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Electrocoagulation has attracted significant attention as an alternative to conventional chemical coagulation because it is capable of removing a wide range of contaminants and has several potential advantages. In contrast to most electrocoagulation research that has been performed with nonporous electrodes, in this study, we demonstrate energy-efficient iron electrocoagulation using porous electrodes. In batch operation, investigation of the external pore structures through optical microscopy suggested that a low porosity electrode with sparse connection between pores may lead to mechanical failure of the pore network during electrolysis, whereas a high porosity electrode is vulnerable to pore clogging. Electrodes with intermediate porosity, instead, only suffered a moderate surface deposition, leading to electrical energy savings of 21% and 36% in terms of electrocoagulant delivery and unit log virus reduction, respectively. Neutron computed tomography revealed the critical role of electrode porosity in utilizing the electrode's internal surface for electrodissolution and effective delivery of electrocoagulant to the bulk. Energy savings of up to 88% in short-term operation were obtained with porous electrodes in a continuous flow-through system. Further investigation on the impact of current density and porosity in long-term operation is desired as well as the capital cost of porous electrodes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

In this study, bovine serum albumin (BSA) is used as a globular protein model to examine the conformational changes that occur during the interaction of BSA with N-hydroxysulfo-succinimide (sodium salt)-functionalized gold nanourchins (GNUs), for which dynamic spectroscopic techniques are employed. The results showed that the absorbance of phosphate-buffered saline-BSA at 278 nm decreased when a GNU was added to the solution due to adsorption, and it decreased further when the GNU was increased. The intensity and width of the peak of local surface plasmon resonance increased, indicating the effect of corona formation. Dynamic UV-vis spectroscopy and scattering revealed a nonlinear behavior of BSA-GNU interaction. The bioplasmonic solution resulted in higher transmission and scattering than the BSA solution. Fourier transform-near-infrared spectra exhibited several bands due to overtones and combinations of the amide group and different proportions of α-helix and β-sheet components in BSA before and after the addition of the GNU. Time-resolved fluorescence spectroscopy demonstrated an initial increase in blueshifted emission, followed by a redshifted quenching of two major peaks of Tyr and tryptophan (Trp). The binding and dissociation constants were determined as Kb = 2.17 × 1010 M-1 and Kd = 4.6 × 10-11, respectively, using the Stern-Volmer relation. Both the dynamic CMOS-based imaging and the cadmium sulfide sensors demonstrated a nonlinear response of bioplasmonic solution. By increasing the GNU, the resistance of the solution decreased in the order of A > S1 > S3, where S3 exhibited the highest initial transmission with a longer desorption time. MATLAB modeling showed 80% surface coverage by the protein in 15 s at 0.05M, equivalent to a thickness of 1.7 nm, which was in agreement with the value determined by using the Stokes-Einstein relation., (2024 Published under an exclusive license by the AVS.)

The development of exopolysaccharide-based polymers is gaining increasing attention in various industrial biotechnology fields for materials such as thickeners, texture modifiers, anti-freeze agents, antioxidants, and antibacterial agents. High-viscosity carboxyethyl-succinoglycan (CE-SG) was directly synthesized from succinoglycan (SG) isolated from Sinorhizobium meliloti Rm 1021, and its structural, rheological, and physiological properties were investigated. The viscosity of CE-SG gradually increased in proportion to the degree of carboxyethylation substitution. In particular, when the molar ratio of SG and 3-chloropropionic acid was 1:100, the viscosity was significantly improved by 21.18 times at a shear rate of 10 s -1 . Increased carboxyethylation of SG also improved the thermal stability of CE-SG. Furthermore, the CE-SG solution showed 90.18 and 91.78 % antibacterial effects against Escherichia coli and Staphylococcus aureus and effective antioxidant activity against DPPH and hydroxyl radicals. In particular, CE-SG hydrogels coordinated with Fe 3+ ions, which improved both viscosity and rheological properties, while also exhibiting reduction-responsive drug release through 1,4-dithiothreitol. The results of this study suggest that SG derivatives, such as CE-SG, can be used as functional biomaterials in various fields such as food, cosmetics, and pharmaceutical industries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Polyvinyl alcohol (PVA)-bacterial succinoglycan (SG) biodegradable films were developed through a solvent-casting method. Effects of the PVA/SG ratio on the thickness, transmittance, water holding capacity, and structural and mechanical properties were investigated by various analytical methods. All the prepared films were transparent and uniform, and XRD and FTIR analyses confirmed that PVA was successfully incorporated into SG. The films also showed excellent UV-blocking ability: up to close to 80% with increasing SG concentration. The formation of effective intermolecular interactions between these polymers was evidenced by their high tensile strength and moisture transport capacity. By measuring the biodegradation rate, it was confirmed that films with high SG content showed the fastest biodegradation rate over 5 days. These results confirm that PVA/SG films are eco-friendly, with both excellent biodegradability and effective UV-blocking ability, suggesting the possibility of industrial applications as a packaging material in various fields in the future.

