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Multiple embryonic origins give rise to forebrain oligodendrocytes (OLs), yet controversies and uncertainty exist regarding their differential contributions. We established intersectional and subtractional strategies to genetically fate map OLs produced by medial ganglionic eminence/preoptic area (MGE/POA), lateral/caudal ganglionic eminences (LGE/CGE), and dorsal pallium in the mouse brain. We found that, contrary to the canonical view, LGE/CGE-derived OLs make minimum contributions to the neocortex and corpus callosum, but dominate piriform cortex and anterior commissure. Additionally, MGE/POA-derived OLs, instead of being entirely eliminated, make small but sustained contribution to cortex with a distribution pattern distinctive from those derived from the dorsal origin. Our study provides a revised and more comprehensive view of cortical and white matter OL origins, and established valuable new tools and strategies for future OL studies.

ABSTRACT Background Systemic inflammation stands as a pivotal factor tightly interwoven with the progression of COVID‐19. This study endeavors to elucidate the significance of three key inflammatory molecules, that is, heparin‐binding protein (HBP), interleukin‐6 (IL‐6), and C‐reactive protein (CRP), in assessing the severity and prognostic implications of COVID‐19. Methods The demographic, clinical, and laboratory data were retrospectively collected from a cohort of 214 adult patients diagnosed with COVID‐19. Patients were divided into two groups: nonsevere (n = 93; 43.5%) and severe (n = 121; 56.5%). Additionally, based on their organ function, patients were categorized into nonorgan failure (n = 137) and organ failure (n = 77) groups. The levels of inflammation‐related cytokines were then compared among these defined groups. Results The severe group was characterized by a higher proportion of males, older age, and longer hospital stays compared to nonsevere cases. Additionally, severe cases exhibited a higher prevalence of underlying diseases and organ failure. Statistical analysis revealed significantly elevated levels of HBP, IL‐6, and CRP in the severe group. HBP, IL‐6, and CRP were identified as independent risk factors for severe COVID‐19. Furthermore, a combined assessment of these biomarkers demonstrated superior diagnostic sensitivity (85.10%) and specificity (95.70%) for predicting COVID‐19 severity. A positive relationship between elevated HBP, IL‐6, and CRP levels and impaired organ function was also observed. The predictive efficiency significantly increased (hazard ratio = 3.631, log‐rank p = 0.003) when two or more of them were combinedly used. Notably, elevated levels of HBP, IL‐6, and CRP were associated with an increased risk of mortality. Conclusions In conclusion, the combined assessment of HBP, IL‐6, and CRP offers enhanced accuracy and specificity in predicting the severity, organ failure, and mortality risk associated with COVID‐19.

Sinomenine hydrochloride (SH) is commonly used in the treatment of rheumatoid arthritis. It activates mast cells and induces anaphylaxis in the clinical setting. Adverse drug reactions can be caused by activation of MAS-associated G protein-coupled receptor X2 (MRGPRX2) on mast cells. Because the ligand binding site of MRGPRX2 is easily contacted in dilute solvents, it can be activated by many opioid drug structures. N-Demethylsinomenine (M-3) has a similar chemical structure to that of the opioid scaffold and is a major metabolite of SH. We sought to clarify whether M-3 induces anaphylaxis synergistically with its prototype in a mouse model. Molecular docking computer simulations suggested a similar binding effect between M-3 and SH. M-3 was chemically synthesized and analyzed by surface plasmon resonance to reveal its affinity for MRGPRX2. Temperature monitoring, in vivo hindlimb swelling and exudation test, and in vitro mast cell degranulation test were used to explore the mechanism of MRGPrx2 mediated allergic reaction triggered by M-3. Reduced M-3-induced inflammation was evident in MrgprB2 (the ortholog of MRGPRX2) conditional (Cpa3-Cre/MrgprB2flox) knockout (MrgprB2-CKO) mice. Additionally, LAD2 human mast cells with MRGPRX2 knockdown showed reduced degranulation. M-3 activated LAD2 cells synergistically with SH as regulated by GRK2 signaling and IP3R/PLC/PKC/P38 molecular signaling pathways. The results indicate that the M-3 metabolite can activate mast cells synergistically with its prototype SH via MRGPRX2 and aggravate anaphylaxis. These findings provide important insights into drug safety.

Iconic memory and short-term memory are not only crucial for perception and cognition, but also of great importance to mental health. Here, we first showed that both types of memory could be improved by improving limiting processes in visual processing through perceptual learning. Normal adults were trained in a contrast detection task for ten days, with their higher-order aberrations (HOA) corrected in real-time. We found that the training improved not only their contrast sensitivity function (CSF), but also their iconic memory and baseline information maintenance for short-term memory, and the relationship between memory and CSF improvements could be well-predicted by an observer model. These results suggest that training the limiting component of a cognitive task with visual perceptual learning could improve visual cognition. They may also provide an empirical foundation for new therapies to treat people with poor sensory memory.

Abstract Background CHF (Congenital hepatic fibrosis) is a rare hereditary disease characterized by periportal fibrosis and ductal plate malformation. Little is known about the clinical presentations and outcome in CHF patients with an extraordinary complication with biliary sepsis. Case summary Our case described a 23-year-old female diagnosed as CHF combined with biliary sepsis. Her blood culture was positive for KP (Klebsiella pneumoniae), and with a high level of CA19-9 (> 1200.00 U/ml, ref: G (p. V1287G) and c.9059T > C (p. L3020P) in PKHD1 gene. After biliary sepsis relieved, her liver function test was normal, and imaging examination results showed no significant difference with the results harvested during her biliary sepsis occurred. Conclusion The diagnosis of CHF complicated with biliary sepsis in the patient was made. Severely biliary sepsis due to KP infection may not inevitably aggravate congential liver abnormality in young patients. Our case provides a good reference for timely treatment of CHF patients with biliary sepsis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease. This study aimed to investigate the involvement of endoplasmic reticulum stress (ERS) in IPF and explore its correlation with immune infiltration.MethodsERS-related differentially expressed genes (ERSRDEGs) were identified by intersecting differentially expressed genes (DEGs) from three Gene Expression Omnibus datasets with ERS-related gene sets. Gene Set Variation Analysis and Gene Ontology were used to explore the potential biological mechanisms underlying ERS. A nomogram was developed using the risk signature derived from the ERSRDEGs to perform risk assessment. The diagnostic value of the risk signature was evaluated using receiver operating characteristics, calibration, and decision curve analyses. The ERS score of patients with IPF was measured using a single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm. Subsequently, a prognostic model based on the ERS scores was established. The proportion of immune cell infiltration was assessed using the ssGSEA and CIBERSORT algorithms. Finally, the expression of ERSRDEGs was validated in vivo and in vitro via RT-qPCR.ResultsThis study developed an 8-ERSRDEGs signature. Based on the expression of these genes, we constructed a diagnostic nomogram model in which agouti-related neuropeptide had a significantly greater impact on the model. The area under the curve values for the predictive value of the ERSRDEGs signature were 0.975 and 1.000 for GSE70866 and GSE110147, respectively. We developed a prognostic model based on the ERS scores of patients with IPF. Furthermore, we classified patients with IPF into two subtypes based on their signatures. The RT-qPCR validation results supported the reliability of most of our conclusions.ConclusionWe developed and verified a risk model using eight ERSRDEGs. These eight genes can potentially affect the progression of IPF by regulating ERS and immune responses.

