pseudoviral particles carrying spike proteins from different SARS-CoV-2 variants, we found that YUM70 was equally effective at blocking viral entry mediated by original and variant spike proteins. Furthermore, YUM70 reduced SARS-CoV-2 infection without impacting cell viability in vitro and suppressed viral protein production following SARS-CoV-2 infection. Additionally, YUM70 rescued the cell viability of multi-cellular human lung and liver 3D organoids transfected with a SARS-CoV-2 replicon. Importantly, YUM70 treatment ameliorated lung damage in transgenic mice infected with SARS-CoV-2, which correlated with reduced weight loss and longer survival. Thus, GRP78 inhibition may be a promising approach to augment existing therapies to block SARS-CoV-2, its variants, and other viruses that utilize GRP78 for entry and infection.

National-scale investigation of dual nitrate isotopes and chloride ion in South Korea: Nitrate source apportionment for stream water.

Nitrate sources in surface water have been identified using dual-isotope compositions of nitrate with various tools to efficiently manage the water quality at the local scale. Correlation between Cl and NO3 has also been used to identify NO3. In this study, we assess the reliability of the dual-isotope approach and Cl in terms of nitrate source apportionment. To this end, we collected stream water samples throughout South Korea to estimate nitrate sources in streams and determine whether the land-use pattern was closely related to nitrate sources. The δ15N-NO3 ranging from -1.3 to 14.8‰ showed a spatial distribution that was lower in mountain ranges (<7‰) than plain areas (>8‰). The Cl concentration in this national-scale distribution was also assessed. The relationship between the proportion of Cl and δ15N-NO3 classifies nitrate sources into areas characterized by three land-use patterns: (1) agricultural and business areas, (2) forests in highlands, and (3) lowland forests, of which (1) had proportions of Cl >50%, while (2) and (3) were <50%. The samples in (3) showed δ15N-NO3 values > 6‰, similar to those of (1). Deuterium excess of samples was negatively correlated (R2 = 0.53) with δ15N-NO3, accounting for the fact that δ15N-NO3 reflected land-use patterns. Samples were dominantly affected by agriculture-derived sources and domestic sewage showed NO3/Cl of <0.4 and δ15N-NO3 of >6‰. These results suggest that nitrate source apportionment should be comprehensively evaluated considering the dual-isotope approach, land-use patterns, and Cl proportions.

Acid mine drainage and smelter-derived sources affecting water geochemistry in the upper Nakdong River, South Korea.

Both the smelter and acid mine drainage (AMD) in uppermost streams impact water geochemistry and deteriorate water quality. Efficient water quality management requires identifying the contribution of each source to stream water geochemistry. In this study, we aimed to determine the natural and anthropogenic sources (AMD and smelting) affecting water geochemistry by considering seasonality. Water samples were collected, from May 2020 to April 2021, in a main channel (Nakdong River) and tributaries in a small watershed including mines and smelters. The watershed is characterized by a carbonate-rich area in the upper-middle reaches and silicate-rich area in the middle-lower reaches. On the plots of Ca/Na vs. Mg/Na and 2(Ca + Mg) vs. HCO3 + 2SO4, the water geochemistry was predominantly explained by the carbonate and silicate weathering associated with sulfuric and carbonic acids. According to typical δ15N values for sources, nitrate contribution from soil-N mainly impacted water geochemistry, regardless of seasonality; the contribution from agricultural activity and sewage was negligible. Water geochemistry in the main channel samples was discriminated before and after passing through the smelter. The effects of the smelter were evident in elevated SO4, Zn, and Tl concentrations and in δ66Zn values; this was further supported by the relationships between Cl/HCO3 and SO4/HCO3 and between δ66Zn and Zn. These results were pronounced during winter, when the flush-out effect was absent. Our results suggest that multi-isotopes and chemical composition analyses can trace multiple sources influencing the water geochemistry in watersheds containing AMD and smelters.

Enhancement in Power Conversion Efficiency of Perovskite Solar Cells by Reduced Non-Radiative Recombination Using a Brij C10-Mixed PEDOT:PSS Hole Transport Layer.

Interface properties between charge transport and perovskite light-absorbing layers have a significant impact on the power conversion efficiency (PCE) of perovskite solar cells (PSCs). Poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) is a polyelectrolyte composite that is widely used as a hole transport layer (HTL) to facilitate hole transport from a perovskite layer to an anode. However, PEDOT:PSS must be modified using a functional additive because PSCs with a pristine PEDOT:PSS HTL do not exhibit a high PCE. Herein, we demonstrate an increase in the PCE of PSCs with a polyethylene glycol hexadecyl ether (Brij C10)-mixed PEDOT:PSS HTL. Photoelectron spectroscopy results show that the Brij C10 content becomes significantly high in the HTL surface composition with an increase in the Brij C10 concentration (0-5 wt%). The enhanced PSC performance, e.g., a PCE increase from 8.05 to 11.40%, is attributed to the reduction in non-radiative recombination at the interface between PEDOT:PSS and perovskite by the insulating Brij C10. These results indicate that the suppression of interface recombination is essential for attaining a high PCE for PSCs.

