OLFM4 promotes the progression of intestinal metaplasia through activation of the MYH9/GSK3ß/ß-catenin pathway.

BACKGROUND: Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression. METHODS: In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM. RESULTS: Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3ß and resulted in increased ß-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells. CONCLUSIONS: OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.

Novel trifluoromethyl ketone derivatives as oral cPLA2/COX-2 dual inhibitors for resolution of inflammation in rheumatoid arthritis.

Thirty-five trifluoromethyl hydrazones and seventeen trifluoromethyl oxime esters were designed and synthesized via molecular hybridization. All the target compounds were initially screened for in vitro anti-inflammatory activity by assessing their inhibitory effect on NO release in LPS-stimulated RAW264.7 cells, and the optimal compound was finally identified as 2-(3-Methoxyphenyl)-N'-((6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-6,9,12,15-tetraen-2-ylidene)acetohydrazide (F26, IC50 = 4.55 ± 0.92 µM) with no cytotoxicity. Moreover, F26 potently reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to indomethacin. The interaction of F26 with COX-2 and cPLA2 was directly verified by the CETSA technique. F26 was found to modulate the phosphorylation levels of p38 MAPK and NF-κB p65, as well as the protein expression of IκB, cPLA2, COX-2, and iNOS in LPS-stimulated rat peritoneal macrophages. Additionally, F26 was observed to prevent the nuclear translocation of NF-κB p65 in LPS-stimulated rat peritoneal macrophages by immunofluorescence localization. Therefore, the aforementioned in vitro experiments demonstrated that F26 blocked the p38 MAPK and NF-κB pathways by binding to COX-2 and cPLA2. In the adjuvant-induced arthritis model, F26 demonstrated a significant effect in preventing arthritis symptoms and inflammatory status in rats, exerting an immunomodulatory role by regulating the homeostasis between Th17 and Treg through inhibition of the p38 MAPK/cPLA2/COX-2/PGE2 and NF-κB pathways. Encouragingly, F26 caused less acute ulcerogenicity in rats at a dose of 50 mg/kg compared to indomethacin. Overall, F26 is a promising candidate worthy of further investigation for treating inflammation and associated pain with lesser gastrointestinal irritation, as well as other symptoms in which cPLA2 and COX-2 are implicated in the pathophysiology.

3-(2-Trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indoles: Mastering anti-inflammation and analgesia while mitigating gastrointestinal side effects.

A series of 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indoles (5-1 to 5-29) were developed and characterized. Most of compounds were found to be potent for inhibiting the production of NO in LPS-induced RAW264.7 cells, of which 3-(3-(4-chlorophenyl)-6-methoxy-2-(trifluoromethyl)-4H-chromen-4-yl)-1H-indole (5-25) was the most optimal (IC50 = 4.82 ± 0.34 µΜ) and was capable of significantly suppressing the release of PGE2. The inhibitory effect of 5-25 on human recombinant COX-2 (IC50 = 51.7 ± 1.3 nM) was measured and molecular docking was performed, determining 5-25 as a COX-2 inhibitor. Additionally, the interaction between 5-25 and COX-2 was determined by the CETSA technique. Then, 5-25 inhibited the degradation of IκB, the phosphorylation and nuclear translocation of NF-κB p65, and the expression of COX-2 and iNOS. Moreover, it was verified that 5-25 exhibited efficacy in rodent models of inflammation and pain, encompassing the paw edema, cotton pellet-induced granuloma, acid-induced writhing, and adjuvant-induced arthritis models. Therefore, the mechanism of 5-25 may be to bind to COX-2 and exert anti-inflammatory and analgesic effects in vitro and in vivo by suppressing the NF-κB pathway. Encouragingly, in comparison with indomethacin, 5-25 exhibited a lower ulcerative potential in rats, as manifested by generating smaller areas and fewer ulcers, less inflammatory infiltration, a lower expression of MMP-9, and less apoptosis. In conclusion, 5-25 is a candidate drug with high activity and low ulcerogenic potential, and it deserves further research for the treatment of inflammation, pain, and other symptoms in which COX-2 plays a role in their pathogenesis.

