3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival

Copyright © 2011 Association for Research in Vision and Ophthalmology. This article is available open access through the publisher’s website at the link below.Purpose. IDO (indoleamine 2,3-dioxygenase) modulates the immune response by depletion of the essential amino acid tryptophan, and IDO overexpression has been shown to prolong corneal allograft survival. This study was conducted to examine the effect of kynurenines, the products of tryptophan breakdown and known to act directly on T lymphocytes, on corneal graft survival. Methods. The effects of kynurenines on T-cell proliferation and death, T-regulatory-cell development, and dendritic cell function, phenotype, and viability were analyzed in vitro. The effect of topical and systemic administration of 3-hydroxykynurenine (3HK) on orthotopic murine corneal allograft survival was examined. Results. T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3HK and 3-hydroxyanthranilic acid (3HAA). This effect was accompanied by significant T-cell death. Neither 3HK nor 3HAA altered dendritic cell function, nor did they induce apoptosis or pathogenicity to corneal endothelial cells. Administration of systemic and topical 3HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of control grafts, 12 days; of treated, 19 and 15 days, respectively; P < 0.0003). While systemic administration of 3HK was associated with a significant depletion of CD4+ T, CD8+ T, and B lymphocytes in peripheral blood, no depletion was found after topical administration. Conclusions. The production of kynurenines, in particular 3HK and 3HAA, may be one mechanism (in addition to tryptophan depletion) by which IDO prolongs graft survival. These molecules have potential as specific agents for preventing allograft rejection in patients at high rejection risk.Fight for Sight and the Wellcome Trust

Suppression of MHC class I surface expression by calreticulin's P-domain in a calreticulin deficient cell line

AbstractCalreticulin (CRT) is an important chaperone protein, comprising an N-domain, P-domain and C-domain. It is involved in the folding and assembly of multi-component protein complexes in the endoplasmic reticulum, and plays a critical role in MHC class I antigen processing and presentation. To dissect the functional role and molecular basis of individual domains of the protein, we have utilized individual domains to rescue impaired protein assembly in a CRT deficient cell line. Unexpectedly, both P-domain fragment and NP domain of CRT not only failed to rescue defective cell surface expression of MHC class I molecules but further inhibited their appearance on the surface of cells. Formation of the TAP-associated peptide-loading complex and trafficking of the few detectable MHC class I molecules were not significantly impaired. Instead, this further suppression of MHC class I molecules on the cell surface appears due to the complex missing antigenic peptides, the third member of fully assembled MHC class I molecules. Therefore the P-domain of calreticulin appears to play a significant role in antigen presentation by MHC class I molecules

Discovering medication patterns for high-complexity drug-using diseases through electronic medical records

An Electronic Medical Record (EMR) is a professional document that contains all data generated during the treatment process. The EMR can utilize various data formats, such as numerical data, text, and images. Mining the information and knowledge hidden in the huge amount of EMR data is an essential requirement for clinical decision support, such as clinical pathway formulation and evidence-based medical research. In this paper, we propose a machine-learning-based framework to mine the hidden medication patterns in EMR text. The framework systematically integrates the Jaccard similarity evaluation, spectral clustering, the modified Latent Dirichlet Allocation and cross-matching among multiple features to find the residuals that describe additional knowledge and clusters hidden in multiple perspectives of highly complex medication patterns. These methods work together, step by step to reveal the underlying medication pattern. We evaluated the method by using real data from EMR text (patients with cirrhotic ascites) from a large hospital in China. The proposed framework outperforms other approaches for medication pattern discovery, especially for this disease with subtle medication treatment variances. The results also revealed little overlap among the discovered patterns; thus, the distinct features of each pattern are well studied through the proposed framework

Highly Efficient Decomposition of Perfluorocarbons for over 1000 Hours via Active Site Regeneration

