CX 3 CR1 + macrophages interact with HSCs to promote HCC through CD8 + T-cell suppression.

BACKGROUND AND AIMS: HSCs contribute to HCC progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX 3 CR1 + macrophages to protumorigenic properties in the peritumoral area. APPROACH AND RESULTS: In single-cell RNA-sequencing analysis of patients with HCC, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14 + CD11b + HLA-DR - macrophages with CX 3 CR1 in the HCC adjacent region where α-smooth muscle actin-expressing activated hepatic stellate cells (aHSCs) showed colocalized expression of CX 3 CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX 3 CR1 + Ly6C + macrophages was mostly observed with decreased CD8 + T cells. In adoptive transfer and in vitro coculture of myeloid cells, we demonstrated that CX 3 CR1 + Ly6C + macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or coculturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX 3 CR1 + Ly6C + macrophages and human blood CD14 + cells, leading to the suppression of CD8 + T-cell proliferation. Moreover, genetic deficiency of CX 3 CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development. CONCLUSIONS: We showed that CX 3 CR1 + Ly6C + macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX 3 CR1 + Ly6C + macrophages, subsequently depriving CD8 + T cells of arginine and promoting HCC.

Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury.

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

Interleukin-33 facilitates liver regeneration through serotonin-involved gut-liver axis.

BACKGROUND AND AIMS: Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms. APPROACH AND RESULTS: We performed PHx in IL-33 -/- , suppression of tumorigenicity 2 (ST2) -/- , and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be normalized in IL-33 -/- but not ST2 -/- mice by recombinant murine IL-33 administration. Furthermore, we observed an increased level of serotonin in portal blood from wild-type mice, but not IL-33 -/- or ST2 -/- mice, after PHx. ST2 deficiency specifically in enterochromaffin cells recapitulated the phenotype of delayed liver regeneration observed in ST2 -/- mice. Moreover, the impeded liver regeneration in IL-33 -/- and ST2 -/- mice was restored to normal levels by the treatment with (±)-2,5-dimethoxy-4-iodoamphetamine, which is an agonist of the 5-hydroxytrytamine receptor (HTR)2A. Notably, in vitro experiments demonstrated that serotonin/HTR2A-induced hepatocyte proliferation is dependent on p70S6K activation. CONCLUSIONS: Our study identified that IL-33 is pro-regenerative in a noninjurious model of liver resection. The underlying mechanism involved IL-33/ST2-induced increase of serotonin release from enterochromaffin cells to portal blood and subsequent HTR2A/p70S6K activation in hepatocytes by serotonin. The findings implicate the potential of targeting the IL-33/ST2/serotonin pathway to reduce the risk of post-hepatectomy liver failure and small-for-size syndrome.

Eosinophils protect against acetaminophen-induced liver injury through cyclooxygenase-mediated IL-4/IL-13 production.

BACKGROUND AND AIMS: A better understanding of the underlying mechanism of acetaminophen (APAP)-induced liver injury (AILI) remains an important endeavor to develop therapeutic approaches. Eosinophils have been detected in liver biopsies of patients with APAP overdose. We recently demonstrated a profound protective role of eosinophils against AILI; however, the molecular mechanism had not been elucidated. APPROACH AND RESULTS: In agreement with our previous data from experiments using genetic deletion of eosinophils, we found that depletion of eosinophils in wild-type (WT) mice by an anti-IL-15 antibody resulted in exacerbated AILI. Moreover, adoptive transfer of eosinophils significantly reduced liver injury and mortality rate in WT mice. Mechanistic studies using eosinophil-specific IL-4/IL-13 knockout mice demonstrated that these cytokines, through inhibiting interferon-γ, mediated the hepatoprotective function of eosinophils. Reverse phase protein array analyses and in vitro experiments using various inhibitors demonstrated that IL-33 stimulation of eosinophils activated p38 mitogen-activated protein kinase (MAPK), and in turn, cyclooxygenases (COX), which triggered NF-κB-mediated IL-4/IL-13 production. In vivo adoptive transfer experiments showed that in contrast to naive eosinophils, those pretreated with COX inhibitors failed to attenuate AILI. CONCLUSIONS: The current study revealed that eosinophil-derived IL-4/IL-13 accounted for the hepatoprotective effect of eosinophils during AILI. The data demonstrated that the p38 MAPK/COX/NF-κB signaling cascade played a critical role in inducing IL-4/IL-13 production by eosinophils in response to IL-33.