Background & Aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients. Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls. Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10−304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10−33; OR = 4.26) and rs7765379 (p = 5.08 × 10−18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels. Conclusions: Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH. Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

PurposeDespite strong efforts to promote human papillomavirus (HPV) vaccine and cervical cancer screening, cervical cancer remains a threat to women’s reproductive health. Some high-risk HPV types play a crucial role in the progression of cervical cancer and precancerous lesions. Therefore, HPV screening has become an important means to prevent, diagnose, and triage cervical cancer. This study aims to leverage artificial intelligence to predict individual risks of cervical intraepithelial neoplasia (CIN) in women with high-risk HPV infection and to recommend the appropriate triage strategy and follow-up period according to the risk level.Materials and methodsA total of 475 cases were collected in this study. The sources were from the Department of Gynecology and Obstetrics in a tertiary hospital, a case report on HPV from the PubMed website, and clinical data of cervical cancer patients from The Cancer Genome Atlas (TCGA) database. Through in-depth study of the interaction between high-risk HPV and its risk factors, the risk factor relationship diagram structure was constructed. A Classification of Lesion Stages (CLS) algorithm was designed to predict cervical lesion stages. The risk levels of patients were analyzed based on all risk factors, and follow-up periods were formulated for each risk level.ResultsOur proposed CLS algorithm predicted the probability of occurrence of CIN3—the precancerous lesion stage of cervical cancer. This prediction was based on patients’ HPV-16 and -18 infection status, age, presence of persistent infection, and HPV type. Follow-up periods of 3–6 months, 6–12 months, and 3- to 5-year intervals were suggested for high-risk, medium-risk, and low-risk patients, respectively.ConclusionA lesion prediction model was constructed to determine the probabilities of occurrence of CIN by analyzing individual data, such as patient lifestyle, physical assessments, and patient complaints, in order to identify high-risk patients. Furthermore, the potential implications of the calculated features were mined to devise prevention strategies.

Abstract Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.

Abstract Background Respiratory syncytial virus (RSV) infection in adults remains less recognized and understood, both socially and clinically, compared to influenza virus infection. This retrospective study aims to delineate and compare the clinical manifestations of adult RSV and influenza virus infections in the lower respiratory tract, thereby enhancing awareness of RSV lower respiratory tract infection and providing strategic insights for its prevention and treatment. Methods Clinical data from January 2019 to December 2020 were analyzed for 74 patients with RSV and 129 patients with influenza A/B virus lower respiratory tract infections who were admitted to respiratory or intensive care units. All patients had complete clinical data with positive IgM and negative IgG viral antibodies. Comparison parameters included onset timing, baseline data, clinical manifestations, supplementary examination results, treatment methods, and prognosis, while logistic regression was employed to ascertain the correlation of clinical features between the two patient groups. Results In comparison to the influenza group, the RSV group presented less frequently with fever at admission but exhibited a higher incidence of dyspnea and wheezing on pulmonary auscultation (P

This study proposes a guidance strategy based on human–machine transition (HMT) for cooperative adaptive cruise control (CACC) truck platoon actuator failures. Existing research on the CACC platoon mainly focuses on upper-level planning and rarely considers platoon planning failures caused by actuator failures. This study proposes that the truck in the platoon creates sufficient space on the target lane through HMT when the actuator fails, thereby promoting lane changes for the entire team. The effectiveness of the proposed strategy is evaluated using the Simulation of Urban Mobility (SUMO) simulation. The results demonstrate that under conditions ensuring the normal operation of traffic flow, this guidance strategy enhances the platoon’s lane-changing capability. In addition, this strategy exhibits stronger robustness and efficiency in different traffic densities. This guidance strategy provides valuable insights into improving the driving efficiency of CACC truck platoons in complex road environments.

Background: The integrity of the radial head is critical to maintaining elbow joint stability. For radial head fractures requiring surgical treatment, headless compression cannulated screw fixation is a less invasive scheme that has fewer complications. The aim of this study was to compare the mechanical stability of different fixation devices, including headless compression cannulated screws and mini-T-plates, for the fixation of transversely unstable radial head fractures.Methods: Forty identical synthetic radius bones were used to construct transverse unstable radial head fracture models. Parallel, cross, and tripod headless compression cannulated screw fixation and mini-T plate fixation were applied. The structural stiffness of each group was compared by static shear loading. Afterward, cyclic loading was performed in each of the three directions of the radial head, and the shear stability of each group was compared by calculating the maximum radial head displacement at the end of the cycle.Findings: The mini-T plate group had the lowest structural stiffness (51.8 ± 7.7 N/mm) and the highest relative displacement of the radial head after cyclic loading (p < 0.05). The tripod headless compression cannulated screw group had the highest structural stiffness among all screw groups (p < 0.05). However, there was no significant difference in the relative displacement of the radial head between the screw groups after cyclic loading in different directions (p > 0.05).Interpretation: In conclusion, the biomechanical stability of the mini-T plate for fixation of transverse unstable radial head fractures is lower than that of headless compression cannulated screws. Tripod fixation provides more stable fixation than parallel and cross fixation with headless compression cannulated screws for the treatment of transversely unstable radial head fractures.

Objectives Near viewing distance (VD) and longer viewing times are associated with myopia. This study aimed to identify the font size and viewing time that guarantee the appropriate VD and pixels per degree (PPD) for children’s online learning.Design This cross-sectional study comprised two experiments. In experiment A, participants read text in five font sizes on three backlit displays (a personal computer, a smartphone and a tablet), an E-ink display and paper for 5 min per font size. In experiment B, participants watched videos for 30 min on three backlit displays.Setting The Peking University People’s Hospital in Beijing (China) and the School of Ophthalmology and Optometry, Wenzhou Medical University (Zhejiang Province, China).Participants Thirty-five participants completed experiment A. Ten of them participated in experiment B.Primary and secondary outcome measures VDs were measured by Clouclip. The corresponding PPD was calculated.Results In experiment A, font size and display type significantly affected VD (F(4840)=149.44, p33 cm for all five font sizes on the PC, the tablet and paper and for 18-pt on the smartphone and 16-pt on E-ink. PPD for 16-pt on the PC, 14-pt on the tablet and all five font sizes on the phone were >60. In experiment B, VD increased over the four previous 5 min periods but decreased slightly on tablets and PCs in the fifth 5 min period. PPD was >60.Conclusion Children demonstrated different VDs and PPDs based on font size and display type. To ensure a 33 cm VD and 60 PPD, the minimum font size for online reading should be 18-pt on smartphones, 16-pt on PCs and E-ink, 10.5-pt on tablets and 9-pt on paper. More attention should be given to children’s VD with continuous video viewing of more than 25 min.Trial registration number ChiCTR2100049584.