Cholesterol is a component of cell membranes and a precursor of hormones, and excess levels are associated with disease development; therefore, it must be maintained within the normal range. Silkworm cocoons are known to contain bioactive substances. Therefore, we compared the bioactivities of pigmented and white silkworm cocoons. Sericin extract of the Yeonnokjam (YN) variety, which contained a high flavonoid content, showed the highest antioxidant activity and inhibited cholesterol biosynthetic enzyme activity. YN-fed mice showed a 26% reduction in serum low-density lipoprotein cholesterol level. In addition, a 27% decrease in cholesterol accumulation in the liver was observed. Mechanistically, YN reduced the expression of 3-hydroxy-3-methylglutaryl-CoA reductase and acetyl-CoA acetyltransferase 2 proteins by 34 and 13%, respectively. In conclusion, YN suppresses cholesterol synthesis in the liver and stimulates bile acid secretion, which contributes to reduction in cholesterol levels, suggesting its potential as a cholesterol-lowering agent., Competing Interests: Conflict of interestNone of the authors of this study have any financial interest or conflict with industries or parties., (© The Korean Society of Food Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Lung adenocarcinoma is a crucial contributor to cancer-related mortality; however, effective treatments remain challenging. The present study aimed to investigate the role of hemoglobin subunit theta 1 (HBQ1), an α subunit of hemoglobin whose expression has recently been reported in non-erythroid cells, in lung adenocarcinoma. Comparative analysis showed that HBQ1 expression was significantly higher in lung adenocarcinoma tissues compared to normal lung tissues. Moreover, high HBQ1 expression was correlated with unfavorable overall survival and progression-free survival in patients, highlighting its potential as a prognostic marker. Our functional experiments revealed that when overexpressed, HBQ1 acts as an oncogene, enhancing cell proliferation, whereas HBQ1 knockdown inhibits it. Additionally, HBQ1 exhibited antioxidant properties by reducing basal reactive oxygen species levels, playing a crucial role in lung adenocarcinoma progression. These findings emphasize the critical role of HBQ1 in driving tumor growth and progression in lung adenocarcinoma. Our in vivo studies further supported the role of HBQ1 in lung adenocarcinoma. HBQ1 knockdown resulted in the inhibition of lung adenocarcinoma growth, demonstrating the potential of HBQ1 as a therapeutic target. Our findings highlight the importance of HBQ1 in lung adenocarcinoma and suggest its potential as both a diagnostic marker and a molecular target for therapeutic interventions.

