A prominent gene activation role for C-terminal binding protein in mediating PcG/trxG proteins through Hox gene regulation.

The evolutionarily conserved C-terminal binding protein (CtBP) has been well characterized as a transcriptional co-repressor. Herein, we report a previously unreported function for CtBP, showing that lowering CtBP dosage genetically suppresses Polycomb group (PcG) loss-of-function phenotypes while enhancing that of trithorax group (trxG) in Drosophila, suggesting that the role of CtBP in gene activation is more pronounced in fly development than previously thought. In fly cells, we show that CtBP is required for the derepression of the most direct PcG target genes, which are highly enriched by homeobox transcription factors, including Hox genes. Using ChIP and co-IP assays, we demonstrate that CtBP is directly required for the molecular switch between H3K27me3 and H3K27ac in the derepressed Hox loci. In addition, CtBP physically interacts with many proteins, such as UTX, CBP, Fs(1)h and RNA Pol II, that have activation roles, potentially assisting in their recruitment to promoters and Polycomb response elements that control Hox gene expression. Therefore, we reveal a prominent activation function for CtBP that confers a major role for the epigenetic program of fly segmentation and development.

A gel-coated air-liquid-interface culture system with tunable substrate stiffness matching healthy and diseased lung tissues.

Since its invention in the late 1980s, the air-liquid-interface (ALI) culture system has been the standard in vitro model for studying human airway biology and pulmonary diseases. However, in a conventional ALI system, cells are cultured on a porous plastic membrane that is much stiffer than human airway tissues. Here, we develop a gel-ALI culture system by simply coating the plastic membrane with a thin layer of hydrogel with tunable stiffness matching that of healthy and fibrotic airway tissues. We determine the optimum gel thickness that does not impair the transport of nutrients and biomolecules essential to cell growth. We show that the gel-ALI system allows human bronchial epithelial cells (HBECs) to proliferate and differentiate into pseudostratified epithelium. Furthermore, we discover that HBECs migrate significantly faster on hydrogel substrates with stiffness matching that of fibrotic lung tissues, highlighting the importance of mechanical cues in human airway remodeling. The developed gel-ALI system provides a facile approach to studying the effects of mechanical cues in human airway biology and in modeling pulmonary diseases.NEW & NOTEWORTHY In a conventional ALI system, cells are cultured on a plastic membrane that is much stiffer than human airway tissues. We develop a gel-ALI system by coating the plastic membrane with a thin layer of hydrogel with tunable stiffness matching that of healthy and fibrotic airway tissues. We discover that human bronchial epithelial cells migrate significantly faster on hydrogel substrates with pathological stiffness, highlighting the importance of mechanical cues in human airway remodeling.

Integrating Polyoxometalates and Silver Clusters into Atomically Precise Molecular Heterojunction.

The Ag cluster-POM assemblies have been shown to possess interesting and potentially useful properties. However, there is no precedent example of atomically precise Ag cluster-POM assemblies showing heterojunction effects in photocatalysis. Herein, the synthesis and total structure determination of the periodically distributed molecular heterojunction [Ag12(SCy)6(CH3CN)12(PW12O40)]n (Ag12-PW12) are reported. The assembly of Ag/W clusters into 3D network can endow the resulting binary structure with an aesthetic topology and unique physicochemical properties. More remarkably, the incorporation of Ag12 cluster with PW12 can efficiently facilitate the separation of photogenerated electrons and holes, thus significantly promoting the catalytic efficiency in selective oxidation of sulfides. The Ag12-PW12 heterojunction can be recovered and reused five times with no drastic change in the catalytic performance. This research is expected to assist in the rational design of cluster-based heterojunction catalysts. The increase of catalytic activity of the Ag12-PW12 assembly in comparison with the unassembled Ag12 and PW12 clusters is attributed to the synergistic effect of Ag12 and PW12 clusters, offering the splendid opportunity for deciphering structure-reactivity relationship of heterostructure-coupled photosystem.

CDC167 exhibits potential as a biomarker for airway inflammation in asthma.