Comparative Analysis of Ketamine and Fentanyl Combined with Dexmedetomidine for Lumbar Anesthesia in Proximal Femur Fractures Among the Elderly.

Objective: This study aimed to compare the effects of ketamine and fentanyl combined with dexmedetomidine in lumbar anesthesia for proximal femur fractures among elderly patients. Design: This study employed a prospective, randomized controlled trial (RCT) design. Settings: The study was conducted at Beijing Jishuitan Hospital. Participants: A total of 100 elderly patients with proximal femur fractures who underwent lumbar anesthesia between January 2022 and January 2023. Intervention: Participants were divided into two groups: the ketamine group (n=49) and the fentanyl group (n=51). The ketamine group received ketamine combined with dexmedetomidine, while the fentanyl group received fentanyl combined with dexmedetomidine. Outcome Measures: The following outcome measures were assessed and compared between the two groups: (1) hemodynamic indexes; (2) visual analogue scale (VAS) scores; (3) stress reaction indexes; (4) Incidence of adverse effects. These comparisons were made using the random number table method. Results: No significant differences were observed in systolic blood pressure (SBP), transcutaneous oxygen saturation (SPO2), and heart rate (HR) between the two groups at each time point (P > .05). SBP and HR of both groups were lower than baseline (T0) from T1 onwards. Throughout the surgery, SBP and HR exhibited a decreasing trend with operation time, followed by an increase post-operation. SPO2 showed minimal fluctuations during surgery in both groups. Preoperatively, VAS scores were comparable between groups (P > .05). However, at 12h, 24h, and 48h post-surgery, VAS scores were significantly lower in the ketamine group (P < .05). Stress indicator levels were similar preoperatively (P > .05), but postoperatively, serum cortisol (Cor), epinephrine (E), and norepinephrine (NE) levels were lower in the ketamine group (P < .05). Conclusion: Dexmedetomidine combined with ketamine demonstrates safety and efficacy in the elderly. It significantly reduces postoperative pain and stress reactions while decreasing the incidence of adverse reactions.

Simulated microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts can be prevented by protection of primary cilia.

Oxidative stress has been considered to be closely related to spaceflight-induced bone loss; however, mechanism is elusive and there are no effective countermeasures. Using cultured rat calvarial osteoblasts exposed to microgravity simulated by a random positioning machine, this study addressed the hypotheses that microgravity-induced shortening of primary cilia leads to oxidative stress and that primary cilium protection prevents oxidative stress and osteogenesis loss. Microgravity was found to induce oxidative stress (as represented by increased levels of reactive oxygen species (ROS) and malondialdehyde production, and decreased activities of antioxidant enzymes), which was perfectly replicated in osteoblasts growing in NG with abrogated primary cilia (created by transfection of an interfering RNA), suggesting the possibility that shortening of primary cilia leads to oxidative stress. Oxidative stress was accompanied by mitochondrial dysfunction (represented by increased mitochondrial ROS and decreased mitochondrial membrane potential) and intracellular Ca2+ overload, and the latter was found to be caused by increased activity of Ca2+ channel transient receptor potential vanilloid 4 (TRPV4), as also evidenced by TRPV4 agonist GSK1016790A-elicited Ca2+ influx. Supplementation of HC-067047, a specific antagonist of TRPV4, attenuated microgravity-induced mitochondrial dysfunction, oxidative stress, and osteogenesis loss. Although TRPV4 was found localized in primary cilia and expressed at low levels in NG, microgravity-induced shortening of primary cilia led to increased TRPV4 levels and Ca2+ influx. When primary cilia were protected by miR-129-3p overexpression or supplementation with a natural flavonoid moslosooflavone, microgravity-induced increased TRPV4 expression, mitochondrial dysfunction, oxidative stress, and osteogenesis loss were all prevented. Our data revealed a new mechanism that primary cilia function as a controller for TRPV4 expression. Microgravity-induced injury on primary cilia leads to increased expression and overactive channel of TRPV4, causing intracellular Ca2+ overload and oxidative stress, and primary cilium protection could be an effective countermeasure against microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts.