Introduction: The occurrence of fatty liver disease, resulting from the accumulation of excessive fat within the liver, has been showing a significant and rapid increase. This study aimed to evaluate the therapeutic effects of Cheong-sang-bang-pung-san extract (CB) on fatty liver disease, and to elucidate the underlying mechanisms. Methods: We used a high-fat diet (HFD)-fed fatty liver mice and free fatty acid (FFA) induced HepG2 cell lipid accumulation model. The levels of serum, hepatic, and intracellular lipid content were assessed. Histopathological staining was used to evaluate the extent of hepatic lipid accumulation. Real-time polymerase chain reaction and Western blotting were conducted to examine the expression of factors associated with lipid metabolism. Results: We demonstrated that treatment with CB dramatically reduced body weight, liver weight, and fat mass, and improved the serum and hepatic lipid profiles in HFD-induced fatty liver mice. Additionally, CB alleviated lipid accumulation in HFD-fed mice by controlling lipid metabolism, including fatty acid uptake, triglyceride and cholesterol synthesis, and fatty acid oxidation, at the mRNA as well as protein levels. In free fatty acid-treated HepG2 cells, CB significantly reduced intracellular lipid accumulation by regulating lipid metabolism via the activation of AMP-activated protein kinase. Conclusion: These findings provide insights into the mechanisms underlying CB's effects on liver steatosis and position of CB as a potential therapeutic candidate for managing lipid metabolic disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kang, Kim, Kim, Kim, Kim and Kim.)

Dyslipidemia is a multifactorial disorder that is a causative factor and risk factor for cardiovascular disease. The incidence of dyslipidemia is expected to increase because of the presence of comorbidities. Although several lipid-lowering drugs have been developed and approved, they are not completely effective and are associated with side effects. Traditional herbal medicine (THM) represents an alternative and complementary approach for managing dyslipidemia because of its low toxicity and beneficial effects, such as anti-inflammatory and antioxidant effects. This review focuses on our current understanding of the antidyslipidemic effect of THMs and discusses the associated regulatory mechanisms. The current findings indicate that THM may lead to the development of novel therapeutic regimens for dyslipidemia., Competing Interests: None., (AJTR Copyright © 2023.)

We fabricated new hydrogels using polyvinyl alcohol (PVA) and succinoglycan (SG) directly isolated and obtained from Sinorhizobium meliloti Rm 1021 via the freeze-thaw method. Both the composition of the hydrogels and the freeze-thaw cycles were optimized to maximize the swelling ratio for the preparation of the PVA/SG hydrogels. During the optimization process, the morphology and conformational change in the hydrogel were analyzed by scanning electron microscopy, rheological measurements, and compressive tests. An optimized hydrogel with a maximum swelling ratio of 17.28 g/g was obtained when the composition of PVA to SG was 50:50 (PVA/SG 50/50) and the total number of freeze-thaw cycles was five. The PVA/SG 50/50 hydrogel had the largest pore with 51.24% porosity and the highest cross-over point (28.17%) between the storage modulus (G') and the loss modulus (G″). The PVA/SG 50/50 hydrogel showed improved thermal stability owing to its interaction with thermally stable SG chains. The improvement in the thermal stability was confirmed by thermogravimetric analysis and differential scanning calorimetry. In addition, the PVA/SG 50/50 hydrogel showed differential drug release according to the corresponding pH under acidic conditions of pH 1.2 and slightly basic conditions of pH 7.4. Furthermore, the cell viability test on the HEK-293 cell line for that hydrogel demonstrated that the PVA/SG 50/50 hydrogel was non-toxic and biocompatible. Therefore, this hydrogel could be a potential scaffold capable of pH-responsive drug delivery for chronic wound dressing applications.

Cerebral ischemic stroke is one of the leading causes of death and disability worldwide. 2'-fucosyllactose (2'-FL), a human milk oligosaccharide, exerts anti-inflammatory effects and plays a protective role in arterial thrombosis; however, its role in ischemic stroke remains unclear. This study aimed to investigate the neuroprotective effects of 2'-FL and its potential mechanisms in a mouse model of ischemic stroke. Neurological score and behavior tests revealed that 2'-FL promoted the recovery of neurological deficits and motor function in middle cerebral artery occlusion (MCAO) mice, and that 2'FL led to a reduction in the size of cerebral infarct. Biochemical studies showed that administration of 2'-FL led to a reduction of reactive oxygen species (ROS)-related products in the brain of MCAO mice. 2'-FL upregulated IL-10 and downregulated TNF-α level. In addition, 2'-FL enhanced M2-type microglial polarization and upregulated CD206 expression at 7 days after MCAO. At 3 days after MCAO, 2'-FL increased IL-4 levels and activated STAT6. Our data show that 2'-FL reduced the neurological symptoms of ischemic stroke and ROS accumulation in the brain through IL-4/STAT6-dependent M2-type microglial polarization in MCAO mice. These results demonstrate that 2'-FL is a potentially effective therapeutic agent for ischemic stroke.