Hepatic recruitment of eosinophils and their protective function during acute liver injury.

BACKGROUND & AIMS: Beyond the classical description of eosinophil functions in parasite infections and allergic diseases, emerging evidence supports a critical role of eosinophils in resolving inflammation and promoting tissue remodeling. However, the role of eosinophils in liver injury and the underlying mechanism of their recruitment into the liver remain unclear. METHODS: Hepatic eosinophils were detected and quantified using flow cytometry and immunohistochemical staining. Eosinophil-deficient (ΔdblGata1) mice were used to investigate the role of eosinophils in 3 models of acute liver injury. In vivo experiments using Il33-/- mice and macrophage-depleted mice, as well as in vitro cultures of eosinophils and macrophages, were performed to interrogate the mechanism of eotaxin-2 (CCL24) production. RESULTS: Hepatic accumulation of eosinophils was observed in patients with acetaminophen (APAP)-induced liver failure, whereas few eosinophils were detectable in healthy liver tissues. In mice treated with APAP, carbon tetrachloride or concanavalin A, eosinophils were recruited into the liver and played a profound protective role. Mice deficient of macrophages or IL-33 exhibited impaired hepatic eosinophil recruitment during acute liver injury. CCL24, but not CCL11, was increased after treatment of each hepatotoxin in an IL-33 and macrophage-dependent manner. In vitro experiments demonstrated that IL-33, by stimulating IL-4 release from eosinophils, promoted the production of CCL24 by macrophages. CONCLUSIONS: This is the first study to demonstrate that hepatic recruitment of and protection by eosinophils occur commonly in various models of acute liver injury. Our findings support further exploration of eosinophils as a therapeutic target to treat APAP-induced acute liver injury. LAY SUMMARY: The current study unveils that eosinophils are recruited into the liver and play a protective function during acute liver injury caused by acetaminophen overdose. The data demonstrate that IL-33-activated eosinophils trigger macrophages to release high amounts of CCL24, which promotes hepatic eosinophil recruitment. Our findings suggest that eosinophils could be an effective cell-based therapy for the treatment of acetaminophen-induced acute liver injury.

Mitochondrial Double-Stranded RNA in Exosome Promotes Interleukin-17 Production Through Toll-Like Receptor 3 in Alcohol-associated Liver Injury.

BACKGROUND AND AIMS: Mitochondrial double-stranded RNA (mtdsRNA) and its innate immune responses have been reported previously; however, mtdsRNA generation and its effects on alcohol-associated liver disease (ALD) remain unclear. Here, we report that hepatic mtdsRNA stimulates toll-like receptor 3 (TLR3) in Kupffer cells through the exosome (Exo) to enhance interleukin (IL)-17A (IL-17A) production in ALD. APPROACH AND RESULTS: Following binge ethanol (EtOH) drinking, IL-17A production primarily increased in γδ T cells of wild-type (WT) mice, whereas the production of IL-17A was mainly facilitated by CD4+ T cells in acute-on-chronic EtOH consumption. These were not observed in TLR3 knockout (KO) or Kupffer cell-depleted WT mice. The expression of polynucleotide phosphorylase, an mtdsRNA-restricting enzyme, was significantly decreased in EtOH-exposed livers and hepatocytes of WT mice. Immunostaining revealed that mtdsRNA colocalized with the mitochondria in EtOH-treated hepatocytes from WT mice and healthy humans. Bioanalyzer analysis revealed that small-sized RNAs were enriched in EtOH-treated Exos (EtOH-Exos) rather than EtOH-treated microvesicles in hepatocytes of WT mice and humans. Quantitative real-time PCR and RNA sequencing analyses indicated that mRNA expression of mitochondrial genes encoded by heavy and light strands was robustly increased in EtOH-Exos from mice and humans. After direct treatment with EtOH-Exos, IL-1ß expression was significantly increased in WT Kupffer cells but not in TLR3 KO Kupffer cells, augmenting IL-17A production of γδ T cells in mice and humans. CONCLUSIONS: EtOH-mediated generation of mtdsRNA contributes to TLR3 activation in Kupffer cells through exosomal delivery. Consequently, increased IL-1ß expression in Kupffer cells triggers IL-17A production in γδ T cells at the early stage that may accelerate IL-17A expression in CD4+ T cells in the later stage of ALD. Therefore, mtdsRNA and TLR3 may function as therapeutic targets in ALD.

