Transcriptional Regulation and Signaling of Type IV IFN with Identification of the ISG Repertoire in an Amphibian Model, Xenopus laevis.

The type IV IFN (IFN-υ) is reported in vertebrates from fish to primary mammals with IFN-υR1 and IL-10R2 as receptor subunits. In this study, the proximal promoter of IFN-υ was identified in the amphibian model, Xenopus laevis, with functional IFN-sensitive responsive element and NF-κB sites, which can be transcriptionally activated by transcription factors, such as IFN regulatory factor (IRF)1, IRF3, IRF7, and p65. It was further found that IFN-υ signals through the classical IFN-stimulated gene (ISG) factor 3 (ISGF3) to induce the expression of ISGs. It seems likely that the promoter elements of the IFN-υ gene in amphibians is similar to type III IFN genes, and that the mechanism involved in IFN-υ induction is very much similar to type I and III IFNs. Using recombinant IFN-υ protein and the X. laevis A6 cell line, >400 ISGs were identified in the transcriptome, including ISGs homologous to humans. However, as many as 268 genes were unrelated to human or zebrafish ISGs, and some of these ISGs were expanded families such as the amphibian novel TRIM protein (AMNTR) family. AMNTR50, a member in the family, was found to be induced by type I, III, and IV IFNs through IFN-sensitive responsive element sites of the proximal promoter, and this molecule has a negative role in regulating the expression of type I, III, and IV IFNs. It is considered that the current study contributes to the understanding of transcription, signaling, and functional aspects of type IV IFN at least in amphibians.

Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA). OBJECTIVES: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor. METHODS: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. MEASUREMENTS AND MAIN RESULTS: In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFß1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis. CONCLUSIONS: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.

Carbonized Polymer Dots-Promoted Photocatalytic Activation of Molecular Oxygen for Efficient and Selective Oxidation of Thioethers to Sulfoxides.

Sulfoxides are essential in pharmaceuticals and chemicals, yet traditional thioether oxidation struggles with selectivity and sustainability. This study introduces carbonized polymer dots (CPDs) as effective photocatalysts for ecofriendly thioether to sulfoxide oxidation, using water and ethanol to enhance reaction selectivity and efficiency under 455 nm blue light. These catalysts not only show remarkable efficacy under mild conditions but also display high selectivity for sulfoxide formation, proving versatile across a broad range of substrates. We further elucidated the catalytic mechanism, confirming the predominant roles of singlet oxygen and superoxide anions through both spectroscopic evidence and quenching experiments. The method extends to the synthesis of pharmaceuticals such as oxfendazole, albendazole sulfoxide, and sulindac, highlighting its practical utility. Overall, our findings present a sustainable and efficient avenue for sulfoxide synthesis, thereby broadening the practical utility of CPDs in photocatalytic transformations.

Fenamates: Forgotten treasure for cancer treatment and prevention: Mechanisms of action, structural modification, and bright future.

Fenamates as classical nonsteroidal anti-inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo-preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/ß-catenin, TGF-ß, p38 MAPK, and NF-κB pathway, and the regulation of the expressions of Sp, EGR-1, NAG-1, ATF-3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs.

Enhanced diversity on connector hubs following sleep deprivation: Evidence from diffusion and functional magnetic resonance imaging.

Sleep deprivation has been demonstrated to exert widespread and intricate impacts on the brain network. The human brain network is a modular network composed of interconnected nodes. This network consists of provincial hubs and connector hubs, with provincial hubs having diverse connectivities within their own modules, while connector hubs distribute their connectivities across different modules. The latter is crucial for integrating information from various modules and ensuring the normal functioning of the modular brain. However, there has been a lack of systematic investigation into the impact of sleep deprivation on brain connector hubs. In this study, we utilized functional connectivity from resting-state functional magnetic resonance imaging, as well as structural connectivity from diffusion-weighted imaging, to systematically explore the variation of connector hub properties in the cerebral cortex after one night of sleep deprivation. The normalized participation coefficients (PCnorm) were utilized to identify connector hubs. In both the functional and structural networks, connector hubs exhibited a significant increase in average PCnorm, indicating the diversity enhancement of the connector hub following sleep deprivation. This enhancement is associated with increased network cost, reduced modularity, and decreased small-worldness, but enhanced global efficiency. This may potentially signify a compensatory mechanism within the brain following sleep deprivation. The significantly affected connector hubs were primarily observed in both the Control Network and Salience Network. We believe that the observed results reflect the increasing demand on the brain to invest more effort at preventing performance deterioration after sleep loss, in exchange for increased communication efficiency, especially involving systems responsible for neural resource allocation and cognitive control. These results have been replicated in an independent dataset. In conclusion, this study has enhanced our understanding of the compensatory mechanism in the brain response to sleep deprivation. This compensation is characterized by an enhancement in the connector hubs responsible for inter-modular communication, especially those related to neural resource and cognitive control. As a result, this compensation comes with a higher network cost but leads to an improvement in global communication efficiency, akin to a more random-like network manner.