Background: Platelet adhesion and aggregation play a crucial role in arterial thrombosis and ischemic stroke. Here, we identify platelet ERO1α (endoplasmic reticulum oxidoreductase 1α) as a novel regulator of Ca 2+ signaling and a potential pharmacological target for treating thrombotic diseases., Methods: Intravital microscopy, animal disease models, and a wide range of cell biological studies were utilized to demonstrate the pathophysiological role of ERO1α in arteriolar and arterial thrombosis and to prove the importance of platelet ERO1α in platelet activation and aggregation. Mass spectrometry, electron microscopy, and biochemical studies were used to investigate the molecular mechanism. We used novel blocking antibodies and small-molecule inhibitors to study whether ERO1α can be targeted to attenuate thrombotic conditions., Results: Megakaryocyte-specific or global deletion of Ero1α in mice similarly reduced platelet thrombus formation in arteriolar and arterial thrombosis without affecting tail bleeding times and blood loss following vascular injury. We observed that platelet ERO1α localized exclusively in the dense tubular system and promoted Ca 2+ mobilization, platelet activation, and aggregation. Platelet ERO1α directly interacted with STIM1 (stromal interaction molecule 1) and SERCA2 (sarco/endoplasmic reticulum Ca 2+ -ATPase 2) and regulated their functions. Such interactions were impaired in mutant STIM1-Cys49/56Ser and mutant SERCA2-Cys875/887Ser. We found that ERO1α modified an allosteric Cys49-Cys56 disulfide bond in STIM1 and a Cys875-Cys887 disulfide bond in SERCA2, contributing to Ca 2+ store content and increasing cytosolic Ca 2+ levels during platelet activation. Inhibition of Ero1α with small-molecule inhibitors but not blocking antibodies attenuated arteriolar and arterial thrombosis and reduced infarct volume following focal brain ischemia in mice., Conclusions: Our results suggest that ERO1α acts as a thiol oxidase for Ca 2+ signaling molecules, STIM1 and SERCA2, and enhances cytosolic Ca 2+ levels, promoting platelet activation and aggregation. Our study provides evidence that ERO1α may be a potential target to reduce thrombotic events., Competing Interests: Disclosures None.

Ulcerative colitis is an inflammatory bowel disease (IBD) with relapsing and remitting patterns, and it is caused by varied factors, such as the intestinal inflammation extent and duration. We examined the preventative effects of human milk oligosaccharides (HMOs) on epithelial barrier integrity and intestinal inflammation in an interleukin (IL)-6-induced cell model and dextran sodium sulfate (DSS)-induced acute mouse colitis model. HMOs including 2'-fucosyllactose (FL) and 3-FL and positive controls including fructooligosaccharide (FOS) and 5-acetylsalicylic acid (5-ASA) were orally administrated once per day to C57BL/6J mice with colitis induced by 5% DSS in the administered drinking water. 2'-FL and 3-FL did not affect the cell viability in Caco-2 cells. Meanwhile, these agents reversed IL-6-reduced intestinal barrier function in Caco-2 cells. Furthermore, 2'-FL and 3-FL reversed the body weight loss and the remarkably short colon lengths in DSS-induced acute colitis mice. Moreover, 2'-FL and 3-FL obviously protected the decreasing expression of zonula occluden-1 and occludin in colon tissue relative to the findings in the DSS-treated control group. 2'-FL and 3-FL significantly reduced IL-6 and tumor necrosis factor-α levels in serum relative to the control findings. The summary of these results shows that HMOs prevent colitis mainly by enhancing intestinal barrier function and advancing anti-inflammatory responses. Therefore, HMOs might suppress inflammatory responses and represent candidate treatments for IBD that protect intestinal integrity.