The Affective Creativity of a Couple in Dementia Care.

The capacity to feel and express themselves in response to worldly surroundings is a defining feature of who a person living with dementia is, and can have profound effects on the ways in which they think, act and express creativity. Drawing on a year of intensive collaborative work with residents living with dementia in an Orthodox Jewish care home in London, I extend our perceptions and understandings of how a couple experiences their day-to-day lives, with particular attention paid to their affective practice in creativity. I demonstrate how the affective creativity of the couple emerges, circulates, and transforms as a spouse's dementia develops, whilst feeling bodies continuously (re)make relations and familiarize themselves with the immediate surroundings through the making of artworks.

Loss of toll-like receptor 3 aggravates hepatic inflammation but ameliorates steatosis in mice.

The importance of toll-like receptor (TLR) 4 in the pathogenesis of steatohepatitis has been well documented; however, little is known about the role of TLR3. In this study, we determined whether the depletion of TLR3 modulated hepatic injury in mice and further aimed to provide mechanistic insights into the TLR3-mediated modulation of diet-induced hepatic inflammation and fat accumulation. Hepatic steatosis and inflammatory response were induced by feeding wild-type (WT) or TLR3 knockout mice a high-fat diet for 8 weeks. Primary liver resident cells, including hepatocytes, Kupffer cells, and hepatic stellate cells (HSCs), were treated with palmitic acid. TLR3 knockout mice fed a high-fat diet showed severe hepatic inflammation accompanied by nuclear factor-κB and IRF3 activation, which is mainly induced by the activation of Kupffer cells. Decreased TLR4 expression was restored in hepatic mononuclear cells and Kupffer cells in TLR3 knockout mice compared to that in the WT. Moreover, hepatic steatosis was decreased in TLR3 knockout mice. Hepatocytes from TLR3 knockout mice exhibited reduced expression of cannabinoid receptors. HSCs from TLR3 knockout mice showed decreased expression of the enzymes involved in endocannabinoid synthesis. In conclusion, this study suggests that the selective modulation of TLR3 could be a novel therapeutic target for the treatment of hepatic inflammation and steatosis.

Towards a Meaningful 3D Map Using a 3D Lidar and a Camera.

Semantic 3D maps are required for various applications including robot navigation and surveying, and their importance has significantly increased. Generally, existing studies on semantic mapping were camera-based approaches that could not be operated in large-scale environments owing to their computational burden. Recently, a method of combining a 3D Lidar with a camera was introduced to address this problem, and a 3D Lidar and a camera were also utilized for semantic 3D mapping. In this study, our algorithm consists of semantic mapping and map refinement. In the semantic mapping, a GPS and an IMU are integrated to estimate the odometry of the system, and subsequently, the point clouds measured from a 3D Lidar are registered by using this information. Furthermore, we use the latest CNN-based semantic segmentation to obtain semantic information on the surrounding environment. To integrate the point cloud with semantic information, we developed incremental semantic labeling including coordinate alignment, error minimization, and semantic information fusion. Additionally, to improve the quality of the generated semantic map, the map refinement is processed in a batch. It enhances the spatial distribution of labels and removes traces produced by moving vehicles effectively. We conduct experiments on challenging sequences to demonstrate that our algorithm outperforms state-of-the-art methods in terms of accuracy and intersection over union.

Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma.

UNLABELLED: Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins. CONCLUSION: IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment.

Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice.

