Hyperpolarized 129Xe Atoms Sense the Presence of Drug Molecules in Nanohosts Revealed by Magnetic Resonance Imaging.

Assessing the effectiveness of nanomedicines involves evaluating the drug content at the target site. Currently, most research focuses on monitoring the signal responses from loaded drugs, neglecting the changes caused by the nanohosts. Here, we propose a strategy to quantitatively evaluate the content of loaded drugs by detecting the signal variations resulting from the alterations in the microenvironment of the nanohosts. Specifically, hyperpolarized (HP) 129Xe atoms are employed as probes to sense the nanohosts' environment and generate a specific magnetic resonance (MR) signal that indicates their accessibility. The introduction of drugs reduces the available space in the nanohosts, leading to a crowded microenvironment that hinders the access of the 129Xe atoms. By employing 129Xe atoms as a signal source to detect the alterations in the microenvironment, we constructed a three-dimensional (3D) map that indicated the concentration of the nanohosts and established a linear relationship to quantitatively measure the drug content within the nanohosts based on the corresponding MR signals. Using the developed strategy, we successfully quantified the uptake of the nanohosts and drugs in living cells through HP 129Xe MR imaging. Overall, the proposed HP 129Xe atom-sensing approach can be used to monitor alterations in the microenvironment of nanohosts induced by loaded drugs and provides a new perspective for the quantitative evaluation of drug presence in various nanomedicines.

Dual-Signal Chemical Exchange Saturation Transfer (Dusi-CEST): An Efficient Strategy for Visualizing Drug Delivery Monitoring in Living Cells.

We report a dual-signal chemical exchange saturation transfer (Dusi-CEST) strategy for drug delivery and detection in living cells. The two signals can be detected by operators in complex environments. This strategy is demonstrated on a cucurbit[6]uril (CB[6]) nanoparticle probe, as an example. The CB[6] probe is equipped with two kinds of hydrophobic cavities: one is found inside CB[6] itself, whereas the other exists inside the nanoparticle. When the probe is dispersed in aqueous solution as part of a hyperpolarized 129Xe NMR experiment, two signals appear at two different chemical shifts (100 and 200 ppm). These two resonances correspond to the NMR signals of 129Xe in the two different cavities. Upon loading with hydrophobic drugs, such as paclitaxel, for intracellular drug delivery, the two resonances undergo significant changes upon drug loading and cargo release, giving rise to a metric enabling the assessment of drug delivery success. The simultaneous change of Dusi-CEST likes a mobile phone that can receive both LTE and Wi-Fi signals, which can help reduce the occurrence of false positives and false negatives in complex biological environments and help improve the accuracy and sensitivity of single-shot detection.

Therapeutic drug monitoring of linezolid and exploring optimal regimens and a toxicity-related nomogram in elderly patients: a multicentre, prospective, non-interventional study.

BACKGROUND: The concentrations of linezolid, its optimal regimen and the associated side effects in elderly patients remain unclear. METHODS: In this multicentre, prospective study, elderly patients receiving linezolid at four tertiary hospitals in Beijing between May 2021 and December 2022 were included. Linezolid concentrations and haematological toxicity were monitored dynamically. Risk factors for linezolid overexposure and moderate-to-severe linezolid-induced thrombocytopenia (M/S LIT) were analysed, and a predictive model of M/S LIT was developed. RESULTS: A total of 860 linezolid concentrations were measured in 313 patients. The median trough concentrations of linezolid were 24.4 (15.3, 35.8) mg/L at 36-72 h and 26.1 (17.0, 38.1) mg/L at 5-10 days (P = 0.132). Severe linezolid exposure was independently associated with age, estimated glomerular filtration rate (eGFR) and the worst SOFA score (SOFA1), and we further recommended dose regimens for elderly patients based on these findings. The incidences of linezolid-induced thrombocytopenia(LIT) and M/S LIT were 73.5% and 47.6%, respectively. M/S LIT was independently correlated with treatment duration, average trough concentration (TDMa), baseline platelet count, eGFR and baseline SOFA score (SOFA0). The developed nomogram predicted M/S LIT with an area under the curve of 0.767 (95% CI 0.715-0.820), a sensitivity of 71.1% and a specificity of 73.2%. CONCLUSIONS: Linezolid trough concentrations increased dramatically in the elderly, by about 10 mg/L in patients aged 65-80 years, followed by a further increase of 10 mg/L for every 10 years of age. Therapeutic drug monitoring is recommended in elderly patients receiving linezolid. The developed nomogram may predict M/S LIT and guide dosage adjustments of linezolid. Clinical trial registration number: ChiCTR2100045707.