Background and Aim: Platelet-derived thrombosis is important in the pathogenesis of cardiovascular diseases. HTB is an optimized herbal medicine including Scutellaria baicalensis Georgi, Alisma orientale Juzepzuk, and Atractylodes japonica Koidzumi. It is widely used in traditional medicine due to its anti-inflammatory and antioxidant effects. However, its antiplatelet and antithrombotic activities have not been completely validated. The current study aimed to examine the inhibitory effect of the novel herb formula HTB against platelet activation and thrombus formation., Experimental Procedure: The antiplatelet activities of HTB via platelet aggregation, granule secretion, reactive oxygen species generation, and intracellular calcium mobilization were evaluated. Moreover, the antithrombotic effect of HTB via FeCl 3 -induced arterial thrombus formation in vivo in mice was assessed. The inhibitory effect of HTB against primary hemostasis was investigated based on transection tail bleeding time., Results and Conclusion: HTB treatment significantly inhibited glycoprotein VI-mediated platelet aggregation, granule secretion, reactive oxygen species generation, and intracellular calcium mobilization. Biochemical studies revealed that HTB inhibited glycoprotein VI-mediated platelet signal transduction during cell activation. Further, its antioxidant effect might be derived by reducing the phosphorylation of the p47 phox /Hic5 axis signalosome. Oral HTB treatment was effective in decreasing FeCl 3 -induced arterial thrombus formation without prolonging the tail bleeding time. HTB can be an effective therapeutic agent against thrombotic diseases., Competing Interests: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (© 2023 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Tiny machine learning (TinyML) has become an emerging field according to the rapid growth in the area of the internet of things (IoT). However, most deep learning algorithms are too complex, require a lot of memory to store data, and consume an enormous amount of energy for calculation/data movement; therefore, the algorithms are not suitable for IoT devices such as various sensors and imaging systems. Furthermore, typical hardware accelerators cannot be embedded in these resource-constrained edge devices, and they are difficult to drive real-time inference processing as well. To perform the real-time processing on these battery-operated devices, deep learning models should be compact and hardware-optimized, and hardware accelerator designs also have to be lightweight and consume extremely low energy. Therefore, we present an optimized network model through model simplification and compression for the hardware to be implemented, and propose a hardware architecture for a lightweight and energy-efficient deep learning accelerator. The experimental results demonstrate that our optimized model successfully performs object detection, and the proposed hardware design achieves 1.25× and 4.27× smaller logic and BRAM size, respectively, and its energy consumption is approximately 10.37× lower than previous similar works with 43.95 fps as a real-time process under an operating frequency of 100 MHz on a Xilinx ZC702 FPGA.

Particle collider experiments would be continued even when one is not present at the laboratory (on-site). To achieve this, we require an e-Science paradigm of studying particle physics anytime anywhere. One of the components for establishing this paradigm is a remote control room for data acquisition (DAQ). We developed and embedded a remote control room at the Korea Institute of Science and Technology Information (KISTI). Since then, we have been adopting on/offline shifts for conducting collider experiments at KISTI, that is, the experiments are done even when we are not on-site. In this paper, we introduce our experience of our remote control room for both CDF and Belle II experiments. This remote control room includes international networks, security, DAQ systems, data transfers, and monitoring systems. We also presented the results of the shifts done in the remote control room at KISTI., (© The Korean Physical Society 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Breast cancer is the leading cause of cancer-related death in women worldwide, despite medical and technological advancements. The RhoBTB family consists of three isoforms: RhoBTB1, RhoBTB2, and RhoBTB3. RhoBTB1 and RhoBTB2 have been proposed as tumor suppressors in breast cancer. However, the roles of RhoBTB3 proteins are unknown in breast cancer. Bioinformatics analysis, including Oncomine, cBioportal, was used to evaluate the potential functions and prognostic values of RhoBTB3 and Col1a1 in breast cancer. qRT-PCR analysis and immunoblotting assay were performed to investigate relevant expression. Functional experiments including proliferation assay, invasion assay, and flow cytometry assay were conducted to determine the role of RhoBTB3 and Col1a1 in breast cancer cells. RhoBTB3 mRNA levels were significantly up-regulated in breast cancer tissues as compared to in adjacent normal tissues. Moreover, RhoBTB3 expression was found to be associated with Col1a1 expression. Decreasing RhoBTB3 expression may lead to decreases in the proliferative and invasive properties of breast cancer cells. Further, Col1a1 knockdown in breast cancer cells limited the proliferative and invasive ability of cancer cells. Knockdown of RhoBTB3 may exert inhibit the proliferation, migration, and metastasis of breast cancer cells by repressing the expression of Col1a1, providing a novel therapeutic strategy for treating breast cancer.