UNLABELLED: The important roles of retinols and their metabolites have recently been emphasized in the interactions between hepatic stellate cells (HSCs) and natural killer (NK) cells. Nevertheless, the expression and role of retinol metabolizing enzyme in both cell types have yet to be clarified. Thus, we investigated the expression of retinol metabolizing enzyme and its role in liver fibrosis. Among several retinol metabolizing enzymes, only alcohol dehydrogenase (ADH) 3 expression was detected in isolated HSCs and NK cells, whereas hepatocytes express all of them. In vitro treatment with 4-methylpyrazole (4-MP), a broad ADH inhibitor, or depletion of the ADH3 gene down-regulated collagen and transforming growth factor-ß1 (TGF-ß1) gene expression, but did not affect α-smooth muscle actin gene expression in cultured HSCs. Additionally, in vitro, treatments with retinol suppressed NK cell activities, whereas inhibition of ADH3 enhanced interferon-γ (IFN-γ) production and cytotoxicity of NK cells against HSCs. In vivo, genetic depletion of the ADH3 gene ameliorated bile duct ligation- and carbon tetrachloride-induced liver fibrosis, in which a higher number of apoptotic HSCs and an enhanced activation of NK cells were detected. Freshly isolated HSCs from ADH3-deficient mice showed reduced expression of collagen and TGF-ß1, but enhanced expression of IFN-γ was detected in NK cells from these mice compared with those of control mice. Using reciprocal bone marrow transplantation of wild-type and ADH3-deficient mice, we demonstrated that ADH3 deficiency in both HSCs and NK cells contributed to the suppressed liver fibrosis. CONCLUSION: ADH3 plays important roles in promoting liver fibrosis by enhancing HSC activation and inhibiting NK cell activity, and could be used as a potential therapeutic target for the treatment of liver fibrosis.

Novel Probability Density Function of Pad Asperity by Wear Effect over Time in Chemical Mechanical Planarization.

Chemical mechanical planarization (CMP) reduces film thickness, eliminates step height, and achieves high levels of planarity in semiconductor manufacturing. However, research into its mechanisms is still in progress, and there are many issues to be resolved. To solve problems in CMP, it is necessary to understand the contact phenomenon that occurs at the pad-wafer interface, especially pad asperity. Moreover, understanding the non-uniform distribution of pad asperity, such as height and radius, is essential for predicting the material removal rate (MRR). In this study, based on the existing Greenwood-Williamson (GW) theory and probability density function (PDF), a modified mathematical model that includes changes in asperity distribution was developed and validated experimentally. The contact model proposed in this study included functions that calculated the time-dependent height and radius wear of the pad asperities. Specifically, the experimentally obtained values were compared with the values obtained by the model, and the comparison results were analyzed. Thereby, it was found that the contact model and MRR model considering the change in asperity wear and distribution due to CMP proposed in this study are in better agreement with the experimental results than the existing model, which shows that the MRR can be predicted by a mathematical model using the change in asperity distribution.

Temporal variations in the surface aragonite saturation state of the Yellow Sea: Observations at the Socheongcho Ocean Research Station during 2017-2022.

Accurately constraining the natural variability of the carbonate system is essential for evaluating long-term changes in coastal areas, which result from the absorption of anthropogenic CO2. This is particularly important given the significant variation in physical and biological processes in these regions. In this regard, the analysis of surface carbonate chemistry in the Yellow Sea was conducted using discrete seawater samples obtained from the Socheongcho Ocean Research Station (37.423°N, 124.738°E) between 2017 and 2022. Our bottle data and sensor pH measurements revealed considerable seasonal variations of aragonite saturation state (ΩAR), typically ranging from 1.6 to 3.9. These variations are particularly pronounced during the summer and early winter. Our dataset serves as a baseline for understanding the long-term changes in ocean acidification in the Yellow Sea, the complex biogeochemical processes in coastal areas, and their impact on ocean acidification.

Comparison of inorganic nitrogen concentrations in airborne particles at inshore and offshore sites in the Yellow Sea (2017-2019): Long-range transport and potential impact on marine productivity.