Necessity for higher teicoplanin doses in older adults: a multicenter prospective observational study in China.

BACKGROUND: Many older adult patients receive low-dose teicoplanin with varied regimens, leading to a lack of clarity on its optimal regimens and toxicity profiles in China. This study aimed to clarify these aspects by analyzing teicoplanin treatment concentrations and toxicities. METHODS: We included older adult patients administered teicoplanin at four tertiary hospitals in Beijing from June 2021 to July 2023, targeting a trough concentration (Cmin) ≥ 10 mg/L. Teicoplanin concentrations and toxicities were monitored dynamically. RESULTS: From 204 patients, we obtained 632 teicoplanin concentrations. Most patients (83.3%) received low-dose regimens. Suboptimal concentrations were found in 66.4% of patients within 7 days of treatment and 17.0% after 15 days. Cmin gradually increased with treatment duration and was influenced initially by creatinine and by both body weight and creatinine from days 8 to 14. The target concentration was achieved in 53.1%, 33.9%, 15.6%, and 5.5% of patients at 3, ≤ 7, 8-14, and ≥ 15 days after withdrawal, respectively. Slow elimination was associated with average Cmin and eGFR. Nephrotoxicity, hepatotoxicity, and thrombocytopenia occurred in 12.5%, 4.1%, and 31.5% of patients, respectively, without significant differences between concentrations. CONCLUSIONS: Most older adult patients were underdosed, indicating a need for dose adjustment. Given the varied risk factors for suboptimal concentrations in different treatment stages, a one-size-fits-all regimen was ineffective. We recommend an initial dose of 400 mg at 12-h intervals for the first three days, with subsequent doses from days 4 to 14 adjusted based on creatinine and body weight; after day 14, a maintenance dose of 200 mg daily is advised. TRIAL REGISTRATION: ChiCTR2100046811; 28/05/2021.

Suppression of long noncoding RNA SNHG6 alleviates cigarette smoke-induced lung inflammation by modulating NF-κB signaling.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a widespread inflammatory disease with a high mortality rate. Long noncoding RNAs play important roles in pulmonary diseases and are potential targets for inflammation intervention. METHODS: The expression of small nucleolar RNA host gene 6 (SNHG6) in mouse lung epithelial cell line MLE12 with or without cigarette smoke extract (CSE) treatment was first detected using quantitative reverse-transcription PCR. ELISA was used to evaluate the release of inflammatory cytokines (TNF-α, IL-1ß, and IL-6). The binding site of miR-182-5p with SNHG6 was predicted by using miRanda, which was verified by double luciferase reporter assay. RESULTS: Here, we revealed that SNHG6 was upregulated in CS-exposed MLE12 alveolar epithelial cells and lungs from COPD-model mice. SNHG6 silencing weakened CS-induced inflammation in MLE12 cells and mouse lungs. Mechanistic investigations revealed that SNHG6 could upregulate IκBα kinase through sponging the microRNA miR-182-5p, followed by activated NF-κB signaling. The suppressive effects of SNHG6 silencing on CS-induced inflammation were blocked by an miR-182-5p inhibitor. CONCLUSION: Overall, our findings suggested that SNHG6 regulates CS-induced inflammation in COPD by activating NF-κB signaling, thereby offering a novel potential target for COPD treatment.

Transcriptome analysis of drought-responsive and drought-tolerant mechanisms in maize leaves under drought stress.