Background: This case-control study aimed to explore an association between foot alignment and development and presentation of the ingrown toenail., Methods: Radiographs were evaluated for hallux interphalangeal angle (HIA), hallux valgus angle (HVA), talonavicular coverage angle (TNC), talo-first metatarsal (Meary's) angle, and calcaneal pitch angle (CP), as well as medial sesamoid position in a cohort of 103 young and healthy patients (mean age of 20.5 years) with ingrown toenails. A control group of 63 patients was included, and the radiographic parameters were compared. Subgroup analysis was performed in patients with lateral (n = 65) or medial (n = 38) nail fold involvement., Results: The overall study group demonstrated a larger TNC and Meary's angle and smaller CP than the control group, while no significant difference was found regarding the HIA and HVA. The lateral nail fold group had a larger HIA when compared to the medial nail fold group. Multiple regression analysis revealed that for ingrown toenail development, the only risk factor was a decrease in the CP. In the case of lateral nail fold involvement, an increase in the HIA found to be the only factor., Conclusion: A lower medial longitudinal arch seems to be a predisposing factor in developing an ingrown toenail. The lateral nail fold involvement was associated with lateral deviation of the distal phalanx. The result of this study could provide information on prevention, treatment, recurrence, and patient counseling of an ingrown toenail in otherwise young and healthy individuals., (Copyright © 2021 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Virus destabilization and inactivation are critical considerations in providing safe drinking water. We demonstrate that iron electrocoagulation simultaneously removed (via sweep flocculation) and inactivated a non-enveloped virus surrogate (MS2 bacteriophage) under slightly acidic conditions, resulting in highly effective virus control (e.g., 5-logs at 20 mg Fe/L and pH 6.4 in 30 min). Electrocoagulation simultaneously generated H 2 O 2 and Fe(II) that can potentially trigger electro-Fenton reactions to produce reactive oxygen species such as • OH and high valent oxoiron(IV) that are capable of inactivating viruses. To date, viral attenuation during water treatment has been largely probed by evaluating infective virions (as plaque forming units) or genomic damage (via the quantitative polymerase chain reaction). In addition to these existing means of assessing virus attenuation, a novel technique of correlating transmission electron micrographs of electrocoagulated MS2 with their computationally altered three-dimensional electron density maps was developed to provide direct visual evidence of capsid morphological damages during electrocoagulation. The majority of coliphages lost at least 10-60% of the capsid protein missing a minimum of one of the 5-fold and two of 3- and 2-fold regions upon electrocoagulation, revealing substantial localized capsid deformation. Attenuated total reflectance-Fourier transform infrared spectroscopy revealed potential oxidation of viral coat proteins and modification of their secondary structures that were attributed to reactive oxygen species. Iron electrocoagulation simultaneously disinfects and coagulates non-enveloped viruses (unlike conventional coagulation), adding to the robustness of multiple barriers necessary for public health protection and appears to be a promising technology for small-scale distributed water treatment.