Secreted MUP1 that reduced under ER stress attenuates ER stress induced insulin resistance through suppressing protein synthesis in hepatocytes.

Disturbed endoplasmic reticulum (ER) stress response driven by the excessive lipid accumulation in the liver is a characteristic feature in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Restoring metabolic homeostasis by targeting ER stress is a potentially therapeutic strategy for NAFLD. Here we aim to identify novel proteins or pathways involved in regulating ER stress response and therapeutic targets for alleviating NAFLD. Proteomic and transcriptomic analysis demonstrated that major urinary proteins (MUPs) were significantly reduced in the livers from NAFLD mouse models. Then we confirmed that MUP1, the major secreted form of MUPs, was reduced at mRNA and protein expression levels in hepatocytes both in vivo and in vitro under ER stress. We further illustrated that MUP1 protein levels in the urine were reduced in mice with NAFLD, which was reversed by GLP-1 receptor agonist treatment. To study the relationship between ER stress and MUP1 biology, our analysis demonstrated that MUP1 was misfolded and trapped in the ER under ER stress in vivo. Interestingly, we discovered that recombinant MUP1 treatment in hepatocytes increased calcium efflux from the ER, which resulted in transient ER stress response, including reduced protein synthesis. These responses facilitated the alleviation of chemical induced ER stress in hepatocytes, which was suggested as "pre-adaptive ER stress". Besides, recombinant MUP1 pretreatment also improved ER stress-induced insulin resistance in hepatocytes. Our findings revealed a novel and critical role of MUP1, and recombinant MUP1 or its potential derivates may serve as a promising therapeutic target for alleviating NAFLD.

ALDH2 rs671 and MTHFR rs1801133 polymorphisms are risk factors for arteriosclerosis in multiple arteries.

BACKGROUND: Arteriosclerosis in multiple arteries has long been associated with heightened cardiovascular risk. Acetaldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR) play an important role in the pathogenesis of arteriosclerosis by participating in the oxidation and reduction reactions in vascular endothelial cells. The purpose was to investigate the relationship of ALDH2 and MTHFR gene polymorphisms with arteriosclerosis in multiple arteries. METHODS: 410 patients with arteriosclerosis in single artery and 472 patients with arteriosclerosis in multiple arteries were included. The relationship between ALDH2 rs671 and MTHFR rs1801133 polymorphisms and arteriosclerosis in single artery and arteriosclerosis in multiple arteries was analyzed. RESULTS: The proportion of ALDH2 rs671 A allele (35.6% vs. 30.9%, P = 0.038) and MTHFR rs1801133 T allele (32.6% vs. 27.1%, P = 0.012) in patients with arteriosclerosis in multiple arteries was significantly higher than that in arteriosclerosis in single artery, respectively. The proportion of history of alcohol consumption in patients with ALDH2 rs671 G/G genotype was higher than those in ALDH2 rs671 G/A genotype and A/A genotype (P < 0.001). The results of logistic regression analysis indicated that ALDH2 rs671 A/A genotype (A/A vs. G/G: OR 1.996, 95% CI: 1.258-3.166, P = 0.003) and MTHFR rs1801133 T/T genotype (T/T vs. C/C: OR 1.943, 95% CI: 1.179-3.203, P = 0.009) may be independent risk factors for arteriosclerosis in multiple arteries (adjusted for age, sex, smoking, drinking, hypertension, and diabetes). CONCLUSIONS: ALDH2 rs671 A/A and MTHFR rs1801133 T/T genotypes may be independent risk factors for arteriosclerosis in multiple arteries.

CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study.