Maize is a major crop essential for food and feed, but its production is threatened by various biotic and abiotic stresses. Drought is one of the most common abiotic stresses, causing severe crop yield reduction. Although several studies have been devoted to selecting drought-tolerant maize lines and detecting the drought-responsive mechanism of maize, the transcriptomic differences between drought-tolerant and drought-susceptible maize lines are still largely unknown. In our study, RNA-seq was performed on leaves of the drought-tolerant line W9706 and the drought-susceptible line B73 after drought treatment. We identified 3147 differentially expressed genes (DEGs) between these two lines. The upregulated DEGs in W9706 were enriched in specific processes, including ABA signaling, wax biosynthesis, CHO metabolism, signal transduction and brassinosteroid biosynthesis-related processes, while the downregulated DEGs were enriched in specific processes, such as stomatal movement. Altogether, transcriptomic analysis suggests that the different drought resistances were correlated with the differential expression of genes, while the drought tolerance of W9706 is due to the more rapid response to stimulus, higher water retention capacity and stable cellular environment under water deficit conditions.

Hyperpolarized Xe NMR signal advancement by metal-organic framework entrapment in aqueous solution.

We report hyperpolarized Xe signal advancement by metal-organic framework (MOF) entrapment (Hyper-SAME) in aqueous solution. The 129Xe NMR signal is drastically promoted by entrapping the Xe into the pores of MOFs. The chemical shift of entrapped 129Xe is clearly distinguishable from that of free 129Xe in water, due to the surface and pore environment of MOFs. The influences from the crystal size of MOFs and their concentration in water are studied. A zinc imidazole MOF, zeolitic imidazole framework-8 (ZIF-8), with particle size of 110 nm at a concentration of 100 mg/mL, was used to give an NMR signal with intensity four times that of free 129Xe in water. Additionally, Hyper-SAME is compatible with hyperpolarized 129Xe chemical exchange saturation transfer. The 129Xe NMR signal can be amplified further by combining the two techniques. More importantly, Hyper-SAME provides a way to make detection of hyperpolarized 129Xe in aqueous solution convenient and broadens the application area of MOFs.

Assessment of functional relevance of genes associated with local temperature variables in Arabidopsis thaliana.

How likely genetic variations associated with environment identified in silico from genome wide association study are functionally relevant to environmental adaptation has been largely unexplored experimentally. Here we analyzed top 29 genes containing polymorphisms associated with local temperature variation (minimum, mean, maximum) among 1129 natural accessions of Arabidopsis thaliana. Their loss-of-function mutants were assessed for growth and stress tolerance at five temperatures. Twenty genes were found to affect growth or tolerance at one or more of these temperatures. Significantly, genes associated with maximum temperature more likely have a detect a function at higher temperature, while genes associated with minimum temperature more likely have a function at lower temperature. In addition, gene variants are distributed more frequently at geographic locations where they apparently offer an enhanced growth or tolerance for five genes tested. Furthermore, variations in a large proportion of the in silico identified genes associated with minimum or mean-temperatures exhibited a significant association with growth phenotypes experimentally assessed at low temperature for a small set of natural accessions. This study shows a functional relevance of gene variants associated with environmental variables and supports the feasibility of the use of local temperature factors in investigating the genetic basis of temperature adaptation.

Machine learning-based radiomics for multiple primary prostate cancer biological characteristics prediction with 18F-PSMA-1007 PET: comparison among different volume segmentation thresholds.

BACKGROUND: PET-based radiomics features could predict the biological characteristics of primary prostate cancer (PCa). However, the optimal thresholds to predict the biological characteristics of PCa are unknown. This study aimed to compare the predictive power of 18F-PSMA-1007 PET radiomics features at different thresholds for predicting multiple biological characteristics. METHODS: One hundred and seventy-three PCa patients with complete preoperative 18F-PSMA-1007 PET examination and clinical data before surgery were collected. The prostate lesions' volumes of interest were semi-automatically sketched with thresholds of 30%, 40%, 50%, and 60% maximum standardized uptake value (SUVmax). The radiomics features were respectively extracted. The prediction models of Gleason score (GS), extracapsular extension (ECE), and vascular invasion (VI) were established using the support vector machine. The performance of models from different thresholding regions was assessed using receiver operating characteristic curve and confusion matrix-derived indexes. RESULTS: For predicting GS, the 50% SUVmax model showed the best predictive performance in training (AUC, 0.82 [95%CI 0.74-0.88]) and testing cohorts (AUC, 0.80 [95%CI 0.66-0.90]). For predicting ECE, the 40% SUVmax model exhibit the best predictive performance (AUC, 0.77 [95%CI 0.68-0.84] and 0.77 [95%CI 0.63-0.88]). As for VI, the 50% SUVmax model had the best predictive performance (AUC, 0.74 [95%CI 0.65-0.82] and 0.74 [95%CI 0.56-0.82]). CONCLUSION: The 18F-1007-PSMA PET-based radiomics features at 40-50% SUVmax showed the best predictive performance for multiple PCa biological characteristics evaluation. Compared to the single PSA model, radiomics features may provide additional benefits in predicting the biological characteristics of PCa.

