A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein.

Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.

Utility of the immature granulocyte percentage for diagnosing acute appendicitis among clinically suspected appendicitis in adult.

BACKGROUND: Acute appendicitis is the most common cause of abdominal surgical emergencies that present at the emergency department (ED). Although early phase of acute appendicitis cannot induce systemic inflammatory responses, it may induce proliferation immature granulocyte before leukocytosis is occurred. Based on this, we hypothesized that IG% may be beneficial for detecting appendicitis, in addition to classic inflammatory markers including the WBC count, a left shift in neutrophils, and CRP, at no additional cost. METHODS: A retrospective observational study was conducted in a tertiary-care, university-affiliated hospital emergency department in adults (>18 years old) with suspected appendicitis from January 1, 2015 to December 31, 2016. The diagnostic performance of IG% and other inflammatory markers, namely white blood cell (WBC) count, proportion of neutrophils, and C-reactive protein (CRP), for acute appendicitis was evaluated. RESULTS: Of 403 patients, 204 (50.6%) were diagnosed with acute appendicitis and 45 (22.0%) had complicated appendicitis. All inflammatory markers, including WBC count, proportion of neutrophils, IG%, and CRP, were statistically different between the appendicitis and nonappendicitis group (P < .01). However, IG% was not clinically useful because the median IG% was the same (0.3 vs 0.3) between the appendicitis and nonappendicitis group. Moreover, the area under the curve for IG% was smaller than for other inflammatory markers (0.57, 0.51-0.63, P < .02). CONCLUSION: The diagnostic ability of IG% for appendicitis is insufficient, and it brings no additional benefit over other inflammatory markers.

Effect of Mn in Li3V2-xMnx(PO4)3 as High Capacity Cathodes for Lithium Batteries.

Li3V2-xMnx(PO4)3 (x = 0, 0.05) cathode materials, which allow extraction of 3 mol of Li from the formula unit, were investigated to achieve a high energy density utilizing multielectron reactions, activated by the V3+/5+ redox reaction. Structural investigation demonstrates that V3+ was replaced by equivalent Mn3+, as confirmed by Rietveld refinement of the X-ray diffraction data and X-ray absorption near edge spectroscopy. The substitution simultaneously lowered the band gap energy from 3.4 to 3.2 eV, according to a density functional theory calculation. In addition to the effect of Mn doping, surface carbonization of Li3V2-xMnx(PO4)3 (x = 0, 0.05) dramatically increased the electric conductivity up to 10-3 S cm-1. As a result, the carbon-coated Li3V2-xMnx(PO4)3 (x = 0.05) delivered a high discharge (reduction) capacity of approximately 180 mAh g-1 at a current of 20 mA g-1 (0.1 C rate) with excellent retention, delivering approximately 163 mAh g-1 at the 200th cycle. Even at 50 C (10 A g-1), the electrode afforded a discharge capacity of 68 mAh g-1 and delivered approximately 104 mAh g-1 (1 C) at -10 °C with the help of Mn doping and carbon coating. The synergetic effects such as a lowered band gap energy by Mn doping and high electric conductivity associated with carbon coating are responsible for the superior electrode performances, including thermal properties with extremely low exothermic heat generation (<0.4 J g-1 for Li0.02V1.95Mn0.05(PO4)3), which is compatible with the layered high energy density of LiNi0.8Co0.15Al0.05O2 and LiNi0.8Co0.1Mn0.1O2 materials.

Synthesis and Electrochemical Reaction of Tin Oxalate-Reduced Graphene Oxide Composite Anode for Rechargeable Lithium Batteries.

Unlike for SnO2, few studies have reported on the use of SnC2O4 as an anode material for rechargeable lithium batteries. Here, we first introduce a SnC2O4-reduced graphene oxide composite produced via hydrothermal reactions followed by a layer-by-layer self-assembly process. The addition of rGO increased the electric conductivity up to ∼10-3 S cm-1. As a result, the SnC2O4-reduced graphene oxide electrode exhibited a high charge (oxidation) capacity of ∼1166 mAh g-1 at a current of 100 mA g-1 (0.1 C-rate) with a good retention delivering approximately 620 mAh g-1 at the 200th cycle. Even at a rate of 10 C (10 A g-1), the composite electrode was able to obtain a charge capacity of 467 mAh g-1. In contrast, the bare SnC2O4 had inferior electrochemical properties relative to those of the SnC2O4-reduced graphene oxide composite: ∼643 mAh g-1 at the first charge, retaining 192 mAh g-1 at the 200th cycle and 289 mAh g-1 at 10 C. This improvement in electrochemical properties is most likely due to the improvement in electric conductivity, which enables facile electron transfer via simultaneous conversion above 0.75 V and de/alloy reactions below 0.75 V: SnC2O4 + 2Li+ + 2e- → Sn + Li2C2O4 + xLi+ + xe- → LixSn on discharge (reduction) and vice versa on charge. This was confirmed by systematic studies of ex situ X-ray diffraction, transmission electron microscopy, and time-of-flight secondary-ion mass spectroscopy.

Synthesis of LiVOPO4 by Emulsion Drying Method for Use as an Anode Material for Rechargeable Lithium Batteries.