Tetrafluoromethane (CF4), the simplest perfluorocarbon (PFC), has the potential to exacerbate global warming. Catalytic hydrolysis is a viable method to degrade CF4, but fluorine poisoning severely restricts both the catalytic performance and catalyst lifetime. In this study, Ga is introduced to effectively assists the defluorination of poisoned Al active sites, leading to highly efficient CF4 decomposition at 600 °C with a catalytic lifetime exceeding 1,000 hours. 27Al and 71Ga magic-angle spinning nuclear magnetic resonance spectroscopy (MAS NMR) showed that the introduced Ga exists as tetracoordinated Ga sites (GaIV), which readily dissociate water to form Ga−OH. In situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and density function theory (DFT) calculations confirmed that Ga−OH assists the defluorination of poisoned Al active sites via a dehydration-like process. As a result, the Ga/Al2O3 catalyst achieved 100 % CF4 decomposition keeping an ultra-long catalytic lifetime and outperforming reported results. This work proposes a new approach for efficient and long-term CF4 decomposition by promoting the regeneration of active sites

MALAT1 Activates the P53 Signaling Pathway by Regulating MDM2 to Promote Ischemic Stroke

Background/Aims: This study focused on evaluating the effect of MALAT1 and MDM2 on ischemic stroke through regulation of the p53 signaling pathway. Materials: Bioinformatics analysis was performed to identify abnormally expressed lncRNAs, mRNAs and their associated pathways. Oxygen-glucose deprivation/reoxygenation (OGD/R) in cells and middle cerebral artery occlusion/reperfusion (MCAO/R) in mice were performed to simulate an ischemic stroke environment. Western blot and qRT-PCR were used to examine lncRNA expression and mRNA levels. Fluorescence in situ hybridization (FISH) LncRNA was used to locate mRNA. MTT and flow cytometry were performed to examine cell proliferation and apoptosis. Finally, immunohistochemistry was used to observe the expression of genes in vivo. Results: MALAT1 and MDM2, which exhibit strong expression in stroke tissues, were subjected to bioinformatics analysis, and the p53 pathway was chosen for further study. MALAT1, MDM2 and p53 signaling pathway-related proteins were all up regulated in OGD/R cells. Furthermore, Malat1, Mdm2 and p53 pathway related-proteins were also up regulated in MCAO/R mice. Both MALAT1 and MDM2 were localized in the nuclei. Down regulation of MALAT1 and MDM2 enhanced cell proliferation ability and reduced apoptosis, resulting in decreased infarct size in MCAO/R brains. Conclusion: These results indicate that MALAT1/MDM2/p53 signaling pathway axis may provide more effective clinical therapeutic strategy for patients with ischemic stroke

Association between pelvic floor muscle strength and sexual function based on PISQ-12—an analysis of data from a multicenter cross-sectional study on 735 nulliparae during pregnancy

BackgroundPelvic floor muscle strength is well-known to be associated with female sexual function. However, there were a few studies that reported on the relationship between pelvic floor muscle strength and female sexual function in pregnant women, and the presented results were inconsistent. Nulliparae represent a specific cohort with simplicity to exclude confounding factors that are caused by parity. The present study aimed to explore the association of pelvic floor muscle strength and sexual function based on the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) of nulliparae during pregnancy.MethodsThis is the second analysis of the baseline data from a randomized controlled trial (RCT), which aimed to study the protective efficacy of pelvic floor muscle training on stress urinary incontinence at 6th week postpartum (registration number: ChiCTR2000029618). Nulliparae aged 20–40 years with singleton pregnancy before 16 weeks of gestation were enrolled in this study, and data, including participants' demographic information, the Modified Oxford Scale (MOS), and PISQ-12, were collected. Eligible nulliparae were divided into two groups: Group MOS &gt; 3 and Group MOS ≤ 3. Demographic information of the two groups was compared. Sexual function based on the PISQ-12 scores of the two groups was compared. A comparison of the PISQ-12 scores between the two groups was calculated by the Mann–Whitney U-test using SPSS version 23.0.ResultsA total of 735 eligible nulliparae were enrolled in this study. Along with MOS grading up, PISQ-12 scores tended to get lower. Of the 735 nulliparae, there were 378 and 357 participants included in Group MOS &gt; 3 and Group MOS ≤ 3, respectively. The PISQ-12 scores of Group MOS &gt; 3 were significantly lower than those of Group MOS ≤ 3 (11 vs. 12, p &lt; 0.001). The scores of the frequency of feeling sexual desire, orgasm achievement, sexual excitement, sexual activity satisfaction, sexual intercourse pain, fear of urinary incontinence, and negative emotion reactions with the sexual intercourse of Group MOS &gt; 3 were lower than those of Group MOS ≤ 3 (p &lt; 0.05).ConclusionPelvic floor muscle strength was positively associated with sexual function based on the questionnaire of young nulliparae during their first trimester. Up to half of the nulliparae during the first trimester were suffering from weak pelvic floor muscle strength and nearly a quarter of the nulliparae were facing this weakness combined with sexual dysfunction.Trial registrationThis study has been registered at http://www.chictr.org.cn (registration number: ChiCTR2000029618)