In Vivo Nitroreductase Imaging via Fluorescence and Chemical Shift Dependent 19 F NMR.

Nitroreductase (NTR) is an important biomarker widely used to evaluate the degree of tumor hypoxia. Although a few optical methods have been reported for detecting nitroreductase at low concentration ranges, an effective strategy for nitroreductase monitoring in vivo without limits to the imaging depth is still lacking. Herein, a novel dual-mode NIR fluorescence and 19 F MRI agent, FCy7-NO2 , is proposed for imaging tumor hypoxia. We show that FCy7-NO2 serves as not only a rapid NIR fluorescence enhanced probe for monitoring and bioimaging of nitroreductase in tumors, but also a novel 19 F MR chemical shift-sensitive contrast agent for selectively detecting nitroreductase catalyzed reduction. Notably, integrating two complementary imaging technologies into FCy7-NO2 enables sensitive detection of nitroreductase in a broad concentration range without tissue-depth limit. In general, this agent has a remarkable response to nitroreductase, which provides a promising method for understanding tumor evolution and its physiological role in the hypoxic microenvironment.

Tissue-level transcriptomic responses to local and distal chilling reveal potential chilling survival mechanisms in maize.

Chilling is a major stress to plants of subtropical and tropical origins including maize (Zea mays L.). To reveal molecular mechanisms underlying chilling tolerance and survival, we investigated transcriptomic responses to chilling stress in differentiated leaves and roots as well as in crowns with meristem activity in maize. Chilling stress on shoots and roots is found to each contributes to seedling lethality in maize. Comparison of maize lines with different chilling tolerance capacities reveals that chilling survival is highly associated with upregulation of abscisic acid biosynthesis and response as well as transcriptional regulators in leaves and crowns. It is also associated with the downregulation of translation in leaves and heat response in crowns. Chilling treatment on whole or part of the plants reveals that response to distal-chilling is very distinct from, and sometimes opposite to, response to local- or whole-plant chilling in both leaves and roots, suggesting a communication between shoots and roots in environmental response. This study thus provides transcriptomic responses in leaves, roots and crowns under differential chilling stresses in maize and reveals potential chilling tolerance and survival mechanisms which lays ground for improving chilling tolerance in crop plants.

Comparative transcription analysis of resistant mutants against four different antibiotics in Pseudomonas aeruginosa.