Are older adults less generous? Age differences in emotion-related social decision making.

In social interaction, age-related differences in emotional processing may lead to varied social decision making between young and older adults. However, previous studies of social decision making have paid less attention to the interactants' emotions, leaving age differences and underlying neural mechanisms unexplored. To address this gap, the present study combined functional and structural magnetic resonance imaging, employing a modified dictator game task with recipients displaying either neutral or sad facial expressions. Behavioral results indicated that although older adults' overall allocations did not differ significantly from those of young adults, older adults' allocations showing a decrease in emotion-related generosity compared to young adults. Using representational similarity analysis, we found that older adults showed reduced neural representations of recipients' emotions and gray matter volume in the right anterior cingulate gyrus (ACC), right insula, and left dorsomedial prefrontal cortex (DMPFC) compared to young adults. More importantly, mediation analyses indicated that age influenced allocations not only through serial mediation of neural representations of the right insula and left DMPFC, but also through serial mediation of the mean gray matter volume of the right ACC and left DMPFC. This study identifies the potential neural pathways through which age affects emotion-related social decision making, advancing our understanding of older adults' social interaction behavior that they may not be less generous unless confronted with individuals with specific emotions.

A new artificial intelligence system for both stomach and small-bowel capsule endoscopy.

BACKGROUND AND AIMS: Despite the benefits of artificial intelligence in small-bowel (SB) capsule endoscopy (CE) image reading, information on its application in the stomach and SB CE is lacking. METHODS: In this multicenter, retrospective diagnostic study, gastric imaging data were added to the deep learning-based SmartScan (SS), which has been described previously. A total of 1069 magnetically controlled GI CE examinations (comprising 2,672,542 gastric images) were used in the training phase for recognizing gastric pathologies, producing a new artificial intelligence algorithm named SS Plus. A total of 342 fully automated, magnetically controlled CE examinations were included in the validation phase. The performance of both senior and junior endoscopists with both the SS Plus-assisted reading (SSP-AR) and conventional reading (CR) modes was assessed. RESULTS: SS Plus was designed to recognize 5 types of gastric lesions and 17 types of SB lesions. SS Plus reduced the number of CE images required for review to 873.90 (median, 1000; interquartile range [IQR], 814.50-1000) versus 44,322.73 (median, 42,393; IQR, 31,722.75-54,971.25) for CR. Furthermore, with SSP-AR, endoscopists took 9.54 minutes (median, 8.51; IQR, 6.05-13.13) to complete the CE video reading. In the 342 CE videos, SS Plus identified 411 gastric and 422 SB lesions, whereas 400 gastric and 368 intestinal lesions were detected with CR. Moreover, junior endoscopists remarkably improved their CE image reading ability with SSP-AR. CONCLUSIONS: Our study shows that the newly upgraded deep learning-based algorithm SS Plus can detect GI lesions and help improve the diagnostic performance of junior endoscopists in interpreting CE videos.

UCHL-3 as a potential biomarker of ovarian cancer.

OBJECTIVE: This study explored promising prognostic and immune therapeutic candidate biomarkers for OC and determined the expression, prognostic value, and immune effects of UCHL3. METHODS: UCHL3 expression and clinical data were investigated using bioinformatic analysis. CCK8 and transwell assays were conducted to evaluate the impact of UCHL3 on proliferation and migration, and the effects of UCHL3 were further validated in a mouse model. Univariate and least absolute shrinkage and selection operator regression analyses were performed to construct a novel UCHL3-related prognostic risk model. Gene set enrichment analysis (GSEA) and immune analysis were performed to identify the significantly involved functions of UCHL3. Finally, bioinformatic analysis and immunohistochemistry were performed to explore the effect of UCHL3 on chemotherapy. RESULTS: UCHL3 expression was upregulated and associated with worse overall survival (OS) in OC. UCHL3 depletion repressed cell proliferation and migration both in vitro and in vivo. Furthermore, 237 genes were differentially expressed between the high and low UCHL3 expression groups. Subsequently, a UCHL3-related prognostic signature was built based on six prognostic genes (PI3, TFAP2B, MUC7, PSMA2, PIK3C2G, and NME1). Independent prognostic analysis suggested that age, tumor mutational burden, and RiskScore can be used as independent prognostic factors. The immune infiltration analysis and GSEA suggested that UCHL3 expression was related to the immune response. In addition, UCHL3 expression was higher in platinum-resistant OC patients than in platinum-sensitive patients. UCHL3 overexpression was associated with poorer OS. CONCLUSION: UCHL3 overexpression contributes to aggressive progression, poor survival, and chemoresistance in OC. Therefore, UCHL3 may be a candidate prognostic biomarker and potential target for controlling progression and platinum resistance in OC.