Current asthma treatments have been discovered to decrease the risk of disease progression. Herein, we aimed to characterize novel potential therapeutic targets for asthma. Differentially expressed genes (DEGs) for GSE64913 and GSE137268 datasets were characterized. Weighted correlation network analysis (WGCNA) was used to identify trait-related module genes within the GSE67472 dataset. The intersection of the module genes of interest, as well as the DEGs, comprised the key module genes that underwent additional candidate gene screening using machine learning. In addition, a bioinformatics-based approach was used to analyze the relative expression levels, diagnostic values, and reverently enriched pathways of the screened candidate genes. Furthermore, the candidate genes were silenced in asthmatic mice, and the inflammation and lung injury in the mice were validated. A total of 1710 DEGs were characterized in GSE64913 and GSE137268 for asthma patients. WGCNA identified 2367 asthma module genes, of which 285 overlapped with 1710 DEGs. Four candidate genes, CDC167, POSTN, SEC14L1, and SERPINB2, were validated using the intersection genes of three machine learning algorithms, including Least Absolute Shrinkage and Selection Operator, Random Forest, and Support Vector Machine. All the candidate genes were significantly upregulated in asthma patients and demonstrated diagnostic utility for asthma. Furthermore, silencing CDC167 reduced the levels of inflammatory cytokines significantly and alleviated lung injury in ovalbumin (OVA)-induced asthmatic mice. Our study demonstrated that CDC167 exhibits potential as diagnostic markers and therapeutic targets for asthma patients.

Regioselective Deacetylation in Nucleosides and Derivatives.

Nucleoside analogues are a promising class of natural compounds in the pharmaceutical industry, and many antiviral, antibacterial and anticancer drugs have been created through structural modification of nucleosides scaffold. Acyl protecting groups, especially the acetyl group, play an important role in the protection of hydroxy groups in nucleoside synthesis and modification; consequently, numerous methodologies have been put forth for the acetylation of free nucleosides. However, for nucleosides that contain different O- and N-based functionalities, selective deprotection of the acetyl group(s) in nucleosides has been studied little, despite its practical significance in simplifying the preparation of partially or differentially substituted nucleoside intermediates. In this mini-review, recent approaches for regioselective deacetylation in acetylated nucleosides and their analogues are summarized and evaluated. Different regioselectivities (primary ester, secondary ester, full de-O-acetylation, and de-N-acetylation) are summarized and discussed in each section.

DUSP5 regulated by YTHDF1-mediated m6A modification promotes epithelial-mesenchymal transition and EGFR-TKI resistance via the TGF-ß/Smad signaling pathway in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) patients have a dismal survival rate because of cancer metastasis and drug resistance. The study aims to identify the genes that concurrently modulate EMT, metastasis and EGFR-TKI resistance, and to investigate the underlying regulatory mechanisms. METHODS: Cox regression and Kaplan-Meier analyses were applied to identify prognostic oncogenes in LUAD. Gene set enrichment analysis (GSEA) was used to indicate the biological functions of the gene. Wound-healing and Transwell assays were used to detect migratory and invasive ability. EGFR-TKI sensitivity was evaluated by assessing the proliferation, clonogenic survival and metastatic capability of cancer cells with treatment with gefitinib. Methylated RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) analyses established the level of m6A modification present on the target gene and the protein's capability to interact with RNA, respectively. Single-sample gene set enrichment (ssGSEA) algorithm used to investigate levels of immune cell infiltration. RESULTS: Our study identified dual-specificity phosphatase 5 (DUSP5) as a novel and powerful predictor of adverse outcomes for LUAD by using public datasets. Functional enrichment analysis found that DUSP5 was positively enriched in EMT and transforming growth factor-beta (TGF-ß) signaling pathway, a prevailing pathway involved in the induction of EMT. As expected, DUSP5 knockdown suppressed EMT via inhibiting the canonical TGF-ß/Smad signaling pathway in in vitro experiments. Consistently, knockdown of DUSP5 was first found to inhibit migratory ability and invasiveness of LUAD cells in in vitro and prevent lung metastasis in in vivo. DUSP5 knockdown re-sensitized gefitinib-resistant LUAD cells to gefitinib, accompanying reversion of EMT progress. In LUAD tissue samples, we found 14 cytosine-phosphate-guanine (CpG) sites of DUSP5 that were negatively associated with DUSP5 gene expression. Importantly, 5'Azacytidine (AZA), an FDA-approved DNA methyltransferase inhibitor, restored DUSP5 expression. Moreover, RIP experiments confirmed that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a m6A reader protein, could bind DUSP5 mRNA. YTHDF1 promoted DUSP5 expression and the malignant phenotype of LUAD cells. In addition, the DUSP5-derived genomic model revealed the two clusters with distinguishable immune features and tumor mutational burden (TMB). CONCLUSIONS: Briefly, our study discovered DUSP5 which was regulated by epigenetic modification, might be a potential therapeutic target, especially in LUAD patients with acquired EGFR-TKI resistance.