The emergence of antibiotic resistance has severely impaired the treatment of infections caused by Pseudomonas aeruginosa. There are few studies related to comparing the antibiotics resistance mechanisms of P. aeruginosa against different antibiotics. In this study, RNA sequencing was used to investigate the differences of transcriptome between wild strain and four antibiotics resistant strains of P. aeruginosa PAO1 (polymyxin B, ciprofloxacin, doxycycline, and ceftriaxone). Compared to the wild strain, 1907, 495, 2402, and 116 differentially expressed genes (DEGs) were identified in polymyxin B, ciprofloxacin, doxycycline, and ceftriaxone resistant PAO1, respectively. After analysis of genes related to antimicrobial resistance, we found genes implicated in biofilm formation (pelB, pelC, pelD, pelE, pelF, pelG, algA, algF, and alg44) were significantly upregulated in polymyxin B-resistant PAO1, efflux pump genes (mexA, mexB, oprM) and biofilm formation genes (pslJ, pslK and pslN) were upregulated in ciprofloxacin-resistant PAO1; other efflux pump genes (mexC, mexD, oprJ) were upregulated in doxycycline-resistant PAO1; ampC were upregulated in ceftriaxone-resistant PAO1. As a consequence of antibiotic resistance, genes related to virulence factors such as type Ⅱ secretion system (lasA, lasB and piv) were significantly upregulated in polymyxin B-resistant PAO1, and type Ⅲ secretion system (exoS, exoT, exoY, exsA, exsB, exsC, exsD, pcrV, popB, popD, pscC, pscE, pscG, and pscJ) were upregulated in doxycycline-resistant PAO1. While, ampC were upregulated in ceftriaxone-resistant PAO1. In addition, variants were obtained in wild type and four antibiotics resistant PAO1. Our findings provide a comparative transcriptome analysis of antibiotic resistant mutants selected by different antibiotics, and might assist in identifying potential therapeutic strategies for P. aeruginosa infection.

Simvastatin attenuates acute lung injury by activation of A2B adenosine receptor.

To explore the protective mechanism of simvastatin in acute lung injury (ALI), the lipopolysaccharide (LPS) induced (5 mg/kg) ALI rat model was used to examine the effects of simvastatin. Following simvastatin treatment, the histopathological evaluation of lung tissues was made using hematoxylin and eosin (H&E) staining. Also, myeloperoxidase (MPO) activity and the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and IL-10 were determined by ELISA. Blood gas analyses of arterial blood samples were performed to assess the pulmonary gas exchange. Moreover, the neutrophil count and total protein content were determined in the bronchoalveolar lavage (BAL) fluid. The ratio of wet lung to dry lung (W/D) and the alveolar fluid clearance (AFC) were calculated to estimate the severity of edema. Lastly, the levels of A2BAR, CFTR, claudin4, and claudin18 were also measured by qRT-PCR and Western blotting. Simvastatin treatment, in a dose-related manner, markedly improved the lung histological injury and decreased the levels of TNF-α, IL-1ß, and increased IL-10 in LPS induced ALI. Also, pulmonary neutrophil count was alleviated. Besides, a decreased ratio of W/D lung also confirmed the simvastatin intervention. Notably, simvastatin reduced the levels of A2BAR, CFTR, and claudin18 but upregulated claudin4 in lung tissues. Additionally, treatment with PSB1115, an antagonist of A2BAR, countered the protective effect of simvastatin in ALI. Our study demonstrates that simvastatin has a protective effect against LPS-induced ALI by activating A2BAR and should be exploited as a novel therapeutic target for the treatment of ALI.

Regulation of the activity of maize glutamate dehydrogenase by ammonium and potassium.

Glutamate dehydrogenase (GDH) is an important enzyme in ammonium metabolism, the activity of which is regulated by multiple factors. In this study, we investigate the effects of ammonium and potassium on the activity of maize GDH. Our results show that both ammonium and potassium play multiple roles in regulating the activity of maize GDH, with the specific roles depending on the concentration of potassium. Together with the structural information of GDH, we propose models for the substrate inhibition of ammonium, and the elimination of substrate inhibition by potassium. These models are supported by the analysis of statistic thermodynamics. We also analyze the binding sites of ammonium and potassium on maize GDH, and the conformational changes of maize GDH. The findings provide insight into the regulation of maize GDH activity by ammonium and potassium and reveal the importance of the dose and ratio of nitrogen and potassium in crop cultivation.

The transcriptome analysis of the whole-body of the gastropod mollusk Limax flavus and screening of putative antimicrobial peptide and protein genes.

The gastropod mollusk Limax flavus, one of the most widespread pests in China, is used to treat infectious diseases in traditional Chinese medicine. However, little genomic information is available for this non-model species. In this study, the whole-body transcriptome of L. flavus was sequenced using next generation sequencing technology. A total of 6.81 Gb clean reads were obtained, which were assembled into 150,766 transcripts with 132,206 annotated unigenes. Functionally classification assigned 30,542 unigenes to 56 Gene Ontology terms, 16,745 unigenes were divided into 26 euKaryotic Ortholog Groups of proteins categories, and 13,854 unigenes were assigned to 230 Kyoto Encyclopedia of Genes and Genomes pathways. Furthermore, we identified 17,251 simple sequence repeats and several kinds of antimicrobial peptide and protein (AMPs) genes. The transcriptome data of L. flavus will provide a valuable genomic resource for further studies on this species, and the AMPs identified in L. flavus will support its medical potential.