Background & Aims: Wilson’s disease is an inherited hepatoneurologic disorder caused by mutations in the copper transporter ATP7B. Liver disease from Wilson’s disease is one leading cause of cirrhosis in adolescents. Current copper chelators and zinc salt treatments improve hepatic presentations but frequently worsen neurologic symptoms. In this study, we showed the function and machinery of neutrophil heterogeneity using a zebrafish/murine/cellular model of Wilson’s disease. Methods: We investigated the neutrophil response in atp7b-/- zebrafish by live imaging, movement tracking, and transcriptional analysis in sorted cells. Experiments were conducted to validate liver neutrophil heterogeneity in Atp7b-/- mice. In vitro experiments were performed in ATP7B-knockout human hepatocellular carcinomas G2 cells and isolated bone marrow neutrophils to reveal the mechanism of neutrophil heterogeneity. Results: Recruitment of neutrophils into the liver is observed in atp7b-/- zebrafish. Pharmacologic stimulation of neutrophils aggravates liver and behavior defects in atp7b-/- zebrafish. Transcriptional analysis in sorted liver neutrophils from atp7b-/- zebrafish reveals a distinct transcriptional profile characteristic of N2 neutrophils. Furthermore, liver N2 neutrophils also were observed in ATP7B-knockout mice, and pharmacologically targeted transforming growth factor β1, DNA methyltransferase, or signal transducer and activator of transcription 3 reduces liver N2 neutrophils and improves liver function and alleviates liver inflammation and fibrosis in ATP7B-knockout mice. Epigenetic silencing of Socs3 expression by transforming growth factor β1 contributes to N2-neutrophil polarization in isolated bone marrow neutrophils. Conclusions: Our findings provide a novel prospect that pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease.

Abstract Background Lung adenocarcinoma (LUAD) is a common cancer with a bad prognosis. Numerous investigations have indicated that the metabolism of fatty acids plays an important role in the occurrence, progression, and treatment of cancer. Consequently, the objective of the current investigation was to elucidate the role and prognostic significance of genes associated with fatty acid metabolism in patients diagnosed with LUAD. Materials and methods The data files were acquired from The Cancer Genome Atlas database and GSE31210 dataset. Univariate Cox and least absolute shrinkage and selection operator regression analyses were conducted to establish a prognostic risk scoring model depending on fatty acid metabolism-associated genes to predict the prognosis of patients with LUAD. pRRophetic algorithm was utilized to evaluate the potential therapeutic agents. Gene set variation analysis combined with cell-type identification based on the estimation of relative subsets of RNA transcript and single-sample gene set enrichment analysis was used to determine the association between immune cell infiltration and risk score. Tumor immune dysfunction and exclusion algorithm was employed to predict immunotherapeutic sensitivity. Results To forecast the prognosis of patients with LUAD, a risk scoring model based on five genes associated with fatty acid metabolism was developed, including LDHA, ALDOA, CYP4B1, DPEP2, and HPGDS. Using the risk score algorithm, patients were divided into higher- and lower-risk categories. Patients classified as minimal risk showed superior prognosis than those with elevated risk. In addition, individuals in the higher-risk group had a proclivity toward chemoresistance and amenable to immunotherapy. Conclusion The prognostic risk scoring model aids in estimating the prognosis of LUAD patients. It may also provide new insights into LUAD carcinogenesis and therapeutic strategies.

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder. How to stratify high risk patients is one of the current challenges for the treatment of HLH. HLH patients usually fulfill multiple but not all eight diagnostic criteria. Different combinations of the fulfilled criteria may naturally cluster into previously undescribed subsets or phenotypes that may have different pathophysiology and demonstrate different risks for a poor outcome. The objectives of this study were to identify HLH subgroups according to the fulfillment of diagnostic criteria and evaluate the risk of multiple organ dysfunction syndrome (MODS) and 30-day mortality for subgroups. We retrospectively collect medical records of patients with discharge diagnosis of HLH between June 2015 and October 2018 from a tertiary children’s hospital in China. Latent class analysis was used to identify class defining variables from HLH diagnostic items, and subgroups were defined according to different combinations of the class defining variables. Results Triglyceride and fibrinogen were identified as the class defining variables. When evaluated in combinations, patients with hypertriglyceridemia and normal fibrinogen levels during hospitalization had the lowest risks for MODS (27.8%, OR = 1) and 30-day mortality (18.8%, OR = 1), and patients with normal triglyceride and hypofibrinogenemia had the highest risks for MODS (86.2%, OR = 16.24, P = 0.0002) and 30-day mortality (57.1%, OR = 5.78, P = 0.0187). The fulfillment status of hypertriglyceridemia and hypofibrinogenemia within 72 h of hospital admission was also associated with the risk of adverse outcomes. Conclusions The fulfillment status of hypertriglyceridemia and hypofibrinogenemia were associated with the risks of MODS and 30-day mortality among pediatric HLH patients. Further studies are needed to validate this association and investigate its clinical utility in the severity evaluation for HLH.

Atractylodes lancea suffers from continuous cropping obstacles that have become a major constraint in its cultivation, but there is still little information on the autotoxic allelochemicals and their interaction with soil microorganisms. In this study, we firstly identified the autotoxic allelochemicals from rhizosphere of A. lancea and determined their autotoxicity. Third-year continuous A. lancea cropping soils, i.e., rhizospheric soil and bulk soil, compared with control soil and one-year natural fallow soil were used to determine soil biochemical properties and microbial community. Eight allelochemicals from A. lancea roots were detected and exhibited significant autotoxicity effects on seed germination and seedling growth of A. lancea with the highest content of dibutyl phthalate in rhizospheric soil and lowest IC50 value of 2,4-di-tert-butylphenol inhibiting seed germination. The contents of soil nutrients and organic matter, pH value, and enzyme activity were altered between different soils, and the parameters of fallow soil were close to those of the unplanted soil. The PCoA analysis indicated that the community composition of both bacteria and fungi were differed significantly among the soil samples. Continuous cropping decreased OTUs numbers of bacterial and fungal communities, and natural fallow restored them. The relative abundance of Proteobacteria, Planctomycetes, and Actinobacteria decreased, and that of Acidobacteria and Ascomycota increased after three years cultivation. The LEfSe analysis identified 115 and 49 biomarkers for bacterial and fungal communities, respectively. The results suggested that natural fallow restored the structure of soil microbial community. Overall, our results revealed that autotoxic allelochemicals caused the variations of soil microenvironments and resulted in replantation problem of A. lancea, and natural fallow alleviated the soil deterioration by remodeling the rhizospheric microbial community and restoring soil biochemical properties. These findings provide important insights and clues for solving the continuous cropping problems and guiding the management of sustainable farmland.