BACKGROUND: Genetic factors have a certain proportion in the risk factors of hypertension. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with hypertension in Hakka population. METHODS: The study included 1,872 hypertensive patients and 1,110 controls. The genotypes of CYP2C19 rs4244285 and rs4986893 of all individuals were detected and analyzed. RESULTS: The genotype and allele distributions of CYP2C19 rs4244285 were significantly different between hypertension group and control group. The CYP2C19 *1/*1 genotype was the most predominant among the subjects (40.8%), followed by the CYP2C19 *1/*2 genotype (40.5%). The percentage of CYP2C19*1, *2, and *3 allele was 64.2%, 30.8%, and 5.0%, respectively. The proportion of intermediate metabolizers (IM) (49.3% vs. 42.9%), poor metabolizers (PM) (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. Multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2, *1/*3, and *2/*2 genotypes may increase susceptibility to hypertension. And the CYP2C19 IM genotype (IM vs. EM: OR 1.514, 95% CI: 1.291-1.775, P < 0.001), PM genotype (PM vs. EM: OR 2.120, 95% CI: 1.638-2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390-1.882, P < 0.001) may increase risk of hypertension. CONCLUSIONS: CYP2C19 loss-of-function (IM, PM genotypes) is independent risk factor for hypertension susceptibility. Specifically, the risk genotypes include CYP2C19 *1/*2, *1/*3, and *2/*2.

Utility of Artificial Intelligence for Real-Time Anatomical Landmark Identification in Ultrasound-Guided Thoracic Paravertebral Block.

Thoracic paravertebral block (TPVB) is a common method of inducing perioperative analgesia in thoracic and abdominal surgery. Identifying anatomical structures in ultrasound images is very important especially for inexperienced anesthesiologists who are unfamiliar with the anatomy. Therefore, our aim was to develop an artificial neural network (ANN) to automatically identify (in real-time) anatomical structures in ultrasound images of TPVB. This study is a retrospective study using ultrasound scans (both video and standard still images) that we acquired. We marked the contours of the paravertebral space (PVS), lung, and bone in the TPVB ultrasound image. Based on the labeled ultrasound images, we used the U-net framework to train and create an ANN that enabled real-time identification of important anatomical structures in ultrasound images. A total of 742 ultrasound images were acquired and labeled in this study. In this ANN, the Intersection over Union (IoU) and Dice similarity coefficient (DSC or Dice coefficient) of the paravertebral space (PVS) were 0.75 and 0.86, respectively, the IoU and DSC of the lung were 0.85 and 0.92, respectively, and the IoU and DSC of the bone were 0.69 and 0.83, respectively. The accuracies of the PVS, lung, and bone were 91.7%, 95.4%, and 74.3%, respectively. For tenfold cross validation, the median interquartile range for PVS IoU and DSC was 0.773 and 0.87, respectively. There was no significant difference in the scores for the PVS, lung, and bone between the two anesthesiologists. We developed an ANN for the real-time automatic identification of thoracic paravertebral anatomy. The performance of the ANN was highly satisfactory. We conclude that AI has good prospects for use in TPVB. Clinical registration number: ChiCTR2200058470 (URL: http://www.chictr.org.cn/showproj.aspx?proj=152839 ; registration date: 2022-04-09).

Three-dimensional heterogeneous electro-Fenton system with reduced graphene oxide based particle electrode for Acyclovir removal.