Nucleic acid-based small molecules as targeted transcription therapeutics for immunoregulation.

Transcription therapy is an emerging approach that centers on identifying the factors associated with the malfunctioning gene transcription machinery that causes diseases and controlling them with designer agents. Until now, the primary research focus in therapeutic gene modulation has been on small-molecule drugs that target epigenetic enzymes and critical signaling pathways. However, nucleic acid-based small molecules have gained popularity in recent years for their amenability to be pre-designed and realize operative control over the dynamic transcription machinery that governs how the immune system responds to diseases. Pyrrole-imidazole polyamides (PIPs) are well-established DNA-based small-molecule gene regulators that overcome the limitations of their conventional counterparts owing to their sequence-targeted specificity, versatile regulatory efficiency, and biocompatibility. Here, we emphasize the rational design of PIPs, their functional mechanisms, and their potential as targeted transcription therapeutics for disease treatment by regulating the immune response. Furthermore, we also discuss the challenges and foresight of this approach in personalized immunotherapy in precision medicine.

Predicting personalized cumulative live birth rate after a complete in vitro fertilization cycle: an analysis of 32,306 treatment cycles in China.

BACKGROUND: The cumulative live birth rate (CLBR) has been regarded as a key measure of in vitro fertilization (IVF) success after a complete treatment cycle. Women undergoing IVF face great psychological pressure and financial burden. A predictive model to estimate CLBR is needed in clinical practice for patient counselling and shaping expectations. METHODS: This retrospective study included 32,306 complete cycles derived from 29,023 couples undergoing IVF treatment from 2014 to 2020 at a university-affiliated fertility center in China. Three predictive models of CLBR were developed based on three phases of a complete cycle: pre-treatment, post-stimulation, and post-treatment. The non-linear relationship was treated with restricted cubic splines. Subjects from 2014 to 2018 were randomly divided into a training set and a test set at a ratio of 7:3 for model derivation and internal validation, while subjects from 2019 to 2020 were used for temporal validation. RESULTS: Predictors of pre-treatment model included female age (non-linear relationship), antral follicle count (non-linear relationship), body mass index, number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, tubal factor, male factor, and scarred uterus. Predictors of post-stimulation model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. Predictors of post-treatment model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), cumulative Day-3 embryos live-birth capacity (non-linear relationship), number of previous IVF attempts, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. The C index of the three models were 0.7559, 0.7744, and 0.8270, respectively. All models were well calibrated (p = 0.687, p = 0.468, p = 0.549). In internal validation, the C index of the three models were 0.7422, 0.7722, 0.8234, respectively; and the calibration P values were all greater than 0.05. In temporal validation, the C index were 0.7430, 0.7722, 0.8234 respectively; however, the calibration P values were less than 0.05. CONCLUSIONS: This study provides three IVF models to predict CLBR according to information from different treatment stage, and these models have been converted into an online calculator ( https://h5.eheren.com/hcyc/pc/index.html#/home ). Internal validation and temporal validation verified the good discrimination of the predictive models. However, temporal validation suggested low accuracy of the predictive models, which might be attributed to time-associated amelioration of IVF practice.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Self-Assembly of Amphiphilic PDI and NDI Derivatives with Opposite Thermoresponsive Fluorescent Behaviors in Aqueous Solution.