Atmospheric deposition of nitrogen is one of the most important external nutrient sources. We investigated the concentrations of NO3- and NH4+ in airborne particles at both an offshore and an inshore site in the Yellow Sea. At the offshore site, devoid of local sources and located downwind from the highly developed areas of Korea and China, the concentrations of atmospheric particulate NO3- and NH4+ were ∼88 ± 101 nmol m-3 and ∼102 ± 102 nmol m-3, respectively, likely due to the transboundary long-range transport of pollutants. The inshore site showed a concentration ∼2 times higher than the offshore site. Considering not only dry inorganic nitrogen deposition but also wet and organic material deposition, the total atmospheric nitrogen deposition was estimated to contribute roughly 10 % to the new production in the Yellow Sea.

Blood Biomarkers in Patients with Parkinson's Disease: A Review in Context of Anesthetic Care.

Parkinson's disease (PD) is the second most common inflammatory neurodegenerative disorder after dementia. Preclinical and epidemiological data strongly suggest that chronic neuroinflammation slowly induces neuronal dysfunction. Activated microglia secrete several neurotoxic substances, such as chemokines and proinflammatory cytokines, which may promote blood-brain barrier (BBB) permeabilization. CD4+ T cells comprise proinflammatory cells such as T helper (Th) 1 and Th17 cells, as well as anti-inflammatory cells such as Th2 and T regulatory cells (Tregs). Th1 and Th17 cells can be detrimental to dopamine neurons, whereas Th2 and Tregs are neuroprotective. The results of studies on the serum levels of cytokines such as IFN-γ and TNF-α secreted by Th1 T cells, IL-8 and IL-10 secreted by Th2 T cells, and IL-17 secreted by Th17 cells in PD patients are not uniform. In addition, the relationships between serum cytokine levels and motor and non-motor symptoms of PD are controversial. Surgical stress and anesthesia induce inflammatory responses by disturbing the balance between pro- and anti-inflammatory cytokines, which may exacerbate the neuroinflammatory response in PD patients. Here we review studies on blood inflammatory biomarkers in PD patients and discuss the roles of surgery and anesthesia in PD progression.

Fast, facile and thermal damage free nanowelding of Ag nanowire for flexible transparent conductive film by pressure-assisted microwave irradiation.

A fast and straightforward fabrication process for producing a robust, flexible, and transparent conductive film was demonstrated using nanowelding of Ag nanowires through pressure-assisted microwave irradiation. This innovative process effectively reduces the sheet resistance of the Ag nanowire transparent conductive film without causing any thermal distortion to the PET substrate. The microwave irradiation induces nanowelding between Ag nanowires, leading to a decrease in sheet resistance by forming nanowelding junctions. This selective heating of Ag nanowires further enhances the reduction in sheet resistance. Additionally, the application of pressure-assisted microwave irradiation allows the Ag nanowires to be embedded into the PET substrate, resulting in the formation of a robust film capable of withstanding cycling bending stress. The pressure-assisted microwave irradiation process proves to be a strong fabrication method for creating Ag nanowire transparent conductive films, especially when dealing with thermally weak substrate materials.

A novel humanized Chi3l1 blocking antibody attenuates acetaminophen-induced liver injury in mice.

Acetaminophen (APAP) overdose is a leading cause of acute liver injury in the USA. The chitinase 3-like-1 (Chi3l1) protein contributes to APAP-induced liver injury (AILI) by promoting hepatic platelet recruitment. Here, we report the development of a Chi3l1-targeting antibody as a potential therapy for AILI. By immunizing a rabbit successively with the human and mouse Chi3l1 proteins, we isolated cross-reactive monoclonal antibodies (mAbs) from single memory B cells. One of the human and mouse Chi3l1 cross-reactive mAbs was humanized and characterized in both in vitro and in vivo biophysical and biological assays. X-ray crystallographic analysis of the lead antibody C59 in complex with the human Chi3l1 protein revealed that the kappa light contributes to majority of the antibody-antigen interaction; and that C59 binds to the 4α-5ß loop and 4α-helix of Chi3l1, which is a functional epitope and hotspot for the development of Chi3l1 blocking antibodies. We humanized the C59 antibody by complementarity-determining region grafting and kappa chain framework region reverse mutations. The humanized C59 antibody exhibited similar efficacy as the parental rabbit antibody C59 in attenuating AILI in vivo. Our findings validate Chi3l1 as a potential drug target for AILI and provide proof of concept of developing Chi3l1 blocking antibody as a therapy for the treatment of AILI.