New pollutant pharmaceutical and personal care products (PPCPs), especially antiviral drugs, have received increasing attention not only due to their increase in usage after the outbreak of COVID-19 epidemics but also due to their adverse impacts on water ecological environment. Electro-Fenton technology is an effective method to remove PPCPs from water. Novel particle electrodes (MMT/rGO/Fe3O4) were synthesized by depositing Fe3O4 nanoparticles on reduced graphene oxide modified montmorillonite and acted as catalysts to promote oxidation performance in a three-dimensional Electro-Fenton (3D-EF) system. The electrodes combined the catalytic property of Fe3O4, hydrophilicity of montmorillonite and electrical conductivity of graphene oxides, and applied for the degradation of Acyclovir (ACV) with high efficiency and ease of operation. At optimal condition, the degradation rate of ACV reached 100% within 120 min, and the applicable pH range could be 3 to 11 in the 3D-EF system. The stability and reusability of MMT/rGO/Fe3O4 particle electrodes were also studied, the removal rate of ACV remained at 92% after 10 cycles, which was just slightly lower than that of the first cycle. Potential degradation mechanisms were also proposed by methanol quenching tests and FT-ICR-MS.

The HMGB1-RAGE axis induces apoptosis in acute respiratory distress syndrome through PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress.

OBJECTIVE: Apoptosis plays a major role in the progression of acute respiratory distress syndrome (ARDS) that may involve the interaction of the high mobility group box 1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). However, the underlying mechanism remains unclear. Thus, we aimed to explore the mechanisms of HMGB1-RAGE axis-induced apoptosis in ARDS. METHODS: Blood samples from ARDS patients and healthy volunteers were collected to investigate the correlation between serum HMGB1 levels and the severity of ARDS in patients. Mouse models of ARDS induced by caecal ligation and perforation and A549 cell models established by stimulation with recombinant human HMGB1 (rHMGB1) were designed to explore lung inflammatory injury and apoptosis. RESULTS: Serum HMGB1 levels were significantly increased in ARDS patients compared to controls, and HMGB1 levels in the Severe group and Nonsurvival group were significantly higher than those in the Mild and Moderate group and Survival group. In vivo, compared to sham mice, ARDS mice showed significant lung inflammatory injury and apoptosis as well as upregulation of HMGB1 and RAGE and endoplasmic reticulum stress (ERs) protein expression. All injury was attenuated by treatment with an HMGB1 inhibitor GA, a RAGE blocker FPS-ZM1, and an ERs inhibitor 4-PBA. In vitro, A549 cells challenged with rHMGB1 exhibited significant increases in the levels of proteins in the RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway and in apoptosis, all of which were significantly inhibited by pre-treatment with lenti-shPERK and an anti-RAGE antibody. CONCLUSION: The HMGB1-RAGE axis induces apoptotic injury during ARDS, possibly through PERK/eIF2α/ATF4-mediated ERs.

Examining the impact perceptual learning artificial-intelligence-based on the incidence of paresthesia when performing the ultrasound-guided popliteal sciatic block: simulation-based randomized study.

OBJECTIVE: To explore the impact of artificial-intelligence perceptual learning when performing the ultrasound-guided popliteal sciatic block. METHODS: This simulation-based randomized study enrolled residents who underwent ultrasound-guided sciatic nerve block training at the Department of Anesthesiology of Beijing Jishuitan Hospital between January 2022 and February 2022. Residents were randomly divided into a traditional teaching group and an AI teaching group. All residents attended the same nerve block theory courses, while those in the AI teaching group participated in training course using an AI-assisted nerve identification system based on a convolutional neural network instead of traditional training. RESULTS: A total of 40 residents were included. The complication rates of paresthesia during puncture in the first month of clinical sciatic nerve block practice after training were significantly lower in the AI teaching group than in the traditional teaching group [11 (4.12%) vs. 36 (14.06%), P = 0.000093]. The rates of paresthesia/pain during injection were significantly lower in the AI teaching group than in the traditional teaching group [6 (2.25%) vs. 17 (6.64%), P = 0.025]. The Assessment Checklist for Ultrasound-Guided Regional Anesthesia (32 ± 3.8 vs. 29.4 ± 3.9, P = 0.001) and nerve block self-rating scores (7.53 ± 1.62 vs. 6.49 ± 1.85, P < 0.001) were significantly higher in the AI teaching group than in the traditional teaching group. There were no significant differences in the remaining indicators. CONCLUSION: The inclusion of an AI-assisted nerve identification system based on convolutional neural network as part of the training program for ultrasound-guided sciatic nerve block via the popliteal approach may reduce the incidence of nerve paresthesia and this might be related to improved perceptual learning. CLINICAL TRIAL: CHiCTR2200055115 , registered on 1/ January /2022.

