Y27, a novel derivative of 4-hydroxyquinoline-3-formamide, prevents the development of murine systemic lupus erythematosus-like diseases in MRL/lpr autoimmune mice and BDF1 hybrid mice

INTRODUCTION: Naturally occurring CD4(+)CD25(+ )regulatory T (Treg) cells are central to the maintenance of peripheral tolerance. Impaired activity and/or a lower frequency of these cells lead to systemic lupus erythematosus (SLE). Manipulating the number or activity of Treg cells is to be a promising strategy in treating it and other autoimmune diseases. We have examined the effects of Y27, a novel derivative of 4-hydroxyquinoline-3-formamide, on SLE-like symptoms in MRL/lpr autoimmune mice and BDF1 hybrid mice. Whether the beneficial effect of Y27 involves modulation of CD4(+)CD25(+ )Treg cells has also been investigated. METHODS: Female MRL/lpr mice that spontaneously develop lupus were treated orally by gavage with Y27 for 10 weeks, starting at 10 weeks of age. BDF1 mice developed a chronic graft-versus-host disease (GVHD) by two weekly intravenous injections of parental female DBA/2 splenic lymphocytes, characterized by immunocomplex-mediated glomerulonephritis resembling SLE. Y27 was administered to chronic GVHD mice for 12 weeks. Nephritic symptoms were monitored and the percentage of CD4(+)CD25(+)FoxP3(+ )Treg peripheral blood leukocyte was detected with mouse regulatory T cell staining kit by flowcytometry. Purified CD4(+)CD25(+ )Tregs were assessed for immune suppressive activity using the mixed lymphocyte reaction. RESULTS: The life-span of MRL/lpr mice treated with Y27 for 10 weeks was significantly prolonged, proteinuria and renal lesion severity were ameliorated, and blood urea nitrogen, triglyceride and serum anti-double-stranded DNA antibodies were decreased. Similar results were found in chronic GVHD mice. Administration of Y27 had little impact on percentage of the peripheral blood lymphocyte CD4(+)CD25(+)Foxp3(+ )Treg cells in both groups of mice. In contrast, the suppressive capacity of CD4(+)CD25(+ )Treg cells in splenocytes was markedly augmented in Y27-treated mice ex vivo. CONCLUSIONS: Experimental evidence of the protect effects of Y27 against autoimmune nephritis has been shown. The mechanism may involve enhancement of the suppressive capacity of CD4(+)CD25(+ )Treg cells

MAPK-dependent hormonal signaling plasticity contributes to overcoming Bacillus thuringiensis toxin action in an insect host

The arms race between entomopathogenic bacteria and their insect hosts is an excellent model for decoding the intricate coevolutionary processes of host-pathogen interaction. Here, we demonstrate that the MAPK signaling pathway is a general switch to trans-regulate differential expression of aminopeptidase N and other midgut genes in an insect host, diamondback moth (Plutella xylostella), thereby countering the virulence effect of Bacillus thuringiensis (Bt) toxins. Moreover, the MAPK cascade is activated and fine-tuned by the crosstalk between two major insect hormones, 20-hydroxyecdysone (20E) and juvenile hormone (JH) to elicit an important physiological response (i.e. Bt resistance) without incurring the significant fitness costs often associated with pathogen resistance. Hormones are well known to orchestrate physiological trade-offs in a wide variety of organisms, and our work decodes a hitherto undescribed function of these classic hormones and suggests that hormonal signaling plasticity is a general cross-kingdom strategy to fend off pathogens

CloudBrain-MRS: An Intelligent Cloud Computing Platform for in vivo Magnetic Resonance Spectroscopy Preprocessing, Quantification, and Analysis

Magnetic resonance spectroscopy (MRS) is an important clinical imaging method for diagnosis of diseases. MRS spectrum is used to observe the signal intensity of metabolites or further infer their concentrations. Although the magnetic resonance vendors commonly provide basic functions of spectra plots and metabolite quantification, the widespread clinical research of MRS is still limited due to the lack of easy-to-use processing software or platform. To address this issue, we have developed CloudBrain-MRS, a cloud-based online platform that provides powerful hardware and advanced algorithms. The platform can be accessed simply through a web browser, without the need of any program installation on the user side. CloudBrain-MRS also integrates the classic LCModel and advanced artificial intelligence algorithms and supports batch preprocessing, quantification, and analysis of MRS data from different vendors. Additionally, the platform offers useful functions: 1) Automatically statistical analysis to find biomarkers for diseases; 2) Consistency verification between the classic and artificial intelligence quantification algorithms; 3) Colorful three-dimensional visualization for easy observation of individual metabolite spectrum. Last, both healthy and mild cognitive impairment patient data are used to demonstrate the functions of the platform. To the best of our knowledge, this is the first cloud computing platform for in vivo MRS with artificial intelligence processing. We have shared our cloud platform at MRSHub, providing free access and service for two years. Please visit https://mrshub.org/software_all/#CloudBrain-MRS or https://csrc.xmu.edu.cn/CloudBrain.html.Comment: 11 pages, 12 figure

Metabolomic profiles of bovine mammary epithelial cells stimulated by lipopolysaccharide