Transcriptomic analysis reveals somatic embryogenesis-associated signaling pathways and gene expression regulation in maize (Zea mays L.).

KEY MESSAGE: Transcriptome analysis of maize embryogenic callus and somatic embryos reveals associated genes reprogramming, hormone signaling pathways and transcriptional regulation involved in somatic embryogenesis in maize. Somatic embryos are widely utilized in propagation and genetic engineering of crop plants. In our laboratory, an elite maize inbred line Y423 that could generate intact somatic embryos was obtained and applied to genetic transformation. To enhance our understanding of regulatory mechanisms during maize somatic embryogenesis, we used RNA-based sequencing (RNA-seq) to characterize the transcriptome of immature embryo (IE), embryogenic callus (EC) and somatic embryo (SE) from maize inbred line Y423. The number of differentially expressed genes (DEGs) in three pairwise comparisons (IE-vs-EC, IE-vs-SE and EC-vs-SE) was 5767, 7084 and 1065, respectively. The expression patterns of DEGs were separated into eight major clusters. Somatic embryogenesis associated genes were mainly grouped into cluster A or B with an expression trend toward up-regulation during dedifferentiation. GO annotation and KEGG pathway analysis revealed that DEGs were implicated in plant hormone signal transduction, stress response and metabolic process. Among the differentially expressed transcription factors, the most frequently represented families were associated with the common stress response or related to cell differentiation, embryogenic patterning and embryonic maturation processes. Genes include hormone response/transduction and stress response, as well as several transcription factors were discussed in this study, which may be potential candidates for further analyses regarding their roles in somatic embryogenesis. Furthermore, the temporal expression patterns of candidate genes were analyzed to reveal their roles in somatic embryogenesis. This transcriptomic data provide insights into future functional studies, which will facilitate further dissections of the molecular mechanisms that control maize somatic embryogenesis.

Engineered Paramagnetic Graphene Quantum Dots with Enhanced Relaxivity for Tumor Imaging.

Nano contrast agents (Nano CA) are nanomaterials used to increase contrast in the medical magnetic resonance imaging (MRI). However, the related relaxation mechanism of the Nano CA is not clear yet and little significant breakthrough in relaxivity enhancement has been achieved. Herein, a new hydrophilic Gd-DOTA complex functionalized with different chain length of PEG was synthesized and incorporated into graphene quantum dots (GQD) to obtain paramagnetic graphene quantum dots (PGQD). We performed a variable-temperature and variable-field intensity NMR study in aqueous solution on the water exchange and rotational dynamics of three different chain lengths of PGQD. The optimal GQD with paramagnetic chain length shows a great improvement in performance on 1H NMR relaxometric studies. In vitro results demonstrated that the relaxivity of the designed PGQD could be controlled by regulating the PEG length, and its relaxivity was ∼16 times higher than that of current commercial MRI contrast agents (e.g., Gd-DTPA), on a "per Gd" basis. The relaxivity of the Nano CA can be rationally tuned to obtain unmatched potentials in MR imaging, exemplified by preparation of the paramagnetic GQD with the enhanced T1 relaxivity. The fabricated PGQDs with suitable PEG length got the best relaxivity at 1.5 T. After intravenous injection, its feeding process by solid tumor could even be monitored by clinically used 1.5 T MRI scanners. This research will also provide an excellent platform for the design and synthesis of highly effective MR contrast agents.