Cell wall modification and lignin biosynthesis involved in disease resistance against Diaporthe citri in harvested pummelo fruit elicited by carvacrol.

BACKGROUND: Phomopsis stem-end rot caused by Diaporthe citri, causes significant commercial postharvest losses of pummelo fruit during storage. Carvacrol (CVR) is a known generally recognized as safe and has the ability to prolong the preservation of harvested fruits. In the present study, the inhibitory effects of CVR treatment at the appropriate concentration on Phomopsis stem-end rot development of harvested pummelo fruit inoculated with D. citri were evaluated by the amounts of cell wall components, the activities and gene expressions of related enzymes involved in cell wall modification and lignin biosynthesis. RESULTS: Results indicated that CVR completely inhibited D. citri growth in vitro at 200 mg L-1 and significantly controlled Phomopsis stem-end rot development in harvested pummelo. The CVR treatment delayed peel softening and browning, and retarded electrolyte leakage, superoxide radical (O2 •- ) production, and malondialdehyde content. The CVR-treated fruit maintained higher amounts of cell wall material, protopectin, hemicelluloses, and cellulose, but exhibited lower water-soluble pectin amount. Moreover, in D. citri-inoculated fruit, CVR treatment suppressed the activities and gene expressions of cell wall disassembling-enzymes, including pectin methylesterase, polygalacturonase, cellulase, and ß-galactosidase, while the development of cell wall degradation was reduced. Meanwhile, the CVR treatment enhanced the lignin biosynthesis by increasing the activities and up-regulating the gene expressions of phenylalanine ammonialyase, cinnamic alcohol dehydrogenase, and peroxidase accompanied with elevated level of lignin in pummelo fruit. CONCLUSION: The disease resistance to D. citri in pummelo fruit elicited by CVR treatment is related to delaying cell wall degradation and enhancing lignin biosynthesis. © 2021 Society of Chemical Industry.

Effective degradation of COVID-19 related drugs by biochar-supported red mud catalyst activated persulfate process: Mechanism and pathway.

With the global spread of the COVID-19 pandemic, the water pollution caused by extensive production and application of COVID-19 related drugs has aroused growing attention. Herein, a novel biochar-supported red mud catalyst (RM-BC) containing abundant free hydroxyl groups was synthesized. The RM-BC activated persulfate process was firstly put forward to degrade COVID-19 related drugs, including arbidol (ARB), chloroquine phosphate, hydroxychloroquine sulfate, and acyclovir. Highly effective removal of these pharmaceuticals was achieved and even 100% of ARB was removed within 12 min at optimum conditions. Mechanism study indicated that SO4 •- and HO• were the predominant radicals, and these radicals were responsible for the formation of DMPOX in electron spin resonance experiments. Fe species (Fe0 and Fe3O4) and oxygen-containing functional groups in RM-BC played crucial roles in the elimination of ARB. Effects of degradation conditions and several common water matrices were also investigated. Finally, the degradation products of ARB were identified by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and possible degradation pathways were proposed. This study demonstrated that RM-BC/PS system would have great potential for the removal of COVID-19 related drug residues in water by the catalyst synthesized from the solid waste.

The amino acid variants in HLA II molecules explain the major association with adult-onset Still's disease in the Han Chinese population.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.

MicroRNA-494-3p prevents liver fibrosis and attenuates hepatic stellate cell activation by inhibiting proliferation and inducing apoptosis through targeting TRAF3.