Probiotics improve symptoms of patients with COVID-19 through gut-lung axis: a systematic review and meta-analysis

BackgroundMulti system symptoms such as gastrointestinal tract and respiratory tract exist in coronavirus disease 2019 (COVID-19) patients. There is a lack of reliable evidence to prove that probiotics are effective in improving these symptoms. In this study, we aimed to evaluate the efficacy of probiotics in meta-analysis.MethodsWe systematically searched PubMed, Embase, Web of Science, and Cochrane Library up to February 15, 2023. Randomized controlled trials or high quality retrospective studies comparing the efficacy of probiotics as supplementation with non-probiotics in improving symptoms for patients with COVID-19 were included. This meta-analysis assessed endpoints using Review Manager 5.3.ResultTen citations comprising 1198 patients with COVID-19 were included. The results showed that probiotics could increase the number of people with overall symptom improvement (RR = 1.62, 95% CI [1.10, 2.38], P = 0.01) and shorten the duration (days) of overall symptoms (MD = −1.26, 95% CI [−2.36, −0.16], P = 0.02). For the duration (days) of specific symptoms, probiotics could improve diarrhea (MD = −2.12, 95% CI [−2.41, −1.83], P &lt; 0.00001), cough (MD = −2.21, 95% CI [-4.56, 0.13], P = 0.06) and shortness of breath (MD = −1.37, 95% CI [-2.22, −0.53], P = 0.001). Probiotics had no obvious effect on fever, headache and weakness. For inflammation, probiotics could effectively reduce C-reactive Protein (CRP) serum level (mg/L) (MD = −4.03, 95% CI [−5.12, −2.93], P &lt; 0.00001). Regarding hospital stay (days), probiotics group was shorter than non-probiotics group (MD = −0.98, 95% CI [−1.95, −0.01], P = 0.05).ConclusionTo some extent probiotics could improve the overall symptoms, inflammatory reaction and shorten hospital stay of patients with COVID-19. Probiotics may improve gastrointestinal symptoms (such as improving intestinal flora and reducing the duration of diarrhea) and further improve respiratory symptoms through the gut-lung axis.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=398309, identifier: CRD42023398309

OsOLP1 contributes to drought tolerance in rice by regulating ABA biosynthesis and lignin accumulation

Rice, as a major staple crop, employs multiple strategies to enhance drought tolerance and subsequently increase yield. Osmotin-like proteins have been shown to promote plant resistance to biotic and abiotic stress. However, the drought resistance mechanism of osmotin-like proteins in rice remains unclear. This study identified a novel osmotin-like protein, OsOLP1, that conforms to the structure and characteristics of the osmotin family and is induced by drought and NaCl stress. CRISPR/Cas9-mediated gene editing and overexpression lines were used to investigate the impact of OsOLP1 on drought tolerance in rice. Compared to wild-type plants, transgenic rice plants overexpressing OsOLP1 showed high drought tolerance with leaf water content of up to 65%, and a survival rate of 53.1% by regulating 96% stomatal closure and more than 2.5-fold proline content promotion through the accumulation of 1.5-fold endogenous ABA, and enhancing about 50% lignin synthesis. However, OsOLP1 knockout lines showed severely reduced ABA content, decreased lignin deposition, and weakened drought tolerance. In conclusion, the finding confirmed that OsOLP1 drought-stress modulation relies on ABA accumulation, stomatal regulation, proline, and lignin accumulation. These results provide new insights into our perspective on rice drought tolerance