National-scale distribution of strontium isotope ratios in environmental samples from South Korea and its implications for provenance studies.

Successful application and accurate interpretation of strontium (Sr) isotope ratios (87Sr/86Sr) requires underlying information about the large-scale variabilities in their signatures from a variety of environmental samples, which can be correlated with the Sr isotopic signatures of underlying local geology. In this national-scale study, we analyzed 87Sr/86Sr in soil, plants, stream water, and Chinese mystery snail (Cipangopaludina chinensis) shells collected from South Korea to evaluate large-scale spatial variabilities, interpret relationships among isotopic signatures of various sample types, and generate spatial distribution isoscapes reflecting the heterogeneity of isotopic signatures across South Korea. Non-parametric comparisons among environmental samples showed non-significant differences in their isotopic ratios. The 87Sr/86Sr of plant and soil samples were strongly correlated (R2adj = 0.93), suggesting that both reflect national-scale lithological properties. Similarly, the 87Sr/86Sr of shells showed strong correlations with the 87Sr/86Sr of both plant and soil samples (R2adj = 0.90). The 87Sr/86Sr signatures of environmental samples in this study aligned with expected Sr isotopic values and generally reflected local geology. Spatial distribution maps of samples showed similar 87Sr/86Sr spatial patterns, with high radiogenic values from granitic and granitic gneiss rocks systems and low radiogenic values from volcanic and sedimentary rock systems. Stream water samples showed significant correlations with soil and plant isotopic ratios, but with a low coefficient of determination (R2adj = 0.68). The deviations were much larger for samples with 87Sr/86Sr > 0.720. Further study is needed to improve the accuracy of baseline determination and interpretation of stream water isotopic variations.

RADIOGRAPHIC MEASUREMENT OF VERTEBRAL HEART SCALE IN KOREAN WILD RACCOON DOGS (NYCTEREUTES PROCYONOIDES KOREENSIS).

Raccoon dogs (Nyctereutes procyonoides koreensis), which belong to the Canidae family, are the second most injured wildlife animals rescued by the Gangwon Wildlife Medical Rescue Center. Various imaging evaluation methods including echocardiography have been developed, but thoracic radiography remains essential for the diagnosis and management of heart disease in dogs. In particular, vertebral heart scale (VHS) measurement is usually used to evaluate the dimensions of the heart silhouette on thoracic radiographs and can measure cardiomegaly more objectively. The VHS of 50 raccoon dogs without cardiac diseases were measured using thoracic radiography in right lateral (RL) and ventrodorsal (VD) recumbent positions. The VHS in the RL view of 50 raccoon dogs was 9.03 ± 0.52 vertebrae (v), which was slightly smaller than the VHS measured in the VD view of 46 raccoon dogs (9.79 ± 0.84 v). In addition, the thoracic morphology of raccoon dogs was determined to be intermediate (thoracic depth-to-width ratio, 0.75-1.25), and thoracic morphology, gender, and weight were not significantly correlated with VHS. The VHS of raccoon dogs in this study will help veterinarians diagnose potential cardiac diseases in raccoon dogs.

The effects of dyes and bleaches on the sorption and desorption of trace elements in human hair.

Trace element concentrations and isotope ratios of hair reflect the blood levels at the time of hair formation, but can be affected by external factors such as dyeing, bleaching, and bathing. To investigate the effect of dyeing, bleaching, and bathing on hair, hair was immersed in tap water, and changes in trace element concentrations and the Sr isotope ratio were observed over time. During soaking, alkaline earth metals (Ca, Mg, and Sr) from tap water were gradually absorbed into the hair over time. After about one day, the adsorption capacity of hair reached a maximum and the reverse reaction started to occur. In contrast, alkaline metals (Na and K) behaved in reverse. In dyed and bleached hair, Na was significantly desorbed from the hair and gradually migrated to the water over time. The adsorption and desorption of trace elements were minimal in untreated original hair, but much higher in dyed and bleached hair. Thus, dyeing and bleaching appear to damage the hair surface structure and greatly promote the exchange of trace elements. The rapid exchange of trace elements, including Sr, between hair and tap water observed in this study indicates that hair samples can be easily contaminated during bathing.