INTRODUCTION AND OBJECTIVES: Alcoholic hepatitis (AH) is characterized by high morbidity and mortality. MicroRNA-494-3p is possibly involved in the regulation of cancers, but its role in AH has been rarely studied. MATERIALS AND METHODS: AH mice model and primarily cultured mice hepatic stellate cells (HSCs) model were constructed. Levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were analyzed by ELISA. Expressions of miRNAs, HSC activation-related proteins and fibrosis-related protein were analyzed by qRT-PCR and Western blot. Cell counting kit, colony formation and flow cytometry assays were used to detect cell viability, proliferation and apoptosis, respectively. The relationship between TNF receptor-associated factor 3 (TRAF3) and miR-494-3p was predicted and verified by TargetScan and dual-luciferase assay, respectively. Results of the above experiments were verified by rescue experiments using TRAF3. RESULTS: Liver damage and miRNA expression were observed in AH mice, and AST and ALT levels were increased in serum of AH mice. MiR-494-3p was reduced in AH liver tissues, and it decreased the levels of α-SMA and fibrosis-related proteins. HSCs were isolated, and activating HSCs or upregulating miR-494-3p had a regulatory effect on the levels of miR-494-3p, HSC activation-related proteins and fibrosis-related proteins as well as cell viability, proliferation and apoptosis. In addition, miR-494-3p targeted TRAF3 and inhibited TRAF3 expression, while overexpressed TRAF3 promoted TRAF3 expression and rescued the regulatory effect of miR-494-3p on the levels of related proteins as well as cell viability, proliferation and apoptosis. CONCLUSIONS: This study provided a novel mechanistic comprehension of the anti-fibrotic effect of miR-494-3p.

Risk factors for acute stroke-associated pneumonia and prediction of neutrophil-to-lymphocyte ratios.

OBJECTIVES: This study aimed to analyze the risk factors for stroke-associated pneumonia (SAP) and assess the predictive effect of neutrophil-to-lymphocyte ratio (NLR) on acute SAP. METHODS: The study included acute stroke patients from April 2018 to June 2019. These patients were divided into the SAP and Non-SAP groups. The patients' history of chronic diseases was assessed, including history of hypertension, diabetes, hyperlipidemia, chronic lung disease, and current smoking status. The clinical characteristics of all studied cases were recorded, including the initial stroke type (cerebral infarction or cerebral hemorrhage), National Institute of Health Stroke Scale (NIHSS) score, indwelling nasogastric tubes, stroke-associated pneumonia within 7 days of hospitalization, and length of hospitalization. The study also recorded the laboratory testing data, including fasting blood glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol, glycosylated hemoglobin, and high-sensitivity C-reactive protein (hsCRP) as well as white blood cell (WBC), neutrophil, and lymphocyte counts. SPSS 19.0 was used for statistical analysis. RESULTS: A total of 328 eligible acute stroke patients were included. Among all participants, SAP occurred in 64 (19.5%) patients. In the SAP group, the patients were older, the proportion of cerebral hemorrhage was higher, the NIHSS score was higher, and more patients had nasogastric tubes (P < 0.05). Concomitantly, the blood glucose, hsCRP, WBC count, neutrophil count, and NLR of the SAP group were significantly higher than those of the Non-SAP group, whereas the lymphocyte count was significantly lower than that of the Non-SAP group (P < 0.05). Multivariable analysis of Binary Logistic regression revealed that stroke type (cerebral hemorrhage), indwelling gastric tube, and NLR were independent risk factors for SAP. Receiver operating characteristic curve analysis demonstrated that the area under the curve for the NLR's ability to predict SAP was 0.861. The optimal cutoff threshold, sensitivity, and specificity were 3.745, 0.891, and 0.727, respectively. CONCLUSIONS: The risk factors for SAP were multifaceted. Cerebral hemorrhage, indwelling nasogastric tube, and high NLR were independent risk factors. An early NLR had a predictive effect on the occurrence of SAP in patients with acute stroke.

Novel sulfonamides against Botrytis cinerea with no positive cross-resistance to commercial fungicides: Design, synthesis and SAR study.