Long non-coding RNA TUG1 promotes airway remodelling by suppressing the miR-145-5p/DUSP6 axis in cigarette smoke-induced COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is primarily caused by cigarette smoke (CS)-induced chronic inflammation. In this study, we investigated the function and mechanism of action of the long non-coding RNA (lncRNA) taurine-up-regulated gene 1 (TUG1) in CS-induced COPD. We found that the expression of TUG1 was significantly higher in the sputum cells and lung tissues of patients with COPD as compared to that in non-smokers, and negatively correlated with the percentage of predicted forced expiratory volume in 1 second. In addition, up-regulation of TUG1 was observed in CS-exposed mice, and knockdown of TUG1 attenuated inflammation and airway remodelling in a mouse model. Moreover, TUG1 expression was higher in CS extract (CSE)-treated human bronchial epithelial cells and lung fibroblasts, whereas inhibition of TUG1 reversed CSE-induced inflammation and collagen deposition in vitro. Mechanistically, TUG1 promoted the expression of dual-specificity phosphatase 6 (DUSP6) by sponging miR-145-5p. DUSP6 overexpression reversed TUG1 knockdown-mediated inhibition of inflammation and airway remodelling. These findings suggested an important role of TUG1 in the pathological alterations associated with CS-mediated airway remodelling in COPD. Thus, TUG1 may be a promising therapeutic target in CS-induced airway inflammation and fibroblast activation.

Free-base porphyrins as CEST MRI contrast agents with highly upfield shifted labile protons.

PURPOSE: CEST has become a preeminent technology for the rapid detection and grading of tumors, securing its widespread use in both laboratory and clinical research. However, many existing CEST MRI agents exhibit a sensitivity limitation due to small chemical shifts between their exchangeable protons and water. We propose a new group of CEST MRI agents, free-base porphyrins and chlorin, with large exchangeable proton chemical shifts from water for enhanced detection. METHODS: To test these newly identified CEST agents, we acquired a series of Z-spectra at multiple pH values and saturation field strengths to determine their CEST properties. The data were analyzed using the quantifying exchange using saturation power method to quantify exchange rates. After identifying several promising candidates, a porphyrin solution was injected into tumor-bearing mice, and MR images were acquired to assess detection feasibility in vivo. RESULTS: Based on the Z-spectra, the inner nitrogen protons in free-base porphyrins and chlorin resonate from -8 to -13.5 ppm from water, far shifted from the majority of endogenous metabolites (0-4 ppm) and Nuclear Overhauser enhancements (-1 to -3.5 ppm) and far removed from the salicylates, imidazoles, and anthranillates (5-12 ppm). The exchange rates are sufficiently slow to intermediate (500-9000 s-1 ) to allow robust detection and were sensitive to substituents on the porphyrin ring. CONCLUSION: These results highlight the capabilities of free-base porphyrins and chlorin as highly upfield CEST MRI agents and provide a new scaffold that can be integrated into a variety of diagnostic or theranostic agents for biomedical applications.

Chronic obstructive pulmonary disease in rheumatoid arthritis: a systematic review and meta-analysis.

BACKGROUND: The risk and prevalence of chronic obstructive pulmonary disease (COPD) in rheumatoid arthritis (RA) is still obscure. The current study was aimed to systematically review and meta-analyse the risk ratio (RR) and prevalence of COPD in RA. METHODS: A comprehensive systematic review was conducted based on PubMed, Web of Science and Cochrane Library from inception to April 30, 2018. The primary outcome of our study was the RR of COPD in RA patients compared with controls, and secondary was the prevalence of COPD in RA patients. Pooled effect sizes were calculated according to fixed effect model or random effects model depending on heterogeneity. RESULTS: Six and eight studies reported the RR and prevalence of COPD in RA respectively. Compared with controls, RA patients have significant increased risk of incident COPD with pooled RR 1.82 (95% CI = 1.55 to 2.10, P <  0.001). The pooled prevalence of COPD in RA patients was 6.2% (95% CI = 4.1 to 8.3%). Meta-regression identified that publication year was an independent covariate negatively associated with the RR of COPD, and smoker proportion of RA population was also positively associated with the prevalence of COPD significantly in RA patients. CONCLUSIONS: The present meta-analysis has demonstrated the significant increased risk and high prevalence of COPD in RA patients. Patients with RA had better cease tobacco use and rheumatologists should pay attention to the monitoring of COPD for the prevention and control of COPD.