SIRT6 positively regulates antiviral response in a bony fish, the Chinese perch Siniperca chuatsi.

SIRT6, a key member of the sirtuin family, plays a pivotal role in regulating a number of vital biological processes, including energy metabolism, oxidative stress, and immune system modulation. Nevertheless, the function of SIRT6 in bony fish, particularly in the context of antiviral immune response, remains largely unexplored. In this study, a sirt6 was cloned and characterized in a commercial fish, the Chinese perch (Siniperca chuatsi). The SIRT6 possesses conserved SIR2 domain with catalytic core region when compared with other vertebrates. Tissue distribution analysis indicated that sirt6 was expressed in all detected tissues, and the sirt6 was significantly induced following infection of infectious haemorrhagic syndrome virus (IHSV). The overexpression of SIRT6 resulted in significant upregulation of interferon-stimulated genes (ISGs), such as viperin, mx, isg15, irf3 and ifp35, and inhibited viral replication. It was further found that SIRT6 was located in nucleus and could enhance the expression of ISGs induced by type I and II IFNs. These findings may provide new information in relation with the function of SIRT6 in vertebrates, and with viral prevention strategy development in aquaculture.

Reference guides for the safe use of drugs during pregnancy: a systematic review and comparative analysis.

PURPOSE: To comprehensively evaluate and compare all the available reference guides for the safe use of drugs during pregnancy, with the goal of determining the scientificity and reliability of these reference guides. METHODS: We searched PubMed, EMbase, CNKI, Wanfang Database, and VIP database to comprehensively identify the available reference guides. Moreover, we selected 103 drugs based on relevant literatures, and compared the recommendations of each drug from different reference guides. RESULTS: A total of 14 available reference guides were identified. However, none of these reference guides assessed the risk of bias of original studies or the quality of current evidence. Seven reference guides adopted expert consensus method to formulate pregnancy recommendations, while the rest reference guides did not report the formation method. Moreover, 77.7% of the selected drugs had inconsistent recommendations among different reference guides. In addition, the referenced human and animal studies for the same drug differed among different reference guides. CONCLUSION: Our results indicate that current reference guides for the safe use of drugs during pregnancy are less scientific and reliable, and there are considerable discrepancies in recommendations from different reference guides concerning drug use during pregnancy. The reasons for the discrepancies in recommendations include ① the literature search in most reference guides was not comprehensive, ② none of the available reference guides assessed the risk of bias of original studies or the quality of current evidence, and ③ the method adopted by current reference guides to formulate recommendations had obvious subjectivity and lacked of scientificity.

Integrative genomic analysis of early neurogenesis reveals a temporal genetic program for differentiation and specification of preplate and Cajal-Retzius neurons.

Neurogenesis in the developing neocortex begins with the generation of the preplate, which consists of early-born neurons including Cajal-Retzius (CR) cells and subplate neurons. Here, utilizing the Ebf2-EGFP transgenic mouse in which EGFP initially labels the preplate neurons then persists in CR cells, we reveal the dynamic transcriptome profiles of early neurogenesis and CR cell differentiation. Genome-wide RNA-seq and ChIP-seq analyses at multiple early neurogenic stages have revealed the temporal gene expression dynamics of early neurogenesis and distinct histone modification patterns in early differentiating neurons. We have identified a new set of coding genes and lncRNAs involved in early neuronal differentiation and validated with functional assays in vitro and in vivo. In addition, at E15.5 when Ebf2-EGFP+ cells are mostly CR neurons, single-cell sequencing analysis of purified Ebf2-EGFP+ cells uncovers molecular heterogeneities in CR neurons, but without apparent clustering of cells with distinct regional origins. Along a pseudotemporal trajectory these cells are classified into three different developing states, revealing genetic cascades from early generic neuronal differentiation to late fate specification during the establishment of CR neuron identity and function. Our findings shed light on the molecular mechanisms governing the early differentiation steps during cortical development, especially CR neuron differentiation.

