Effect of bifidobacteria on intestinal injury and flora in a mouse model of ulcerative colitis

Purpose: To investigate the effect of bifidobacteria on intestinal injury and flora in a mouse model of ulcerative colitis (UC).Methods: Mouse model of UC was produced using dextran sulphate sodium (DSS). The mice were divided into seven groups, viz, reference group, MRS-L medium-negative control group, mesalaminepositive control group, high dose bifidobacteria (MIMBb75) group, middle dose MIMBb75 group and low dose MIMBb75 group. Normal mice were used as control. All mice were sacrificed at day 7 of treatment, and colon length, hemoglobin concentration and intestinal flora were determined.Results: Bifidobacteria inhibited UC-induced decreases in mice hemoglobin and UC-induced colon shortening. In addition, it augmented the diversity of intestinal flora and increased the number of bacteroides and Clostridium leptum.Conclusion: Bifidobacteria plays a therapeutic role in UC via regulation of intestinal microflora.Keywords: Bifidobacteria, MIMBb75, Ulcerative colitis, Intestinal injury, Intestinal flor

Reduction of the HIV Protease Inhibitor-Induced ER Stress and Inflammatory Response by Raltegravir in Macrophages

Background HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages. Methodology and Principal Findings In this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages. Conclusion and Significance Raltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART

Impaired bidirectional communication between interneurons and oligodendrocyte precursor cells affects social cognitive behavior

Cortical neural circuits are complex but very precise networks of balanced excitation and inhibition. Yet, the molecular and cellular mechanisms that form the balance are just beginning to emerge. Here, using conditional γ-aminobutyric acid receptor B1- deficient mice we identify a γ-aminobutyric acid/tumor necrosis factor superfamily member 12-mediated bidirectional communication pathway between parvalbumin-positive fast spiking interneurons and oligodendrocyte precursor cells that determines the density and function of interneurons in the developing medial prefrontal cortex. Interruption of the GABAergic signaling to oligodendrocyte precursor cells results in reduced myelination and hypoactivity of interneurons, strong changes of cortical network activities and impaired social cognitive behavior. In conclusion, glial transmitter receptors are pivotal elements in finetuning distinct brain functions

Risk Factors and Medico-Economic Effect of Pancreatic Fistula after Pancreaticoduodenectomy

The study aimed to uncover the risk factors for the new defined pancreatic fistula (PF) and clinical related PF (CR-PF) after pancreaticoduodenectomy (PD) surgery and to evaluate the medico-economic effect of patients. A total of 412 patients were classified into two groups according to different criteria, PF and NOPF according to PF occurrence: CR-PF (grades B and C) and NOCR-PF (grade A) based on PF severity. A total of 28 factors were evaluated by univariate and multivariate logistic regression test. Hospital charges and stays of these patients were assessed. The results showed that more hospital stages and charges are needed for patients in PF and CR-PF groups than in NOPF and NOCR-PF groups (P<0.05). The excessive drinking, soft remnant pancreas, preoperative albumin, and intraoperative blood transfusion are risk factors affecting both PF and CR-PF incidence. More professional surgeons can effectively reduce the PF and CR-PF incidence. Patients with PF and CR-PF need more hospital costs and stages than that in NOPF and NOCR-PF groups. It is critical that surgeons know the risk factors related to PF and CR-PF so as to take corresponding therapeutic regimens for each patient

Profiling of mismatch discrimination in RNAi enabled rational design of allele-specific siRNAs

Silencing specificity is a critical issue in the therapeutic applications of siRNA, particularly in the treatment of single nucleotide polymorphism (SNP) diseases where discrimination against single nucleotide variation is demanded. However, no generally applicable guidelines are available for the design of such allele-specific siRNAs. In this paper, the issue was approached by using a reporter-based assay. With a panel of 20 siRNAs and 240 variously mismatched target reporters, we first demonstrated that the mismatches were discriminated in a position-dependent order, which was however independent of their sequence contexts using position 4th, 12th and 17th as examples. A general model was further built for mismatch discrimination at all positions using 230 additional reporter constructs specifically designed to contain mismatches distributed evenly along the target regions of different siRNAs. This model was successfully employed to design allele-specific siRNAs targeting disease-causing mutations of PIK3CA gene at two SNP sites. Furthermore, conformational distortion of siRNA-target duplex was observed to correlate with the compromise of gene silencing. In summary, these findings could dramatically simplify the design of allele-specific siRNAs and might also provide guide to increase the specificity of therapeutic siRNAs

Human Cataract Mutations in EPHA2 SAM Domain Alter Receptor Stability and Function