Abstract Background Lung cancer is the most common malignant tumor, and it has a high mortality rate. However, the study of miRNA-mRNA regulatory networks in the plasma of patients with non-small cell lung cancer (NSCLC) is insufficient. Therefore, this study explored the differential expression of mRNA and miRNA in the plasma of NSCLC patients. Methods The Gene Expression Omnibus (GEO) database was used to download microarray datasets, and the differentially expressed miRNAs (DEMs) were analyzed. We predicted transcription factors and target genes of the DEMs by using FunRich software and the TargetScanHuman database, respectively. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for GO annotation and KEGG enrichment analysis of downstream target genes. We constructed protein-protein interaction (PPI) and DEM-hub gene networks using the STRING database and Cytoscape software. The GSE20189 dataset was used to screen out the key hub gene. Using The Cancer Genome Atlas (TCGA) and UALCAN databases to analyze the expression and prognosis of the key hub gene and DEMs. Then, GSE17681 and GSE137140 datasets were used to validate DEMs expression. Finally, the receiver operating characteristic (ROC) curve was used to verify the ability of the DEMs to distinguish lung cancer patients from healthy patients. Results Four upregulated candidate DEMs (hsa-miR199a-5p, hsa-miR-186-5p, hsa-miR-328-3p, and hsa-let-7d-3p) were screened from 3 databases, and 6 upstream transcription factors and 2253 downstream target genes were predicted. These genes were mainly enriched in cancer pathways and PI3k-Akt pathways. Among the top 30 hub genes, the expression of KLHL3 was consistent with the GSE20189 dataset. Except for let-7d-3p, the expression of other DEMs and KLHL3 in tissues were consistent with those in plasma. LUSC patients with high let-7d-3p expression had poor overall survival rates (OS). External validation demonstrated that the expression of hsa-miR-199a-5p and hsa-miR-186-5p in peripheral blood of NSCLC patients was higher than the healthy controls. The ROC curve confirmed that the DEMs could better distinguish lung cancer patients from healthy people. Conclusion The results showed that miR-199a-5p and miR-186-5p may be noninvasive diagnostic biomarkers for NSCLC patients. MiR-199a-5p-KLHL3 may be involved in the occurrence and development of NSCLC.

Background Left atrial thrombus (LAT) often complicates with atrial fibrillation (AF). The evidence whether fibrin D-dimer levels could be used as a predictive biomarker for LAT is contradictory. This study firstly investigated the relationship between ‘normal range’ D-dimer and prevalent LAT. Second, we explored factors contributing to normal D-dimer levels in the presence of LAT. Methods We studied 244 AF patients with LAT (mean age: 59.9 years, SD:11.7; 53.3% female): of these, 103 (42.2%) had normal D-dimer, 25 (10.2%) had atrial thrombus exclusion score (ATE score) of 0 19 (16.7%) males had CHA 2 DS 2 -VASc score of 0, 21(16.2%) females had CHA 2 DS 2 -VASc score of 1 and 16 had overlapped ATE score of 0 and CHA 2 DS 2 -VASc score of 0 (N = 8 if male) or CHA 2 DS 2 -VASc score of 1(N = 8 if female). Using multivariate binary analysis, larger left atrial diameter (LAD; adjusted OR: 1.06, 1.03−1.10, p = 0.001) were associated with increased D-dimer. Patients with high body mass index (BMI), hypertension history and previous anticoagulation were more likely to show normal range D-dimer levels in the presence of LAT. Conclusions A high prevalence (42.2%) of ‘normal range’ D-dimer levels was found in AF patients with LAT, especially in those with hypertension, high BMI and prior anticoagulation. D-dimer levels of those patients with larger LAD were more likely to be increased.

ObjectiveTo improve the accuracy of the diagnosis of familial progressive intrahepatic cholestasis type 3 (PFIC3, https://www.omim.org/entry/602347).Materials and methodsBetween September 2019 and March 2021, we recruited four patients with PFIC3 from two liver centers in East China. Molecular genetic findings of ATP-binding cassette subfamily B member 4 [ATP binding cassette transporter A4 (ABCB4), https://www.omim.org/entry/171060] were prospectively examined, and clinical records, laboratory readouts, and macroscopic and microscopic appearances of the liver were analyzed.ResultsFour patients experienced cholestasis, mild jaundice, and elevated levels of serum direct bilirubin, γ-glutamyltransferase, or total bile acids. All patients had moderate-to-severe liver fibrosis or biliary cirrhosis, and their liver biopsy specimens stained positive with rhodamine. Molecular immunohistochemistry revealed reduced or absent MDR3 expression in all liver specimens. A novel mutation of ABCB4 (c.1560 + 2T > A) was identified in patients with PFIC3, which is of high clinical significance and may help understand mutant ABCB4 pathogenesis.ConclusionMDR3 immunohistochemistry and molecular genetic analyses of ABCB4 are essential for the accurate diagnosis of PFIC3.

PurposeGiven the increasing prevalence of autism spectrum disorder (ASD) and the public health problems it creates; early identification and interventions are needed to improve the prognosis of ASD. Hence, this study surveyed different groups of people who are likely to have early contact with autistic children to provide an informed basis for early detection and effective diagnosis and interventions.MethodsThree groups of people were recruited for the study from Changshou District and Wushan County of Chongqing, in Western China: 269 medical workers, 181 educators, and 188 community residents. Their understanding and knowledge of autism was measured using a self-made questionnaire.ResultsThe positive finding was that the three groups had a certain level of understanding of autism, but they had some misunderstandings of the core problems, and there were significant differences in the understanding of autism among the three groups. Younger medical workers knew more about autism than older ones did. The ability of educators and community residents to identify autistic symptoms was positively related to their level of education and their experience with autistic children. Television and the internet were the main sources of information about autism for participants.ConclusionsThe medical workers, educators, and community residents in the investigated areas in western China may be able to identify early signs of autism but have an inadequate understanding of autism. In areas far from cities, it is necessary to strengthen the training of medical workers in primary health care to promote autism screening and referral in educational institutions and communities. Using internet technology to provide public education and professional training about autism in remote areas could be a very promising method in Western China.

Background and aimsDeciding when to suspect hemophagocytic lymphohistiocytosis (HLH) and perform diagnostic tests in patients with acute infection of Epstein-Barr virus (EBV) is challenging, given the high prevalence of EBV infection, the life-threatening risk of EBV-HLH, the relatively low incidence of EBV-HLH, and the wide spectrum of disease presentations. The aim of this study was to develop an EBV-HLH screening model for pediatric patients diagnosed with acute infection of EBV.MethodsAn inpatient cohort with 3183 pediatric patients who were diagnosed with active infection of EBV was used to construct and validate the EBV-HLH screening score model. The model parameters were selected from common laboratory parameters using the method of Akaike Information Criterion-optimal selection through cross-validation under logistic regression. Performance of the score was evaluated and compared with the performance of screening methods using the number of cytopenias lineages.ResultsThe EBV-HLH screening score has five parameters, including hemoglobin, platelet, neutrophil, albumin, and lactate dehydrogenase. Using a cut-of value of 29, the scoring model had a sensitivity of 89.2% and a specificity of 89.5% in the validation set. The false negative rate, false positive rate, positive predictive value, and negative predictive value in the validation set was 10.8%, 10.5%, 26.8%, and 99.5%, respectively, similar to that of the training set.ConclusionsWith five common laboratory parameters, the EBV-HLH score provides a simple tool to assist the identification of EBV patients who require further evaluation of HLH. Further studies are needed to evaluate the generalizability of the score and optimize the diagnose process for EBV-HLH.