Neural correlates of valence-dependent belief and value updating during uncertainty reduction: An fNIRS study.

Selective use of new information is crucial for adaptive decision-making. Combining a gamble bidding task with assessing cortical responses using functional near-infrared spectroscopy (fNIRS), we investigated potential effects of information valence on behavioral and neural processes of belief and value updating during uncertainty reduction in young adults. By modeling changes in the participants' expressed subjective values using a Bayesian model, we dissociated processes of (i) updating beliefs about statistical properties of the gamble, (ii) updating values of a gamble based on new information about its winning probabilities, as well as (iii) expectancy violation. The results showed that participants used new information to update their beliefs and values about the gambles in a quasi-optimal manner, as reflected in the selective updating only in situations with reducible uncertainty. Furthermore, their updating was valence-dependent: information indicating an increase in winning probability was underweighted, whereas information about a decrease in winning probability was updated in good agreement with predictions of the Bayesian decision theory. Results of model-based and moderation analyses showed that this valence-dependent asymmetry was associated with a distinct contribution of expectancy violation, besides belief updating, to value updating after experiencing new positive information regarding winning probabilities. In line with the behavioral results, we replicated previous findings showing involvements of frontoparietal brain regions in the different components of updating. Furthermore, this study provided novel results suggesting a valence-dependent recruitment of brain regions. Individuals with stronger oxyhemoglobin responses during value updating was more in line with predictions of the Bayesian model while integrating new information that indicates an increase in winning probability. Taken together, this study provides first results showing expectancy violation as a contributing factor to sub-optimal valence-dependent updating during uncertainty reduction and suggests limitations of normative Bayesian decision theory.

A Catalytic Alkylation of Ketones via sp3 C-H Bond Activation.

We identified a ternary hybrid catalyst system composed of an acridinium photoredox catalyst, a thiophosphoric imide (TPI) catalyst, and a titanium complex catalyst that promoted an intermolecular addition reaction of organic molecules with various ketones through sp3 C-H bond activation. The thiyl radical generated via single-electron oxidation of TPI by the excited photoredox catalyst abstracted a hydrogen atom from organic molecules such as toluene, benzyl alcohol, alkenes, aldehydes, and THF. The thus-generated carbon-centered radical species underwent addition to ketones and aldehydes. This intrinsically unfavorable step was promoted by single-electron reduction of the intermediate alkoxy radical by catalytically generated titanium(III) species. This reaction provided an efficient and straightforward route to a broad range of tertiary alcohols and was successfully applied to late-stage functionalization of drugs or their derivatives. The proposed mechanism was supported by both experimental and theoretical studies.

Three-dimensional pelvic ultrasound is a practical tool for the assessment of anal fistula.

OBJECTIVE: This study aims to investigate the diagnostic value of three-dimensional pelvic ultrasound in the preoperative assessment of anal fistula compared with findings of MRI and surgery. METHODS: A total of 67 patients (62 males) with suspected anal fistula were analyzed retrospectively. Preoperative three-dimensional pelvic ultrasound and magnetic resonance imaging were performed in all patients. The number of internal openings and the type of fistula were recorded. The accuracy of three-dimensional pelvic ultrasound was determined by comparing these parameters with surgical outcomes. RESULTS: At surgery, 5 (6%) were extrasphincteric, 10 (12%) were suprasphincteric, 11 (14%) were intersphincteric, and 55 (68%) were transsphincteric. There was no significant difference in the accuracy of pelvic 3D US and MRI, based on internal openings (97.92%, 94.79%), anal fistulas (97.01%, 94.03%), and those under Parks classification (97.53%, 93.83%). CONCLUSION: Three-dimensional pelvic ultrasound is a reproducible and accurate method for determining the type of fistula and detecting internal openings and anal fistulas.

Empirical validation of the information-motivation-behavioral skills model of gestational weight management behavior: a framework for intervention.