Thirty-four novel compounds were synthesized using chesulfamide (N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide), a high-profile fungicide, as the lead compound, and their structures were characterized by 1H NMR, 13C NMR, MS and elemental analysis. Additionally, the structure of (1S,2R)-2-((3-bromophenethyl)amino)-N-(4-chloro-2-trifluoromethylphenyl)cyclohexane-1-sulfonamide (IV-9) was confirmed by X-ray single crystal diffraction. The mycelium inhibition tests, spore germination inhibition tests, tomato pot tests and field trials were performed against strains of B. cinerea. Bioassay results showed that most of target compounds had good fungicidal activity against B. cinerea, in particular, IV-9 exhibited similar or superior effects to procymidone, boscalid and pyrisoxazole in all in vitro and in vivo tests. Moreover, there was no positive cross-resistance found between the compound IV-9 and eight commercial fungicides (azoxystrobin, boscalid, chlorothalonil, diethofencarb, fludioxonil, procymidone, pyrimethanil and pyrisoxazole) in the cross-resistance validation test performed by an innovative method.

Efficacy and safety of corticosteroid therapy in patients with cardiac arrest: a systematic review of randomised controlled trials.

PURPOSES: The role of corticosteroid therapy in patients with cardiac arrest (CA) is uncertain. We aimed to evaluate the efficacy and safety of corticosteroid therapy in CA patients. METHODS: Randomised controlled trials were identified using PubMed, EMBASE, Cochrane Central Register of Controlled Trials, the Chinese National Knowledge Infrastructure and the Chinese Biomedical Literature Database. The primary outcome was overall survival. Secondary outcomes were positive neurological status and probability of sustained restoration of spontaneous circulation (ROSC). Complications were infection and bleeding. Given the significant heterogeneity across previous studies, combining the data using meta-analysis was deemed not appropriate. RESULTS: Five studies (551 patients) met the criteria. Two studies of co-intervention therapy (corticosteroid, vasopressin and epinephrine protocol) found that this approach could benefit in-hospital CA patient survival rates at hospital discharge, improve neurological function at hospital discharge and yield sustained ROSC rate. However, further two studies failed to demonstrate that corticosteroid therapy alone could improve survival and neurological outcomes among CA patients. Additionally, corticosteroid therapy did not increase the risk of infection and bleeding. CONCLUSIONS: Due to the inherent limitations of the studies in this review, we have not been able to reach definitive conclusions. Larger-scale and better-designed studies are therefore recommended, to further evaluate the potential and rational use of corticosteroid therapy in CA patients.

Clinical features and current treatments of adult-onset Still's disease: a multicentre survey of 517 patients in China.

OBJECTIVES: As a rare systemic autoinflammatory disease, adult-onset Still's disease (AOSD) has heterogeneous clinical manifestations, response to treatment and outcome. This study tried to assess the clinical characteristics, laboratory tests, and treatments of Chinese AOSD patients, and make a retrospective analysis. METHODS: We collected from 7 hospitals in China a total of 517 Chinese patients with AOSD who satisfied the Yamaguchi criteria. We retrospectively evaluated their clinical features, laboratory tests, treatments and compared them with published data from different studies. All the data in this study were from medical records and further statistic analyses. RESULTS: We evaluated a total of 517 AOSD patients, 72% female, average age of onset was 37.7; spiking fever, rash and arthralgia occurred in 472 (91.3%), 413 (79.9%), 378 (73.1%) cases, respectively. There were 439/513 (85.6%) cases with leukocytosis and 456/476 (95.8%) cases with raised serum ferritin. The highest frequently used medications and regimens for remission were glucocorticoids (498/517, 96.3%), methotrexate (273/517, 52.8%) and hydroxychloroquine (174/517, 33.7%). 84.4%. 357/423 of AOSD cases were able to achieve initial remission with different regimens, mostly including glucocorticoids, methotrexate or hydroxychloroquine. 47.2% of them (244/517) received 30