Highly crystalline ß-LiVOPO4 was synthesized from a water-in-oil emulsion. At 400 °C in ambient air, removal of the oil phase from the emulsion precipitates resulted in a poorly crystalline intermediate compound. On increasing the temperature to 750 °C under Ar, a single phase was formed. Rietveld refinement of the X-ray diffraction (XRD) data obtained from the product heated at 750 °C indicated that the product has an orthorhombic ß-LiVOPO4 olivine structure with no impurities. Although the ß-LiVOPO4 had an irreversible capacity in the first cycle, the electrode exhibited stable cyclability for 100 cycles, maintaining approximately 85.5% (573 mAh g-1) of the first charge capacity (670 mAh g-1). In addition, the ß-LiVOPO4 electrode had a high capacity even at high rates: 601 mAh g-1 at 1C rate (670 mA g-1) and 373 mAh g-1 at 30C rates (20.1 A g-1). Consolidating the results from XRD, X-ray photoelectron spectroscopy, and time-of-flight secondary mass spectroscopy, we suggest that the electrochemical activity of the ß-LiVOPO4 arises from the conversion reaction accompanied by the formation of Li2O and Li3PO4. In addition, the ion-conducting Li3PO4 contributes to high capacity delivery at high rates up to a C-rate of 30.

Texture direction of combined microgrooves and submicroscale topographies of titanium substrata influence adhesion, proliferation, and differentiation in human primary cells.

OBJECTIVE: This study aimed to identify the optimal micro- and submicroscale topographies of titanium (Ti) substrata that would most significantly influence adhesion, proliferation, and other activities of these cells. DESIGN: Truncated V-shaped microgrooves in 60 µm-wide and 10 µm-deep cross-sections with 0°, 30°, 60°, or 90° angles between the microgrooves and ridge-top submicroscale texture were created on the Ti substrata (designated NE60/10-0°, NE60/10-30°, NE60/10-60° and NE60/10-90°, respectively). Ground titanium with submicroscale texture but with no microgrooves was used as the control substratum, NE0. Scanning electron microscopic observation and the assays determining the cell adhesion, cell proliferation and osteoblast differentiation were performed. RESULTS: Cells more actively migrated into the microgrooves on NE60/10-30° than into the microgrooves on any other substrata tested, suggesting that the cells utilise the increased surface area of the substrata at the microscale level. NE60/10-0° and NE60/10-30° substrata generally enhanced adhesion, proliferation, alkaline phosphatase activity, and osteoblast differentiation of human primary cells when compared to other Ti substrata, and significant correlations were observed between these cellular activities. CONCLUSIONS: Here, we show that the contact guidance of human primary cells grown on Ti substrata can be controlled more by specific submicroscale textures on ridge tops than by the dimensions of surface microgrooves only. Also, the degree of angles created between the submicroscale textures and microgrooves on Ti substrata significantly affect cell adhesion, proliferation and differentiation in human primary cells.

SIRT1 modulates high-mobility group box 1-induced osteoclastogenic cytokines in human periodontal ligament cells.

Bone resorptive cytokines contribute to bone loss in periodontal disease. However, the involvement of SIRT1 in high-mobility group box 1 (HMGB1)-induced osteoclastic cytokine production remains unknown. The aim of this study was to investigate the role of SIRT1 in the responses of human periodontal ligament cells to HMGB1 and to identify the underlying mechanisms. The effect of HMGB1 on osteoclastic cytokine expression and secretion, and the regulatory mechanisms involved were studied by ELISA, reverse transcription-polymerase chain reaction, and Western blot analysis. HMGB1 upregulated the mRNA expression levels of the osteoclastic cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-11, and IL-17. In addition, HMGB1 upregulated RANKL mRNA expression, and SIRT1 mRNA and protein expression. The upregulation of these cytokines by HMGB1 was attenuated by pretreatment with inhibitors of p38 mitogen-activated protein kinase and NF-κB, as well as neutralizing antibodies against Toll-like receptors 2 and 4. Inhibition of SIRT1 by sirtinol or SIRT1 siRNA blocked the HMGB1-stimulated expression of RANKL and cytokines. These results suggest that the inhibition of SIRT1 may attenuate HMGB1-mediated periodontal bone resorption through the modulation of osteoclastogenic cytokine levels in human periodontal ligament cells.

Endoplasmic reticulum stress is involved in hydrogen peroxide induced apoptosis in immortalized and malignant human oral keratinocytes.

BACKGROUND: Although hydrogen peroxide may play an important role in the development of cancer, it can be an efficient inducer of apoptosis in cancer cells; the exact mechanism by which this action occurs is not completely understood in oral cancer cells. METHOD: In this study, the mechanisms by which H(2)O(2) inhibited growth and induced apoptosis were differentially investigated using HPV-immortalized human oral keratinocytes (IHOK) and oral cancer cells (HN4). RESULTS: H(2)O(2) treatment sensitively and dose-dependently induced growth inhibition and typical apoptosis in IHOK and HN4 cells, as demonstrated by a decreased level of cell viability, an increased population of cells in the sub-G(0)/G(1) phase, ladder formation of the genomic DNA, chromatin condensation and accumulation of Annexin V(+)/PI(+) cells. Furthermore, the expression of Bax, p53 and p21(WAF1/CIP1) increased, whereas the expression of Bcl-2 decreased in immortalized and malignant keratinocytes that were treated with H(2)O(2). In addition, cytochrome-c from the mitochondria was observed in H(2)O(2)-treated IHOK and oral cancer cells, and this was accompanied by the activation of caspase-3 and -9. Additionally, H(2)O(2) treatment induced upregulation of CHOP, GRP78 and several representative endoplasmic reticulum (ER) stress-responsive proteins, including heme oxygenase-1. CONCLUSION: Overall, these results suggest that H(2)O(2) triggers apoptosis via the mitochondrial and ER stress pathway in IHOK and HN4 cells, and that increasing the cellular levels of H(2)O(2) sufficiently may lead to selective killing of oral cancer cells and therefore be therapeutically useful.