Abstract Background Lung cancer is one of the most lethal and most prevalent malignant tumors worldwide, and lung squamous cell carcinoma (LUSC) is one of the major histological subtypes. Although numerous biomarkers have been found to be associated with prognosis in LUSC, the prediction effect of a single gene biomarker is insufficient, especially for glycolysis-related genes. Therefore, we aimed to develop a novel glycolysis-related gene signature to predict survival in patients with LUSC. Methods The mRNA expression files and LUSC clinical information were obtained from The Cancer Genome Atlas (TCGA) dataset. Results Based on Gene Set Enrichment Analysis (GSEA), we found 5 glycolysis-related gene sets that were significantly enriched in LUSC tissues. Univariate and multivariate Cox proportional regression models were performed to choose prognostic-related gene signatures. Based on a Cox proportional regression model, a risk score for a three-gene signature (HKDC1, ALDH7A1, and MDH1) was established to divide patients into high-risk and low-risk subgroups. Multivariate Cox regression analysis indicated that the risk score for this three-gene signature can be used as an independent prognostic indicator in LUSC. Additionally, based on the cBioPortal database, the rate of genomic alterations in the HKDC1, ALDH7A1, and MDH1 genes were 1.9, 1.1, and 5% in LUSC patients, respectively. Conclusion A glycolysis-based three-gene signature could serve as a novel biomarker in predicting the prognosis of patients with LUSC and it also provides additional gene targets that can be used to cure LUSC patients.

Abstract Background Epithelial-mesenchymal transition (EMT) is a key process in the onset and development of idiopathic pulmonary fibrosis (IPF) with unclear mechanisms. Our previous studies found that bleomycin and tunicamycin could induce ER stress and consequently trigger EMT accompanying with IL-32 overexpression. This study was aimed to investigate the effects of IL-32 on EMT and ER stress to elucidate the pathogenesis of IPF. Methods Human lung adenocarcinoma A549 cells were treated with recombinant human (rh)IL-32, IL-32 siRNA and EMT inducer tunicamycin, or 4-phenylbutyric acid (4-PBA), respectively. Then the cell morphology was observed and the expression of ER-related markers and EMT-related markers were detected by RT-qPCR or western blotting. Results Stimulation of A549 cells with rhIL-32 led to a morphological change from a pebble-like shape to an elongated shape in a portion of the cells, accompanied by down regulated expression of the epithelial cell marker E-cadherin and up regulated expression of the mesenchymal cell markers N-cadherin, Vimentin, and Zeb-1. However, these rhIL-32 induced changes were inhibited by the ER stress inhibitor 4-PBA. Suppression of IL-32 expression with siRNA inhibited TM-induced EMT. Further stimulation of the A549 cells with rhIL-32 demonstrated an increase in the expression of GRP78, although this increase was also inhibited by 4-PBA. Conclusions These results suggest that IL-32 induces EMT in A549 cells by triggering ER stress, and IL-32 may be a novel marker for IPF.

Respiratory syncytial virus (RSV) is a common virus that causes respiratory infection, especially severe respiratory infection in infants and young children, the elderly people over 65 years old, and people with weak immunity. Currently, RSV infection has no effective vaccine and antiviral treatment. The number of deaths due to RSV infection increases every year. Moreover, RSV A infection occurs in a large number and has severe clinical symptoms and complications than RSV B infection. Therefore, the development of a simple, rapid, and inexpensive detection method with high amplification efficiency, high sensitivity, and specificity is very important for the diagnosis of RSV A or RSV B infection, which can help in the early clinical medication and prevent the progress of the disease. Therefore, we developed an integrated trinity test with an RPA-CRISPR/Cas12a-fluorescence (termed IT-RAISE) assay system to detect RSV A or RSV B. The characteristic of the IT-RAISE system is that after target recognition, the reporter single-stranded DNA (ssDNA) is cleaved by Cas12a that is activated by different crRNAs to detect the generated fluorescent signal. This method is simple and helps in adding all reagents rapidly. It is a high-sensitive method that can detect 1.38 × 101 copies/μl of the target sequences, and it can distinguish RSV A or RSV B infection within 37 min. In addition, clinical specimens were detected for IT-RAISE system. It was found that the sensitivity and specificity of RSV A were 73.08 and 90%, respectively, and those of RSV B were 42.86 and 93.33%, respectively. The cost of ONE specimen for IT-RAISE system was approximately $ 2.6 (excluding rapid RNA extraction and reverse transcription costs). IT-RAISE system has good clinical application prospects for detecting RSV A or RSV B infection; it is a simple, rapid, and inexpensive method with high amplification efficiency, high sensitivity, and high specificity. The IT-RAISE system might also detect other viral or bacterial infections.

A patient with pneumonia had a fever for 2 weeks. After the initial anti-infection treatment failed, he was diagnosed with C. psittaci pneumonia complicated with organizing pneumonia, through next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF) and lung biopsy. He was treated with antibiotics and corticosteroids for 2 months.

BackgroundThe benefits of extracorporeal membrane oxygenation in patients with refractory septic shock remain controversial. Current guidelines on the management of refractory septic shock recommend the consideration of extracorporeal membrane oxygenation as a salvage therapy. The difference between adults and children with septic refractory shock treated with extracorporeal membrane oxygenation has not been previously analyzed. We aimed to review peer-reviewed publications on the role of extracorporeal membrane oxygenation in adults and children with refractory septic shock.MethodsStudies reporting on mortality in both adults and children with refractory septic shock supported with extracorporeal membrane oxygenation published in PubMed, Cochrane Library, and Embase databases were included in the meta-analysis. Study eligibility was independently assessed by two authors, and disagreements were resolved by a third author. The outcome measure was survival at discharge. Subgroup analysis included the adult and pediatric groups.ResultsOf the 293 articles screened, 14 original articles were identified for systematic review and meta-analysis. The cumulative estimate of survival (14 studies, 535 patients) in the cohort was 39% (95% confidence interval [CI]: 27–51%). During the subgroup analysis, the cumulative estimate of survival at discharge in the adult group (6 studies, 276 patients) in the cohort was 18% (95% CI: 10–27%), and that in the pediatric group (8 studies, 259 patients) was 53% (95% CI: 47–59%).ConclusionsThe survival rate of adults with refractory septic shock requiring extracorporeal membrane oxygenation was 18%, and children with refractory septic shock requiring extracorporeal membrane oxygenation had a higher survival rate (53%) than adults.