The cellular and molecular mechanisms underlying the pathogenesis of cataracts leading to visual impairment remain poorly understood. In recent studies, several mutations in the cytoplasmic sterile-α-motif (SAM) domain of human EPHA2 on chromosome 1p36 have been associated with hereditary cataracts in several families. Here, we have investigated how these SAM domain mutations affect EPHA2 activity. We showed that the SAM domain mutations dramatically destabilized the EPHA2 protein in a proteasome-dependent pathway, as evidenced by the increase of EPHA2 receptor levels in the presence of the proteasome inhibitor MG132. In addition, the expression of wild-type EPHA2 promoted the migration of the mouse lens epithelial αTN4-1 cells in the absence of ligand stimulation, whereas the mutants exhibited significantly reduced activity. In contrast, stimulation of EPHA2 with its ligand ephrin-A5 eradicates the enhancement of cell migration accompanied by Akt activation. Taken together, our studies suggest that the SAM domain of the EPHA2 protein plays critical roles in enhancing the stability of EPHA2 by modulating the proteasome-dependent process. Furthermore, activation of Akt switches EPHA2 from promoting to inhibiting cell migration upon ephrin-A5 binding. Our results provide the first report of multiple EPHA2 cataract mutations contributing to the destabilization of the receptor and causing the loss of cell migration activity

Bioinformatic Analysis Identifies Three Potentially Key Differentially Expressed Genes in Peripheral Blood Mononuclear Cells of Patients with Takayasu’s Arteritis

Objective This study aimed to identify several potentially key genes associated with the pathogenesis of Takayasu’s arteritis (TA). This identification may lead to a deeper mechanistic understanding of TA etiology and pave the way for potential therapeutic approaches. Materials and Methods In this experimental study, the microarray dataset GSE33910, which includes expression data for peripheral blood mononuclear cell (PBMC) samples isolated from TA patients and normal volunteers, was downloaded from the publicly accessible Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified in PBMCs of TA patients compared with normal controls. Gene ontology (GO) enrichment analysis of DEGs and analysis of protein-protein interaction (PPI) network were carried out. Several hub proteins were extracted from the PPI network based on node degrees and random walk algorithm. Additionally, transcription factors (TFs) were predicted and the corresponding regulatory network was constructed. Results A total of 932 DEGs (372 up- and 560 down-regulated genes) were identified in PBMCs from TA patients. Interestingly, up-regulated and down-regulated genes were involved in different GO terms and pathways. A PPI network of proteins encoded by DEGs was constructed and RHOA, FOS, EGR1, and GNB1 were considered to be hub proteins with both higher random walk score and node degree. A total of 13 TFs were predicted to be differentially expressed. A total of 49 DEGs had been reported to be associated with TA in the Comparative Toxicogenomics Database (CTD). The only TA marker gene in the CTD database was NOS2, confirmed by three studies. However, NOS2 was not significantly altered in the analyzed microarray dataset. Nevertheless,NOS3 was a significantly down-regulated gene and was involved in the platelet activation pathway. Conclusion RHOA, FOS, and EGR1 are potential candidate genes for the diagnosis and therapy of TA

Integrated control of braking-yaw-roll stability under steering-braking conditions

Abstract Sharp steering-braking at a high speed exposes sport utility vehicles with high gravity centers and narrow wheel tracks to the risks of tire locking, sideslip and rollover. To avoid these risks and ensure braking safety, yaw stability and roll stability upon steering-braking, a braking-yaw-roll stability integrated control strategy was proposed, which consists of a supervisor, an upper and a lower controller for the front and rear axle independent drive electric vehicle. In the supervisor, a nonlinear vehicle predictive model was constructed and four control modes were proposed according to the vehicle status and rollover indexes. The weight coefficients between braking force, yaw stability and roll stability are determined dynamically by the control mode and output to the upper controller. The upper controller used a nonlinear model predictive control to determine the longitudinal braking force distribution of the four wheels. And in the lower controller, the regenerative braking torque and friction braking torque of each wheel were distributed. Finally, simulation verifications were carried out on the high and low adhesion roads. The results show that the control strategy proposed in this study can effectively prevent the vehicle from rollover while ensuring braking safety and yaw stability

Total Variation Regularized Low-Rank Model With Directional Information for Hyperspectral Image Restoration

Hyperspectral images (HSIs) are unavoidably polluted by various kinds of noise, which decrease the potential of subsequent processes in HSIs applications. Due to the diversity and complexity of HSIs mixed noise, including impulse noise, Gaussian noise, stripe noise and deadlines, traditional restoration technology cannot be used directly. In this paper, a novel HSIs restoration approach is proposed that integrates low-rank (LR) prior and spatial-spectral total variation with directional information. Specifically, by analyzing the characteristic of spatial-dependent edge and texture directional structure, a spatial-spectral directional total variation (SSDTV) regularization is defined. Then, considering the HSIs as a cube data, the proposed method utilizes SSDTV regularization to characterize spatial-spectral smoothness, as well as LR regularization to constrain spectral consistency. Finally, an extended alternating direction method of multipliers algorithm is designed to achieve simple and fast implementation, in which the complex optimization problem is separated into several easier subproblems. Both simulated and real-world HSIs experiments indicated that the proposed method is effective and numerically feasible for HSIs Restoration