Bovine mammary epithelial cells (bMECs) are the main cells of the dairy cow mammary gland. In addition to their role in milk production, they are effector cells of mammary immunity. However, there is little information about changes in metabolites of bMECs when stimulated by lipopolysaccharide (LPS). This study describes a metabolomics analysis of the LPS-stimulated bMECs to provide a basis for the identification of potential diagnostic screening biomarkers and possible treatments for bovine mammary gland inflammation. In the present study, bMECs were challenged with 500 ng/mL LPS and samples were taken at 0 h, 12 h and 24 h post stimulation. Metabolic changes were investigated using high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF MS) with univariate and multivariate statistical analyses. Clustering and metabolic pathway changes were established by MetaboAnalyst. Sixty-three differential metabolites were identified, including glycerophosphocholine, glycerol-3-phosphate, L-carnitine, L-aspartate, glutathione, prostaglandin G2, α-linolenic acid and linoleic acid. They were mainly involved in eight pathways, including D-glutamine and D-glutamic acid metabolism; linoleic acid metabolism; α-linolenic metabolism; and phospholipid metabolism. The results suggest that bMECs are able to regulate pro-inflammatory, anti-inflammatory, antioxidation and energy-producing related metabolites through lipid, antioxidation and energy metabolism in response to inflammatory stimuli

One for Multiple: Physics-informed Synthetic Data Boosts Generalizable Deep Learning for Fast MRI Reconstruction

Magnetic resonance imaging (MRI) is a principal radiological modality that provides radiation-free, abundant, and diverse information about the whole human body for medical diagnosis, but suffers from prolonged scan time. The scan time can be significantly reduced through k-space undersampling but the introduced artifacts need to be removed in image reconstruction. Although deep learning (DL) has emerged as a powerful tool for image reconstruction in fast MRI, its potential in multiple imaging scenarios remains largely untapped. This is because not only collecting large-scale and diverse realistic training data is generally costly and privacy-restricted, but also existing DL methods are hard to handle the practically inevitable mismatch between training and target data. Here, we present a Physics-Informed Synthetic data learning framework for Fast MRI, called PISF, which is the first to enable generalizable DL for multi-scenario MRI reconstruction using solely one trained model. For a 2D image, the reconstruction is separated into many 1D basic problems and starts with the 1D data synthesis, to facilitate generalization. We demonstrate that training DL models on synthetic data, integrated with enhanced learning techniques, can achieve comparable or even better in vivo MRI reconstruction compared to models trained on a matched realistic dataset, reducing the demand for real-world MRI data by up to 96%. Moreover, our PISF shows impressive generalizability in multi-vendor multi-center imaging. Its excellent adaptability to patients has been verified through 10 experienced doctors' evaluations. PISF provides a feasible and cost-effective way to markedly boost the widespread usage of DL in various fast MRI applications, while freeing from the intractable ethical and practical considerations of in vivo human data acquisitions.Comment: 22 pages, 9 figures, 1 tabl

MAPK-activated transcription factor PxJun suppresses PxABCB1 expression and confers resistance to Bacillus thuringiensis Cry1Ac toxin in Plutella xylostella (L.)

Deciphering the molecular mechanisms underlying insect resistance to Cry toxins produced by Bacillus thuringiensis (Bt) is pivotal for the sustainable utilization of Bt biopesticides and transgenic Bt crops. Previously, we identified that MAPK-mediated reduced expression of the PxABCB1 gene is associated with Bt Cry1Ac resistance in the diamondback moth, Plutella xylostella (L.). However, the underlying transcriptional regulation mechanism remains enigmatic. Herein, the PxABCB1 promoter in Cry1Ac-susceptible and Cry1Ac-resistant P. xylostella strains was cloned and analyzed and found to contain a putative Jun binding site (JBS). A dual-luciferase reporter assay and yeast one-hybrid assay (Y1H) demonstrated that the transcription factor PxJun repressed PxABCB1 expression by interacting with this JBS. The expression levels of PxJun were increased in the midguts of all resistant strains compared to the susceptible strain. Silencing of PxJun expression significantly elevated PxABCB1 expression and Cry1Ac susceptibility in the resistant NIL-R strain, and silencing of PxMAP4K4 expression decreased PxJun expression and also increased PxABCB1 expression. These results indicate that MAPK-activated PxJun suppresses PxABCB1 expression to confer Cry1Ac resistance in P. xylostella, deepening our understanding of the transcriptional regulation of midgut Cry receptor genes and the molecular basis of insect resistance to Bt Cry toxins.ImportanceThe transcriptional regulation mechanisms underlying reduced expression of Bt toxin receptor genes in Bt-resistant insects remain elusive. This study unveils that a transcription factor PxJun activated by the MAPK signaling pathway represses PxABCB1 expression and confers Cry1Ac resistance in P. xylostella Our results provide new insights into the transcriptional regulation mechanisms of midgut Cry receptor genes and deepen our understanding of the molecular basis of insect resistance to Bt Cry toxins. To our knowledge, this study identified the first transcription factor that can be involved in the transcriptional regulation mechanisms of midgut Cry receptor genes in Bt-resistant insects

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data