This work presents a study of the thermally induced aggregation of perylene diimide (PDI) and naphthalene diimide (NDI) derivatives modified with oligo ethylene glycol (OEG) chains in aqueous solution. Water-soluble and flexible OEG side chains were introduced into the π-core of glutamate-modified NDI and PDI structures, and the aggregation process was modulated by heating or cooling in water. Interestingly, a rare opposite temperature response of fluorescent behavior from the two amphiphilic chromophores was revealed, in which the PDI exhibited fluorescent enhancement, while fluorescent quenching upon temperature increase was observed from the NDI assembly. The mechanism of thermally induced aggregation is clearly explained by studies with various spectroscopic techniques including UV-visible, fluorescence, 1H NMR, 2D NMR spectroscopy, and SEM observation as well as control experiments operated in DMSO solution. It is found that although similar J-aggregates were formed by both amphiphilic chromophores in aqueous solution, the temperature response of the aggregates to temperature was opposite. The degree of PDI aggregation decreased, while that of NDI increased upon temperature rising. This research paves a valuable way for understanding the complicated supramolecular behaviors of amphiphilic chromophores.

Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis.

BACKGROUND: Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome. METHODS: A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement. RESULTS: Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6-39.9%) and 5% (95% CI, 0-18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203-1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect. CONCLUSIONS: The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect. IMPACT: This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS. The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS. This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

Optimal model averaging for partially linear models with missing response variables and error-prone covariates.

We consider the problem of optimal model averaging for partially linear models when the responses are missing at random and some covariates are measured with error. A novel weight choice criterion based on the Mallows-type criterion is proposed for the weight vector to be used in the model averaging. The resulting model averaging estimator for the partially linear models is shown to be asymptotically optimal under some regularity conditions in terms of achieving the smallest possible squared loss. In addition, the existence of a local minimizing weight vector and its convergence rate to the risk-based optimal weight vector are established. Simulation studies suggest that the proposed model averaging method generally outperforms existing methods. As an illustration, the proposed method is applied to analyze an HIV-CD4 dataset.

Transformation of Metal-Organic Framework from Kinetic to Thermodynamic Product for Controlled Delivery of Vitamin C.

A biocompatible metal-organic framework (MOF), named HSTC-4, constructed using the flexible 4,4'-oxybis(benzoic acid) (OBA), was developed to enable efficient loading and controlled release of vitamin C (VC) through a combination of strategies involving ligand length, structure design, and metal selection. The kinetic product HSTC-4 demonstrates a propensity for transforming into the thermodynamically stable HSTC-5 under external stimuli, such as photoillumination and vacuum heating, as witnessed by single-crystal to single-crystal transformation. Density functional theory (DFT) calculations reveal that the VC guest molecules exhibit stronger binding affinity with HSTC-5 due to its narrower pores compared to HSTC-4, resulting in a slower release of VC from VC@HSTC-5. Furthermore, precise control over VC release can be achieved by introducing surface modifications involving SiO2 onto the structure of VC@HSCT-5, while simultaneously adjusting environmental factors such as pH and temperature conditions. Preliminary cell culture experiments and cytotoxicity assays highlight the biocompatibility of HSTC-5, suggesting that it is a promising platform for sustained drug delivery and diverse biomedical applications.

Associations of MMP9 polymorphism with the risk of severe pneumonia in a Southern Chinese children population.

BACKGROUND: Severe pneumonia frequently causes irreversible sequelae and represents a major health burden for children under the age of 5. Matrix Metallopeptidase 9 (MMP9) is a zinc-dependent endopeptidase that is involved in various cellular processes. The correlation between MMP9 and the risk of severe childhood pneumonia remains unclear. METHODS: Here we assemble a case-control cohort to study the association of genetic variants in MMP9 gene with severe childhood pneumonia susceptibility in a Southern Chinese population (1034 cases and 8426 controls). RESULTS: Our results indicate that the allele G in rs3918262 SNP was significantly associated with an increased risk of severe pneumonia. Bioinformatic analyses by expression quantitative trait loci (eQTL), RegulomeDB and FORGEdb database analysis showed that rs3918262 SNP has potential regulatory effect on translational efficiency and protein level of MMP9 gene. Furthermore, MMP9 concentrations were significantly up-regulated in the bronchoalveolar lavages (BALs) of children with severe pneumonia. CONCLUSION: In summary, our findings suggest that MMP9 is a novel predisposing gene for childhood pneumonia.