Background. Non-small-cell lung cancer (NSCLC) is the most common malignant tumor among males and females worldwide. Hypoxia is a typical feature of the tumor microenvironment, and it affects cancer development. Circular RNAs (circRNAs) have been reported to sponge miRNAs to regulate target gene expression and play an essential role in tumorigenesis and progression. This study is aimed at identifying whether circRNAs could be used as the diagnostic biomarkers for NSCLC. Methods. The heterogeneity of samples in this study was assessed by principal component analysis (PCA). Furthermore, the Gene Expression Omnibus (GEO) database was normalized by the affy R package. We further screened the differentially expressed genes (DEGs) and differentially expressed circular RNAs (DEcircRNAs) using the DEseq2 R package. Moreover, we analyzed the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment of DEGs using the cluster profile R package. Besides, the Gene Set Enrichment Analysis (GSEA) was used to identify the biological function of DEGs. The interaction between DEGs and the competing endogenous RNAs (ceRNA) network was detected using STRING and visualized using Cytoscape. Starbase predicted the miRNAs of target hub genes, and miRanda predicted the target miRNAs of circRNAs. The RNA-seq profiler and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Then, the variables were assessed by the univariate and multivariate Cox proportional hazard regression models. Significant variables in the univariate Cox proportional hazard regression model were included in the multivariate Cox proportional hazard regression model to analyze the association between the variables of clinical features. Furthermore, the overall survival of variables was determined by the Kaplan-Meier survival curve, and the time-dependent receiver operating characteristic (ROC) curve analysis was used to calculate and validate the risk score in NSCLC patients. Moreover, predictive nomograms were constructed and used to predict the prognostic features between the high-risk and low-risk score groups. Results. We screened a total of 2039 DEGs, including 1293 upregulated DEGs and 746 downregulated DEGs in hypoxia-treated A549 cells. A549 cells treated with hypoxia had a total of 70 DEcircRNAs, including 21 upregulated and 49 downregulated DEcircRNAs, compared to A549 cells treated with normoxia. The upregulated genes were significantly enriched in 284 GO terms and 42 KEGG pathways, while the downregulated genes were significantly enriched in 184 GO terms and 25 KEGG pathways. Moreover, the function analysis by GSEA showed enrichment in the enzyme-linked receptor protein signaling pathway, hypoxia-inducible factor- (HIF-) 1 signaling pathway, and G protein-coupled receptor (GPCR) downstream signaling. Furthermore, six hub modules and 10 hub genes, CDC45, EXO1, PLK1, RFC4, CCNB1, CDC6, MCM10, DLGAP5, AURKA, and POLE2, were identified. The ceRNA network was constructed, and it consisted of 4 circRNAs, 14 miRNAs, and 38 mRNAs. The ROC curve was constructed and calculated. The area under the curve (AUC) value was 0.62, and the optimal threshold was 0.28. Based on the optimal threshold, the patients were divided into the high-risk score and low-risk score groups. The survival rate in the high-risk score group was lower than that in the low-risk score group. The expression of SERPINE1, STC2, and LPCAT1; clinical stage; and age of the patient were significantly correlated with the high-risk score. Moreover, nomograms were established based on the risk factors in multivariate analysis, and the median survival time, 3-year survival probability, and 5-year survival were possibly predicted according to nomograms. Conclusion. The ceRNA network associated with NSCLC was identified, and the hub genes, circRNAs, might act as the potential biomarkers for NSCLC.

Abstract Objective Tumor cells could acquire drug resistance through cell autophagy. This study aimed to explore the role of SNHG16 in sorafenib‐resistant HCC cells and its mechanism with miR‐23b‐3p. Methods The sorafenib‐resistant Hep3B cell model was established. The SNHG16 and miR‐23b‐3p gene expressions were determined in normal HCC and sorafenib‐resistant HCC tissues. Detection of the expression of SNHG16 and miR‐23b‐3p and its respective correlation with survival rate were performed. Target genes to SNHG16 and miR‐23b‐3p were predicted, and verified by dual‐fluorescent reporter assay. The effects of SNHG16 and miR‐23b‐3p on SNHG16, miR‐23b‐3p, EGR1 expression, viability, apoptosis as well as LC3II/LC3 expression in Hep3B and Hep3B/So cells were detected by qRT‐PCR, CCK‐8, flow cytometry, and western blot. In in vivo studies, the NOD/SCID mice model was established to explore the effects of Hep3B and Hep3B/So cells with inhibited SNHG16 or miR‐23b‐3p on tumor size, EGR1 expression, and autophagy. Results High SNHG16 expression in HCC‐resistant tissues and low miR‐23b‐3p expression in all HCC tissues were detected, and the two were negatively correlated. Low SNHG16 and high miR‐23b‐3p were related to a high survival rate of HCC patients. Moreover, SNHG16 overexpression promoted Hep3B/So cell viability and autophagy, suppressed apoptosis by inhibiting miR‐23b‐3p expression through up‐regulating EGR1, however, the effect of si‐SNHG16 was opposite. In in vivo studies, miR‐23b‐3p inhibitor suppressed the high sorafenib sensitivity in Hep3B/So cells caused by SNHG16 silencing through promoting viability, autophagy, and suppressing apoptosis. Conclusion SNHG16 promotes Hep3B/So cell viability, autophagy, and inhibits apoptosis to maintain its resistance to sorafenib through regulating the expression of miR‐23b‐3p via sponging EGR1.

Summary: The mammillary body is a hypothalamic nucleus that has important functions in memory and spatial navigation, but its developmental principles remain not well understood. Here, we identify progenitor-specific Fezf2 expression in the developing mammillary body and develop an intersectional fate-mapping approach to demonstrate that Fezf2+ mammillary progenitors generate mammillary neurons in a rostral-dorsal-lateral to caudal-ventral-medial fashion. Axonal tracing from different temporal cohorts of labeled mammillary neurons reveal their topographical organization. Unsupervised hierarchical clustering based on intrinsic properties further identify two distinct neuronal clusters independent of birthdates in the medial nuclei. In addition, we generate Fezf2 knockout mice and observe the smaller mammillary body with largely normal anatomy and mildly affected cellular electrophysiology, in contrast to more severe deficits in neuronal differentiation and projection in many other brain regions. These results indicate that Fezf2 may function differently in the mammillary body. Our results provide important insights for mammillary development and connectivity.

BACKGROUND:The relationship between poor oral health conditions and cognitive decline is unclear. OBJECTIVE:To examine the association between oral health and cognition in humans and rats. METHODS:In humans: a cross-sectional study was conducted. Cognitive levels were evaluated by the Mini Mental State Examination (MMSE); oral conditions were reflected by the number of missing index teeth, bleeding on probing, and probing pocket depth (PD). In rats: a ligature-induced (Lig) periodontitis model and Aβ25-35-induced model of Alzheimer's disease (AD) were established; tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), and C-reactive protein levels in the hippocampus and cerebral cortex were detected. RESULTS:MMSE scores for the number of missing index teeth ≥ 7 group were significantly lower than those in the ≤ 6 group. A negative relationship (correlation coefficient ρ = -0.310, P = 0.002) was observed between MMSE scores and number of missing index teeth. More missing index teeth and lower education levels were independent risk factors for cognitive decline. A negative relationship (correlation coefficient ρ = -0.214, P = 0.031) was observed between MMSE scores and average PD. TNF-α and IL-6 levels in the hippocampus of the Lig+AD group were significantly higher than those of the AD group. IL-1 and IL-6 levels in the cerebral cortex of the Lig+AD group were significantly higher than those of the AD group. CONCLUSION:Poor oral health conditions including more missing index teeth and higher average PD may be risk factors for cognitive decline. Periodontitis may increase inflammatory cytokines in rat models of AD.