Viral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID-19. The SARS-CoV-2 open reading frame 8 (ORF8) is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 variants with ORF8 deleted are associated with mild disease outcomes, but the molecular mechanism behind this is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar to but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering a robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expression for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that was highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study reveals how SARS-CoV-2 ORF8 by a viral mimicry of the IL-17 cytokine contributes to COVID-19 severe inflammation. IMPORTANCE Patients infected with SARS-CoV-2 variants lacking open reading frame 8 (ORF8) have been associated with milder infection and disease outcome, but the molecular mechanism behind how this viral accessory protein mediates disease pathogenesis is not yet known. In our study, we revealed that secreted ORF8 protein mimics host IL-17 to activate IL-17 receptors A and C (IL-17RA/C) and induces a significantly stronger inflammatory response than host IL-17A, providing molecular insights into the role of ORF8 in COVID-19 pathogenesis and serving as a potential therapeutic target.

Cubital tunnel syndrome associated with previous ganglion cyst excision in the elbow: a case report.

Cubital tunnel syndrome refers to compression neuropathy caused by pressure on the ulnar nerve pathway around the elbow. A 63-year-old male patient visited the clinic complaining of decreased sensation and weakness in his left ring finger and little finger, stating that the symptoms first began 6 months prior. He had undergone surgery to remove a ganglion cyst from his left elbow joint about 5 years prior in Mongolia. Magnetic resonance imaging revealed a cystic mass located at the previous surgical site, which was compressing the ulnar nerve within the cubital tunnel. Ulnar nerve decompression and anterior transposition were performed, and the cystic mass was excised. Upon pathological examination, the mass was diagnosed as a ganglion cyst. The patient's symptoms including sensory dysfunction and weakness improved over the 1-year follow-up period. This report describes a rare case of ganglion cyst recurrence compressing the ulnar nerve in the cubital tunnel after previous ganglion cyst excision.

Spatial distributions of oxygen and hydrogen isotopes in multi-level groundwater across South Korea: A case study of mountainous regions.

This study presents the spatial distributions of stable isotopes for groundwater according to well depth and spring water across South Korea, using an interpolation model to provide baseline information for hydrological studies. In total, 888 groundwater and 108 spring water samples were collected across South Korea; their oxygen and hydrogen isotopic compositions (δ18O and δ2H) were analyzed. δ18O and δ2H values biased toward the summer local meteoric water line and low d-excess values indicate that summer precipitation is important for groundwater recharge. The δ18O and δ2H values for groundwater and spring water decrease progressively from the southwest to the northeast on the Korean Peninsula. Based on eight hydrological regions, the average δ18O values of groundwater and spring water are negatively correlated with latitude, but they are positively correlated with temperature. This result indicates that the spatial distributions of groundwater isotopic values in South Korea are significantly influenced by latitude and altitude effects associated with the movement of the North Pacific air mass in summer. Spring waters showed a negative correlation between δ18O and d-excess, with more depleted 18O values than groundwater, indicating that local recharge and flow within mountainous areas is dominant. Considering that the correlation in multi-level groundwater located in northern regions is similar to that of spring water, the contribution of regional groundwater flow, which is recharged in mountainous areas, is considered to be higher in the northern regions. The spatial distribution of δ18O in groundwater gradually approached the spatial distribution of spring water with increasing well depth, indicating that the contribution of regional groundwater flow may be greater in deep groundwater. Our results provide estimates for data-poor regions, supporting the investigation of links between groundwater and other hydrological factors.

Spatial distributions of strontium isotope ratios in human hair and tap water from South Korea.

Natural variations of 87Sr/86Sr ratios in biological samples, such as human hair, provide a biological record of provenance. Spatial distribution maps reflecting heterogeneity in isotopic signatures across large geographical regions are helpful for discerning the provenance and mobility of organisms. In this national-scale study conducted across South Korea, we investigated the spatial distribution patterns of 87Sr/86Sr ratios in human hair and tap water samples to determine their spatial variabilities and the relationships of isotopic signatures between hair and tap water. The strontium isoscapes of tap water and hair showed similar spatial distribution patterns. Non-parametric comparison indicated no significant differences in isotopic ratios between the two sample types. The 87Sr/86Sr ratios in human hair showed a significant and strong correlation with the ratios in tap water in eastern Korea, suggesting potential use of 87Sr/86Sr ratios in provenance studies. However, tap water and hair samples from western Korea did not show significant correlation between them, overall reducing the predictive power of the hair 87Sr/86Sr ratios for provenance studies. The deviation between 87Sr/86Srtap water and 87Sr/86Srhair was much larger in western coastal areas than in eastern Korea. Relatively high utilization of groundwater or exogenous materials, such as Asian dust, may have been responsible for this pattern. To fully utilize the potential of the strontium isotope signature as a biorecorder in provenance studies, it is essential to evaluate the effects of groundwater and other exogenous materials on the isotope signatures of hair and other biological samples. In this study, only hair samples from males were used to develop 87Sr/86Sr isoscapes. Therefore, further studies are required to examine the applicability of 87Sr/86Sr hair isoscapes based solely on human hair samples from males to forensic and provenance studies of human hair samples from females.