Gestational and Postpartum Exposure to PM2.5 Components and Glucose Metabolism in Chinese Women: A Prospective Cohort Study.

Pregnant women are physiologically prone to glucose intolerance, while the puerperium represents a critical phase for recovery. However, how air pollution disrupts glucose homeostasis during the gestational and early postpartum periods remains unclear. This prospective cohort study conducted an oral glucose tolerance test and measured the insulin levels of 834 pregnant women in Guangzhou, with a follow-up for 443 puerperae at 6-8 weeks postpartum. Residential PM2.5 and five chemical components were estimated by an established spatiotemporal model. The adjusted linear model showed that an IQR increase in gestational PM2.5 exposure was associated with an increase of 0.17 mmol/L (95% CI: 0.06, 0.28) in fasting plasma glucose (FPG) and 0.24 (95% CI: 0.05, 0.42) in the insulin resistance index. Postpartum PM2.5 exposure was linked to a 0.17 mmol/L (95% CI: 0.05, 0.28) elevation in FPG per IQR, with a strengthened association found in women with gestational diabetes (Pinteraction = 0.003). In the quantile-based g-computation model, NO3- consistently contributed to the combined effect of PM2.5 components on gestational and postpartum FPG. This study was the first to suggest that PM2.5 components were associated with exacerbated gestational insulin resistance and elevated postpartum FPG. Targeted interventions reducing the emissions of toxic PM2.5 components are essential to improving maternal glucose metabolism.

Gestational Exposure to PM2.5 and Specific Constituents, Meconium Metabolites, and Neonatal Neurobehavioral Development: A Cohort Study.

Exposure to fine particulate matter (PM2.5) during pregnancy has been inversely associated with neonatal neurological development. However, the associations of exposure to specific PM2.5 constituents with neonatal neurological development remain unclear. We investigated these associations and examined the mediating role of meconium metabolites in a Chinese birth cohort consisting of 294 mother-infant pairs. Our results revealed that exposure to PM2.5 and its specific constituents (i.e., organic matter, black carbon, sulfate, nitrate, and ammonium) in the second trimester, but not in the first or third trimester, was inversely associated with the total neonatal behavioral neurological assessment (NBNA) scores. The PM2.5 constituent mixture in the second trimester was also inversely associated with NBNA scores, and sulfate was identified as the largest contributor. Furthermore, meconium metabolome analysis identified four metabolites, namely, threonine, lysine, leucine, and saccharopine, that were associated with both PM2.5 constituents and NBNA scores. Threonine was identified as an important mediator, accounting for a considerable proportion (14.53-15.33%) of the observed inverse associations. Our findings suggest that maternal exposure to PM2.5 and specific constituents may adversely affect neonatal behavioral development, in which meconium metabolites may play a mediating role.

Prognostic value of virtual portal pressure gradient response in compensated cirrhotic patients treated with carvedilol.

AIM: This study aimed to assess the prognostic significance of virtual portal pressure gradient (vPPG) response to carvedilol in patients with compensated cirrhosis (CC). METHODS: Compensated cirrhosis patients with high-risk varices were prospectively enrolled to receive carvedilol for prevention of first variceal hemorrhage (VH) and followed up for 1 year. The vPPG response was defined as a reduction of vPPG >10% from baseline after 1-month therapy. Logistic and Cox regression analyses were performed to identify independent predictors for vPPG response and first decompensation, respectively. Competitive risk models were constructed to predict disease progression, and validated using the C-index, Kaplan-Meier analysis, competitive risk analysis, and calibration curves. RESULTS: A total of 129 patients completed this study, of whom 56 (43.4%) achieved vPPG response and were referred as vPPG responders. Baseline vPPG, red color sign, Model for End-stage Liver Disease score, serum monocyte chemoattractant protein-1 (MCP-1), and laminin levels significantly correlated with vPPG response, which itself was further documented as an independent predictor of VH, ascites, and overall decompensation events in CC. Moreover, the red color sign or Child-Turcotte-Pugh score effectively predicted VH, while ascites correlated well with portal flow velocity or MCP-1. The predictive models for VH and ascites showed a good discrimination with C-index values of 0.747 and 0.689 respectively, and the high consistency on calibration curves. CONCLUSION: The vPPG response could be used as a noninvasive tool for prediction of disease progression in patients with CC.