Abstract Background To investigate the unique features of inflammatory bowel disease (IBD) in children, we wanted to identify whether there might be a strong correlation between the disease phenotype and its prognosis at various ages in paediatric patients. Methods We collected data from patients diagnosed with IBD (ulcerative colitis (UC) or Crohn’s disease (CD)) from 2002 to 2016. The diagnosis was made according to the Porto criteria and Paris Classification. Patient characteristics, clinical manifestations and treatments were collected. Risk factors for surgery, mortality and relapse were analysed by Cox proportional hazard models. Results Of the 143 patients, 113 had CD, and 30 had UC; there were 89 males and 54 females with a median age of 9 years (y). Thirteen patients in the 0–2 y group were identified as having mutations in IL-10 receptor A, and this mutation was significantly more common in this age group than in 3–9 and 10–16 y patients. The risk factor for surgery was the B3 phenotype; risk factors for death were age 0–2 y and B3 phenotype; 0–2 y, B3 phenotype and steroid dependency were risk factors for early relapse. Conclusions Clinical manifestations of the onset of IBD in infants and toddlers were extensive and aggressive and were closely associated with early relapse and death. It is of particular interest that some of these patients developed IBD due to monogenic disorders; thus, introduction of genetic testing is essential for these patients.

Background/Aims: Epithelial to mesenchymal transition (EMT) is a crucial process involved in pulmonary fibrosis. This study aimed to explore the role of histone deacetylases (HDACs) and endoplasmic reticulum (ER) stress in EMT in human lung epithelial cells. Methods: Human lung adenocarcinoma A549 cells were treated with bleomycin and tunicamycin to induce EMT. The proliferation of A549 cells was detected by MTT assay. The expression of HDACs and EMT markers was detected by PCR and Western blot analysis. The secretion of TGF-β1 and collagen I was examined by ELISA. Results: A549 cells switched from a cobblestone-like appearance to an elongated fibroblast like appearance after exposure to tunicamycin or bleomycin, accompanied by increased expression of N-cadherin, α-SMA and Collagen I. Meanwhile, GRP78 was upregulated in A549 cells exposed to tunicamycin or bleomycin. These changes induced by tunicamycin or bleomycin could be abrogated by 4-PBA. Moreover, tunicamycin and bleomycin promoted the expression of HDAC2 and HDAC6, and HDACs inhibitor SAHA abrogated the morphological and biochemical changes in A549 cells. 4-PBA and SAHA inhibited the upregulation of pulmonary fibrosis factors TGF-β1 and IL-32 and the activation of Smad pathway induced by tunicamycin or bleomycin. Conclusions: We provide the first evidence that tunicamycin and bleomycin induce ER stress and EMT in lung epithelial cells via the upregulation of HDACs. HDACs inhibitor could inhibit ER stress induced upregulation of pulmonary fibrosis factors and the activation of Smad pathway. HDACs inhibitors are promising agents for the therapy of pulmonary fibrosis.

Abstract Background Pathways directing endogenous stem/progenitor cells to restore normal architecture and function of damaged/diseased lungs remain underexplored. Published data have revealed that alveolar progenitor type II cell (ATIIC)-derived signaling promotes re-epithelialization of injured alveoli, yet the underlying mechanism is unknown. Here we aim to define the role of ATIIC-derived exosome miRNA signaling in controlling ATIIC-specific proliferation or differentiation in response to injury. Methods Pluripotent stem cell-derived cultures, which contain early lung stem/progenitor populations that can subsequently differentiate into ATIICs, were used as a model for unbiased screening and identification of ATIIC phenotype-specific exosome miRNA signaling, and human induced pluripotent stem cell-derived ATIICs (hiPSC-ATIICs) were employed to examine the molecular basis of key exosome miRNA signaling in promoting ATIIC-specific proliferation. QRT-PCR was performed to examine expression pattern of ATIIC-derived key exosome miRNA in an alveolar injury model and in injured human lungs. Results We show that human ATIIC line (A549)-derived exosome miR-371b-5p promotes ATIIC-specific proliferation, but not differentiation, in differentiating cultures of pluripotent stem cells. Using 3′UTR-driven luciferase reporters, we identified PTEN as a direct target of miR-371b-5p. Transfection of miR-371b-5p mimic into hiPSC-ATIICs leads to significantly decreased expression of endogenous PTEN, which stimulates phosphorylation of Akt and its downstream substrates, GSK3β and FOXOs, promoting cell proliferation. While not expressed in normal ATIIC phenotypes, the exosome miR-371b-5p expression is significantly induced after hiPSC-ATIICs or hATIICs (human primary ATIICs) are subjected to bleomycin-induced injury. To rule out that the ATIIC-derived exosome-miRNAs are merely a cell culture phenomenon, we transplanted hiPSC-ATIICs into bleomycin-challenged lungs of mice, and found that the transplanted hiPSC-ATIICs engraft and express exosome miR-371b-5p, along with additional survival of numerous mouse ATIICs in bleomycin-injured lungs. Consistent with these findings, significant levels of exosome miR-371b-5p were also detected in lavage samples of patients with acute pneumonia, but not in those from patients without pulmonary disorders. Conclusions Collectively, our data strongly suggest that ATIIC-derived exosome miR-371b-5p may serve as a niche signaling to augment ATIIC survival/proliferation, promoting re-epithelialization of injured alveoli, and thus provide a promising novel target to develop treatment for currently incurable lung diseases.

How to precisely quantify the binocular eye balance (i.e., the contribution that each eye makes to the binocular percept) across a range of spatial frequencies using a binocular combination task, is an important issue in both clinical and basic research. In this study, we aimed to compare the precision of a binocular orientation combination paradigm with that of the standard binocular phase combination paradigm in measuring the binocular eye balance at low to high spatial frequencies. Nine normal adults (average age: 24.6 ± 2.0 years old) participated. Subjects viewed an LED screen dichoptically with polarized glasses in a dark room. The method of constant stimuli was used to quantitatively assess the point of subjective equality (PSE), i.e., the interocular contrast ratio when two eyes are balanced in binocular combination, for stimulus spatial frequencies from 0.5 to 8 cycles/degree. Precision was quantified by the variance [i.e., standard error (SE), obtained from 100 bootstrap estimates] associated to the PSE. Using stimuli whose interocular phase difference at the edge of the gratings was matched at 45°, we found that the orientation paradigm provides more precision than the standard binocular phase combination paradigm, especially at high frequencies (Experiment 1). Such differences remained when using stimuli that had three times larger interocular phase difference (Experiment 2) or displayed at four times higher stimuli resolution (Experiment 3). Our results indicate that a binocular combination tasked based on orientation rather than phase, provides a more precise estimate of binocular eye balance in human adults at high spatial frequencies, thus allowing a binocular balance to be assessed within the spatial region where amblyopes are most defective (i.e., high spatial frequencies).