Impact of vertical stratification on the 2020 spring bloom in the Yellow Sea.

The Yellow Sea is one of the world's most abundant marine resources, providing food and economic benefits to the Korean and Chinese populations. In spring 2020, a decrease in the intensity of phytoplankton bloom was observed. While one study attributed this decline to a decrease in nutrient associated with the COVID-19 pandemic, our previous research proposed weakened thermal stratification accompanied by a surface cooling anomaly as the cause. However, the relationship between the marine environment and ecosystem has not been fully elucidated. Using observations and marine physical-biogeochemical model data, we identified the weakened stratification as a critical factor for suppressing the 2020 spring bloom. Intense vertical mixing hindered the accumulation of nutrient and chlorophyll-a concentrations within the euphotic zone, resulting in a diminished phytoplankton bloom. In contrast, reduced nitrate and phosphate concentrations in 2020 were insignificant compared to those in 2017-2019, despite the notable decline in PM2.5 in March 2020 due to COVID-19. In April 2020, nutrient levels fell within the range of interannual variability based on long-term observations, reflecting a negligible effect on the spring phytoplankton bloom. Our findings provide insight into the importance of marine physical factors on the phytoplankton biomass in the Yellow Sea.

Monthly and seasonal variations in the surface carbonate system and air-sea CO2 flux of the Yellow Sea.

Surface carbonate chemistry in the Yellow Sea was investigated based on discrete seawater samples collected from 2017 to 2020 at the Socheongcho Ocean Research Station (S-ORS; 37.423°N, 124.738°E). Records of carbon parameters, including seawater CO2 partial pressure (pCO2), revealed considerable seasonal variations, with amplitudes comparable to those observed across the western part of the Yellow Sea. The study site acted as a modest sink (-0.13 mol C m-2 yr-1) for atmospheric CO2. Biological processes (primary production and respiration) and physical conditions (temperature and degree of stratification) determined seawater pCO2, which fluctuated on an intraseasonal timescale between oversaturated and undersaturated with respect to atmospheric pCO2. Variation in pCO2 was significant in summer, depending on the biological carbon drawdown and tidal mixing-induced upwelling (increased pCO2 up to ~1000 µatm). The intraseasonal variability in seawater pCO2 may bias estimated air-sea CO2 fluxes, if measurements with a coarser (seasonal) time resolution are used.

Effect of Pregabalin Combined with Duloxetine and Tramadol on Allodynia in Chronic Postischemic Pain and Spinal Nerve Ligation Mouse Models.

Although there are various drugs for Neuropathic pain (NP), the effects of single drugs are often not very satisfactory. The analgesic effects of different combinations of pregabalin, duloxetine, and tramadol or the combination of all three are still unclear. Mixtures of two or three drugs at low and high concentrations (7.5, 10, 15, and 20 mg/kg pregabalin; 7.5, 10, 15, and 30 mg/kg duloxetine; 5 and 10 mg/kg tramadol) were administered to chronic postischemic pain (CPIP) and spinal nerve ligation (SNL) model mice. The effects of these combinations of drugs on mechanical allodynia were investigated. The expression of the glial fibrillary acidic protein (GFAP) in the spinal cord and dorsal root ganglia (DRGs) was measured. The combination of pregabalin, duloxetine, and tramadol significantly alleviated mechanical hyperalgesia in mice with CPIP and SNL. After the administration of this drug combination, the expression of GFAP in the spinal cord and DRGs was lower in the CPIP and SNL model mice than in control mice. This result suggests that the combination of these three drugs may be advantageous for the treatment of NP because it can reduce side effects by preventing the overuse of a single drug class and exert increased analgesic effects via synergism.