Seaweeds are thought to be promising candidates for functional foods and to help prevent thrombotic and related cardiovascular diseases. Codium fragile (Suringer) Hariot has been traditionally used as a culinary ingredient, and it possesses a range of biological activities, including the inhibition of platelet function. However, the mechanism of this inhibition is unclear. The aim of this study was to examine the inhibitory effect of C. fragile in platelet function. The antiplatelet activity of C. fragile on agonist-activated platelet aggregation, granule secretion, calcium mobilization, platelet spreading, and clot retraction was assessed. The phosphorylation of c-Src, Syk, PLCγ2, and several proteins involving in the αIIbβ3 integrin outside-in signaling pathway were also studied in thrombin and CRP-stimulated platelets. The antithrombotic effect was investigated in mice using ferric chloride-induced arterial thrombus formation in vivo . Transection tail bleeding time was used to evaluate whether C. fragile inhibited primary hemostasis. The main components and contents of C. fragile ethanol extract were confirmed by GC-MS analysis. C. fragile significantly impaired agonist-induced platelet aggregation granule secretion, calcium mobilization, platelet spreading, and clot retraction. Biochemical analysis revealed that C. fragile inhibited the agonist-induced activation of c-Src, Syk, and PLCγ2, as well as the phosphorylation of PI3K, AKT, and mitogen-activated protein kinases (MAPKs). The inhibitory effect of C. fragile resulted from an inhibition of platelet αIIbβ3 integrin outside-in signal transduction during cell activation. Oral administration of C. fragile efficiently blocked FeCl 3 -induced arterial thrombus formation in vivo without prolonging bleeding time. GC-MS analysis revealed that phytol was the main constituent and the total content of isomers was 160.8 mg/kg. Our results demonstrated that C. fragile suppresses not only the inside-out signaling of αIIbβ3 integrin but also outside-in signal transmission. Therefore, C. fragile could be an effective antiplatelet therapeutic candidate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kim, Kim and Kim.)

Background: Platelet-neutrophil interactions contribute to vascular occlusion and tissue damage in thromboinflammatory disease. Platelet glycoprotein Ibα (GPIbα), a key receptor for the cell-cell interaction, is believed to be constitutively active for ligand binding. Here, we established the role of platelet-derived protein disulfide isomerase (PDI) in reducing the allosteric disulfide bonds in GPIbα and enhancing the ligand-binding activity under thromboinflammatory conditions., Methods: Bioinformatic analysis identified 2 potential allosteric disulfide bonds in GPIbα. Agglutination assays, flow cytometry, surface plasmon resonance analysis, a protein-protein docking model, proximity ligation assays, and mass spectrometry were used to demonstrate a direct interaction between PDI and GPIbα and to determine a role for PDI in regulating GPIbα function and platelet-neutrophil interactions. Also, real-time microscopy and animal disease models were used to study the pathophysiological role of PDI-GPIbα signaling under thromboinflammatory conditions., Results: Deletion or inhibition of platelet PDI significantly reduced GPIbα-mediated platelet agglutination. Studies using PDI-null platelets and recombinant PDI or Anfibatide, a clinical-stage GPIbα inhibitor, revealed that the oxidoreductase activity of platelet surface-bound PDI was required for the ligand-binding function of GPIbα. PDI directly bound to the extracellular domain of GPIbα on the platelet surface and reduced the Cys4-Cys17 and Cys209-Cys248 disulfide bonds. Real-time microscopy with platelet-specific PDI conditional knockout and sickle cell disease mice demonstrated that PDI-regulated GPIbα function was essential for platelet-neutrophil interactions and vascular occlusion under thromboinflammatory conditions. Studies using a mouse model of ischemia/reperfusion-induced stroke indicated that PDI-GPIbα signaling played a crucial role in tissue damage., Conclusions: Our results demonstrate that PDI-facilitated cleavage of the allosteric disulfide bonds tightly regulates GPIbα function, promoting platelet-neutrophil interactions, vascular occlusion, and tissue damage under thromboinflammatory conditions.