BACKGROUND: Unhealthy gestational weight gain is a modifiable risk factor for adverse maternal and child health. Appropriate and effective intervention strategies that focus on behavioral change or maintenance are critical in weight management during pregnancy. Our aim was to uncover the influencing factors and psychosocial mechanisms of gestational weight control behavior, and to construct a behavioral model suitable for intervention based on Information-Motivation-Behavioral skills (IMB) model. METHODS: A sample of 559 pregnant women from a municipal maternal and child healthcare facility in Jiangsu Province, China was enrolled in this cross-sectional empirical study. Partial least square structural equation modelling was used to verify the hypothesized model, and post hoc analyses was used to test the effect of parity and pre-pregnancy BMI on the model. RESULTS: The IMB model elements can predict gestational weight management (GWM) behavior well, with information being the most influential factor. As predicted, information affects GWM directly (ß = 0.325, p < 0.05) and indirectly (ß = 0.054, p < 0.05) through behavioral skills. Likewise, motivation has direct (ß = 0.461, p < 0.05) effects on GWM, and has indirect (ß = 0.071, p < 0.05) effects through behavioral skills. Behavioral skills have a direct impact (ß = 0.154, p < 0.05). The model had a goodness of fit (GOF = 0.421) and was robust when tested in subgroups of different parity or pre-pregnancy BMI. CONCLUSION: Findings from this study supported the predictions of the IMB model for GWM behavior, and identified its modifiable determinants. The tested behavior model for GWM can serve as a new validated intervention strategy in weight management among pregnant women.

Molecular characterization and immunological properties of Echinococcus granulosus sensu stricto (G1) ADK1 and ADK8.

Adenylate kinases (ADKs) are one of the important enzymes regulating adenosine triphosphate (ATP) metabolism in Echinococcus granulosus sensu lato. The objective of the present study was to explore the molecular characteristics and immunological properties of E. granulosus sensu stricto (G1) adenylate kinase 1 (EgADK1) and adenylate kinase 8 (EgADK8). EgADK1 and EgADK8 were cloned and expressed, and the molecular characteristics of EgADK1 and EgADK8 were analyzed through different bioinformatics tools. Western blotting was used to examine the reactogenicity of recombinant adenylate kinase 1 (rEgADK1) and recombinant adenylate kinase 8 (rEgADK8) and to evaluate their diagnostic value. The expression profiles of EgADK1 and EgADK8 in 18-day-old strobilated worms and protoscoleces were analyzed by quantitative real-time PCR, and their distribution in 18-day-old strobilated worms, the germinal layer, and protoscoleces was determined by immunofluorescence localization. EgADK1 and EgADK8 were successfully cloned and expressed. Bioinformatics analysis predicted that EgADK1 and EgADK8 have multiple phosphorylation sites and B-cell epitopes. Compared with EgADK8, EgADK1 and other parasite ADKs have higher sequence similarity. In addition, both cystic echinococcosis (CE)-positive sheep sera and Cysticercus tenuicollis-infected goat sera could recognize rEgADK1 and rEgADK8. EgADK1 and EgADK8 were localized in protoscoleces, the germinal layer, and 18-day-old strobilated worms. EgADK1 and EgADK8 showed no significant difference in their transcription level in 18-day-old strobilated worms and protoscoleces, suggesting that EgADK1 and EgADK8 may play an important role in the growth and development of E. granulosus sensu lato. Since EgADK1 and EgADK8 can be recognized by other parasite-positive sera, they are not suitable as candidate antigens for the diagnosis of CE.

Aluminum phytotoxicity induced structural and ultrastructural changes in submerged plant Vallisneria natans.

Aluminum (Al) is a concentration-dependent toxic metal found in the crust of earth that has no recognized biological use. Nonetheless, the mechanism of Al toxicity to submerged plants remains obscure, especially from a cell/subcellular structure and functional group perspective. Therefore, multiple dosages of Al3+ (0, 0.3, 0.6, 1.2, and 1.5 mg/L) were applied hydroponically to the submerged plant Vallisneria natans in order to determine the accumulation potential of Al at the subcellular level and their ultrastructural toxicity. More severe structural and ultrastructural damage was determined when V. natans exposed to ≥ 0.6 mg/L Al3+. In 1.2 and 1.5 mg/L Al3+ treatment groups, the total chlorophyll content of leaves significantly reduced 3.342, 3.838 mg/g FW, some leaves even exhibited chlorosis and fragility. Under 0.3 mg/L Al3+ exposure, the middle-age and young leaves were potent phytoexcluders, whereas at 1.5 mg/L Al3+, a large amount of Al could be transferred from the roots to other parts, among which the aged leaves were the most receptive tissues (7.306 mg/g). Scanning/Transmission electron microscopy analysis displayed the Al-mediated disruption of vascular bundle structure in leaf cells, intercellular space and several vegetative tissues, and demonstrated that Al in vacuole and chloroplast subcellular segregation into electron dense deposition. Al and P accumulation in the roots, stolons and leaves varied significantly among treatments and different tissues (P < 0.05). Fourier transform infrared spectroscopy of plant biomass also indicated possible metabolites (amine, unsaturated hydrocarbon, etc.) of V. natans that may bind Al3+. Conclusively, results revealed that Al3+ disrupts the cellular structure of leaves and roots or binds to functional groups of biological tissues, thereby affecting plant nutrient uptake and photosynthesis. Findings might have scientific and practical significance for the restoration of submerged vegetation in Al-contaminated lakes.