Transforming growth factor β (TGFβ) induced differentiation of lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. This study aimed to evaluate the effect of curcumin on TGFβ induced differentiation of lung fibroblasts to myofibroblasts and explore the underlying mechanism. Mouse lung fibroblasts were cultured and treated with TGFβ2 and curcumin or rosiglitazone. Cell vitality was examined by MTT assay. The secretion of collagen-1 was assessed by ELISA. α smooth muscle actin (αSMA) was visualized by immunofluorescence technique. The expression of peroxisome proliferator activated receptor γ (PPARγ) and platelet derived growth factor R β (PDGFRβ) was detected by PCR and Western blot analysis. We found that curcumin and rosiglitazone inhibited the proliferation and TGFβ induced differentiation of mouse lung fibroblasts. In addition, curcumin and rosiglitazone inhibited collagen-1 secretion and αSMA expression in mouse lung fibroblasts. Furthermore, curcumin and rosiglitazone upregulated PPARγ and downregulated PDGFRβ expression in mouse lung fibroblasts. In conclusion, our study reveals novel mechanism by which curcumin inhibits TGFβ2 driven differentiation of lung fibroblasts to myofibroblasts. Curcumin could potentially be used for effective treatment of pulmonary fibrosis.

Ampelopsis megalophylla is an important species used in Chinese folk medicine. Flavonoids, the most important active components of plants, greatly determine the quality of A. megalophylla. However, biosynthesis of flavonoids at the molecular and genetic levels in A. megalophylla is not well understood. In this study, we performed chemical analysis and transcriptome analysis of A. megalophylla in different seasons (i.e., May, August, and October). Accumulation of flavonoids was higher in May than in the other two months. Genes involved in the flavonoid biosynthesis pathway, such as chalcone synthase, anthocyanidin synthase, flavanone 3-hydroxylase, flavonoid-3′,5′-hydroxylase, caffeoyl-CoA O-methyltransferase, dihydroflavonol 4-reductase, 4-coumarate-CoA ligase, phenylalanine ammonia-lyase, cinnamate 4-hydroxylase, flavonoid 3′-monooxygenase, shikimate O-hydroxycinnamoyltransferase, and leucoanthocyanidin reductase, were identified based on transcriptome data. Fifty ATP binding cassette (ABC) transporter, nine SNARE, forty-nine GST, and eighty-four glycosyltransferases unigenes related to flavonoid transport and biomodification were also found. Moreover, seventy-eight cytochrome P450s and multiple transcription factors (five MYB, two bHLH, and three WD40 family genes) may be associated with the regulation of the flavonoid biosynthesis process. These results provide insights into the molecular processes of flavonoid biosynthesis in A. megalophylla and offer a significant resource for the application of genetic engineering in developing varieties with improved quality.

AIM: To analyze the outcome of treating post-traumatic endophthalmitis in children.METHODS: Twenty-four 2～11 year-old children(24 eyes)with post-traumatic endophthalmitis that presented to our hospital from June 2006 to Feburary 2014 were retrospectively analyzed. All cases were performed intravitreal injection of vancomycin(1mg/0.1mL)and ceftazidime(2.25mg/0.1mL)and dexamethasone(0.4mg/0.1mL)immediately after being identified. The second day after injection, 23 eyes were received lensectomy and vitrectomy with silicone oil(n=10)or C3F8(n=3)or clean air(n=8)or irrigating solution(n=2)tamponade. Only one eye was reinjected at 72h after the first injection. The visual outcomes were evaluated.RESULTS: After follow-up 6～78mo, the inflammation of all cases were controled, 4 cases of eyeball atrophy(3 cases of silicone oil eye). Other 7 silicone oil filled eyes were received silicone oic extraction and IOL implantation. Twelve eyes presented with visual acuity of lower than 0.02, 4 eyes achieved 0.02～0.1, 4 eyes were 0.15～0.3,only 4 eyes reached 0.5～1.0. The final visual acuity improved in 16 eyes(70%), remained unchanged in 4 eyes(17%)and decreased in 3 eyes(13%). One case did not fit.CONCLUSION: Early diagnosis of endophthalmitis in open-globe injury, intravitreal injection of antibiotics and vitrectomy can salvage more than a half of injuried eyes in children.

AIM: To evaluate and compare the accuracy of IOL-Master and A-scan in measuring the axial length of silicone oil-filled eyes, and to explore the clinical value of IOL-Master in calculating intraocular lens diopter of the silicone oil-filled eyes. METHODS: An analysis was made of 30 patients(30 eyes)who received cataract surgery combined with silicone oil removal in our hospital from June 2012 to December 2012. Before the operation and one month afterwards, the axial length was measured by both IOL-Master and A-scan, and all the results were divided into two groups: A-scan group and IOL-Master group. Then we used IOL-Master to calculate the intraocular lens diopter and to estimate the postoperative refraction. Postoperative refraction was measured one month after operation and compared with the preoperative estimates. RESULTS: Before silicon oil removal, there was significant difference between the axial lengths obtained by IOL-Master and those by A-scan, with the former much smaller than the latter. After the operation, there was no significant difference between the axial lengths obtained by the two methods. The axial lengths measured by IOL-Master before and after operation were not significantly different. No significant difference was observed between the postoperative refraction and the preoperative estimates, either.CONCLUSION: IOL-Master is a more preferable method to measure axial length than A-scan. However, in cases where IOL-Master cannot be applied, A-scan together with other methods should be used.

Variants at the 9p21 locus have been associated with coronary artery disease (CAD); coronary artery calcification (CAC) is related to CAD and other cardiovascular events. To determine the association of the 9p21 locus with CAD in the presence and absence of CAC, 4 groups were enrolled in a case-control study, including 527 CAD patients without CAC, 692 CAD patients with CAC, 585 individuals with simple CAC but no CAD, and 725 healthy controls. The rs1333049 representing the locus was associated with CAD in the presence of CAC (odds ratio = 1.38 in allelic analysis, 95%CI, 1.19-1.60, P

Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P

AIM: To determine whether the 23-gauge(23G)vitrecomy cutter could replace scissors in conventional 20-gauge(20G)pars plana vitrectomy for treating severe proliferative diabetic retinopathy(PDR).METHODS:Non-comparative interventional case series. Totally 27 eyes of 27 patients with PDR stageⅥ confirmed by funduscopy and B-ultrasound scan were enrolled. They underwent 20G vitrectomy, in which 23G vitrectomy cutter replaced scissors to remove neuvascular membrane. All 27 eyes received complete panretinal photocoagulation, 17 eyes received no tamponade, 6 eyes were 12% C3F8 tamponade, 4 eyes were filled with silicone oil. The follow up time was 3mo. The operation duration time, iatrogenic retinal tear and retinal bleeding need electric coagulation, best corrected visual acuity(BCVA), retinal reattachment were analyzed.RESULTS: The operative time was 35-120(average 79.19±29.82)min; intraoperative iatrogenic retinal breaks were detected in 2 eyes(7%). At the end of 3mo follow up, BCVA>0.1 were in 9 eyes, from 0.05-0.1 in 10 eyes, CONCLUSION: The 23G vitrectomy cutter could replace scissors in conventional 20G pars plana vitrectomy for treating severe PDR.