Rationale: Microvascular inflammation and endothelial dysfunction secondary to unchecked activation of endothelium play a critical role in the pathophysiology of sepsis and organ failure. The intrinsic signaling mechanisms responsible for dampening excessive activation of endothelial cells are not completely understood., Objective: To determine the central role of YAP (Yes-associated protein), the major transcriptional coactivator of the Hippo pathway, in modulating the strength and magnitude of endothelial activation and vascular inflammation., Methods and Results: Endothelial-specific YAP knockout mice showed increased basal expression of E-selectin and ICAM (intercellular adhesion molecule)-1 in endothelial cells, a greater number of adherent neutrophils in postcapillary venules and increased neutrophil counts in bronchoalveolar lavage fluid. Lipopolysaccharide challenge of these mice augmented NF-κB (nuclear factor-κB) activation, expression of endothelial adhesion proteins, neutrophil and monocyte adhesion to cremaster muscle venules, transendothelial neutrophil migration, and lung inflammatory injury. Deletion of YAP in endothelial cells also markedly augmented the inflammatory response and cardiovascular dysfunction in a polymicrobial sepsis model induced by cecal ligation and puncture. YAP functioned by interacting with the E3 ubiquitin-protein ligase TLR (Toll-like receptor) signaling adaptor TRAF6 (tumor necrosis factor receptor-associated factor 6) to ubiquitinate TRAF6, and thus promoted TRAF6 degradation and modification resulting in inhibition of NF-κB activation. TRAF6 depletion in endothelial cells rescued the augmented inflammatory phenotype in mice with endothelial cell-specific deletion of YAP., Conclusions: YAP modulates the activation of endothelial cells and suppresses vascular inflammation through preventing TRAF6-mediated NF-κB activation and is hence essential for limiting the severity of sepsis-induced inflammation and organ failure., (© 2018 American Heart Association, Inc.)

Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell-cell interactions in a mouse model of sickle cell disease. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50-500 nM ARQ 092 significantly blocks αMβ2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets. Treatment of isolated platelets and neutrophils with ARQ 092 inhibited heterotypic cell-cell aggregation under shear conditions. Intravital microscopic studies demonstrated that short-term oral administration of ARQ 092 or hydroxyurea, a major therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with tumor necrosis factor-α. Co-administration of hydroxyurea and ARQ 092 further reduced the adhesive function of neutrophils in venules and neutrophil transmigration into alveoli, inhibited expression of E-selectin and intercellular adhesion molecule-1 in cremaster vessels, and improved survival in these mice. Ex vivo studies in sickle cell disease mice suggested that co-administration of hydroxyurea and ARQ 092 efficiently blocks neutrophil and platelet activation and that the beneficial effect of hydroxyurea results from nitric oxide production. Our results provide important evidence that ARQ 092 could be a novel drug for the prevention and treatment of acute vaso-occlusive complications in patients with sickle cell disease., (Copyright© Ferrata Storti Foundation.)

The concept of intelligent toothbrush, capable of monitoring brushing motion, orientation through the grip axis, during toothbrushing was suggested in our previous study. In this study, we describe a tooth brushing pattern classification algorithm using three-axis accelerometer and three-axis magnetic sensor. We have found that inappropriate tooth brushing pattern showed specific moving patterns. In order to trace the position and orientation of toothbrush in a mouth, we need to know absolute coordinate information of toothbrush. By applying tilt-compensated azimuth (heading) calculation algorithm, which is generally used in small telematics devices, we could find the inclination and orientation information of toothbrush. To assess the feasibility of the proposed algorithm, 8 brushing patterns were preformed by 6 individual healthy subjects. The proposed algorithm showed the detection ratio of 98%. This study showed that the proposed monitoring system was conceived to aid dental care personnel in patient education and instruction in oral hygiene regarding brushing style.

The design of an intelligent toothbrush, capable of monitoring brushing motion, orientation through the grip axis, during toothbrushing is described. Inappropriate tooth-brushing styles, even in adults, sometimes cause dental problems, cavities, gingivitis, etc. This smart system provides user to monitor his or her brushing pattern using accelerometer and magnetic sensors for evaluation of toothbrushing style. Directional information of toothbrush with respect to the earth's magnetic field and activity data were measured by a miniaturized low-power micro-controller, MSP430 and transmitted to personal computer by 2.4 GHz radio transmitter, nRF2401. A personal computer provides an on-line display of activity and orientation measurements during toothbrushing. The signal trace is then analyzed to extract clinically relevant information. This preliminary study showed that the proposed monitoring system was conceived to aid dental care personnel in patient education and instruction in oral hygiene regarding brushing style.