Kasugamycin Is a Novel Chitinase 1 Inhibitor with Strong Antifibrotic Effects on Pulmonary Fibrosis.

Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-ß (transforming growth factor-ß) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In in vivo bleomycin- and TGF-ß-stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-ß-associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in in vivo lungs and in vitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

Expansion of granulocytic myeloid-derived suppressor cells in patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS), caused by novel bunyavirus (SFTSV), is a hemorrhagic fever with a high mortality rate of over 10%. We have previously shown that granulocytic myeloid-derived suppressor cell (gMDSC) might affect arginine metabolism, which was associated with decreased platelet count and T lymphocyte dysfunction in this disease. The study was designed to investigate the expression of the gMDSCs subsets in SFTS patients, and to evaluate its association with disease severity. A prospective study was performed on 166 confirmed SFTSV infected patients. Sequential blood samples were collected during hospitalization and after recovery. SFTSV RNA was quantified by real-time RT-PCR. The gMDSCs and NK cells were determined by flow cytometry analysis, which were associated with disease severity. Elevation of the activated gMDSC was observed in SFTS patients at the acute phase, with a significantly higher level of gMDSC attained in 79 severe and 29 fatal SFTS patients than in the mild patients. The NK cells were depleted at the early infection and not restored to normal level until 4 months after the disease. The expansion of gMDSC was accompanied by the elevated expressions of CD3-ζ of NK and Arginase-1, in contrast with the decreased reactive oxygen species (ROS) in gMDSC. The levels of NK, CD3-ζ of NK, viral load, and platelet count were significantly associated with the level of gMDSC. Expansion of gMDSC was demonstrated in SFTS, which was associated with severe disease and suppressed antiviral NK cell via other mechanisms than Arginase-1 or ROS.

Effectiveness of Vitamin C Solution in Reducing Adverse Reactions Caused by Painless Lugol Chromoendoscopy: A Multicenter Randomized Controlled Trial.

GOAL: The purpose of this study was to evaluate the effectiveness of vitamin C solution (VCS) in reducing adverse reactions caused by painless Lugol chromoendoscopy. BACKGROUND: Lugol chromoendoscopy is an effective method for screening superficial esophageal squamous cell carcinoma, although Lugol iodine solution (LIS) causes mucosal irritation. STUDY: In 4 hospitals in China, patients were randomized and divided into a distilled water (DW) group, an sodium thiosulfate solution (STS) group and a VCS group. Patients' esophageal mucosal surfaces were stained with either 1.2% or 0.5% LIS and then sprayed with DW, STS, or VCS at various concentrations. For the current randomized study, 1610 patients were enrolled in the 1.2% LIS group and 1355 patients were enrolled in the 0.5% LIS group. In addition, 150 patients were enrolled to assess the discoloration effect. The primary outcome for evaluation was the incidence of acute or late adverse reactions after Lugol iodine staining. The secondary outcome for evaluation was the discoloration effect on esophageal iodine-stained mucosa. RESULTS: VCS significantly reduced the occurrence of acute adverse reactions due to staining from 1.2% LIS. The effect of VCS was similar to that of STS but better than that of DW ( P <0.05). Regarding 0.5% LIS staining, VCS reduced the incidence of acute adverse reactions and heartburn within 1 week ( P <0.05). Both VCS and STS had similar effects. In addition, compared with spraying NS, VCS caused rapid decolorization of iodine-stained esophageal mucosa. After 120 seconds of deiodination, the color of the esophageal mucosa faded by 90%, which is similar to the results seen in the STS group. This contrasts with the results seen in the DW group, which showed fading by only 50.97% ( P <0.05). CONCLUSION: VCS can effectively reduce adverse reactions caused by different concentrations of LIS, indicating its important clinical application in the screening of superficial esophageal squamous cell carcinoma.