A comprehensive approach for quantifying source-specific ecological and health risks of potentially toxic elements in agricultural soil.

Given the pollution prevalence of potentially hazardous elements (PTEs) in agricultural soils worldwide, it is crucial to establish a comprehensive approach to accurately assess soil contamination, and quantitatively allocate sources and source-specific risks. In the study, soil contamination was assessed through environmental capacity based on the local geochemical baseline established using PTE contents of the subsoil. The sources of PTEs were quantified through positive matrix factorization (PMF) and GIS mapping. Ecological risk (ER) and human health risk (HHR) models based on PMF were used to evaluate source-specific ER and HHR. Taking Jieyang City as an example, obvious contamination of As, Pb, Cd, Zn and Hg was observed in agricultural soils, and 94.40% of sites had high-to-medium capacity for local PTE contamination. Four sources were apportioned including agricultural activities (17.36%), industrial activities (20.49%), natural sources (34.60%) and traffic emissions (27.55%). The study area was at moderate ER level (121.21) with industrial activities contributing the most (41.26%). The carcinogenic risks (3.21E-05 for children and 1.42E-05 for adults) were within the tolerable range, and non-carcinogenic risks (7.08E-01 for children and 7.70E-02 for adults) were not significant. Agricultural activities were the largest source to the carcinogenic (47.17% for children and 46.31% for adults) and non carcinogenic risks (53.55% for children and 53.03% for adults). Therefore, industrial activities and agricultural activities were the priority control sources to reduce ecological risk and protect human health, respectively.

A random item effects generalized partial credit model with a multiple imputation-based scoring procedure.

PURPOSE: Random item effects item response theory (IRT) models have received much attention for more than a decade. However, more research is needed on random item effects IRT models for polytomous data. Additionally, to improve the utility of this new class of IRT models, the scoring issue must be addressed. METHODS: We proposed a new random item effects generalized partial credit model (GPCM), which considers both random person and random item and category-specific effects. In addition, we introduced a multiple imputation (MI)-based scoring procedure that applies to various random item effects IRT models. To evaluate the proposed model and scoring procedure, we analyzed data from a Quality of Life (QoL) scale for the Chronically Mentally III and conducted a preliminary simulation study. RESULTS: In the empirical data analysis, we found that patient scores generated based on the proposed model and scoring procedure were almost identical to those obtained through the conventional GPCM and scoring method. However, the standard errors (SEs) associated with the scores were slightly larger when the proposed approach was utilized. In the simulation study, we observed adequate recovery of the model parameters and patient scores. CONCLUSION: The proposed model and MI-based scoring procedure contribute to the literature. The proposed model substantially reduces the number of free parameters in comparison to a conventional GPCM, which can be desired when sample sizes are small, e.g., special populations. In addition, the MI-based scoring procedure addresses the scoring issue and can be easily extended for scoring with other random item effects IRT models.

Targeting PRMT1 prevents acute and chronic graft-versus-host disease.

Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4+ T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of T helper (Th)17 cells, germinal center B cells, and plasma cells. The PRMT1 inhibitor also controlled acute GVHD (aGVHD) in mice by decreasing the percentage of Th17 cells. Moreover, inhibiting PRMT1 also weakened Th17 cell differentiation, B cell proliferation, and antibody production in cells from cGVHD patients. Additionally, further studies revealed that PRMT1 regulated B cell proliferation and antibody secretion by methylating isocitrate dehydrogenase 2 (IDH2). We observed asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 promoted IDH2 homodimerization, which enhanced IDH2 activity, further increasing B cell proliferation and antibody production. Collectively, this study provides a rationale for the application of PRMT1 inhibitors in the prevention of aGVHD and cGVHD.