The proinflammatory cytokines IL-1β and TNF-α induce the expression of Synoviolin, an E3 ubiquitin ligase, in mouse synovial fibroblasts via the Erk1/2-ETS1 pathway

The overgrowth of synovial tissues is critical in the pathogenesis of rheumatoid arthritis (RA). The expression of Synoviolin (SYN), an E3 ubiquitin ligase, is upregulated in arthritic synovial fibroblasts and is involved in the overgrowth of synovial cells during RA. However, the molecular mechanisms involved in the elevated SYN expression are not known. Here, we found that SYN expression is elevated in the synovial fibroblasts from mice with collagen-induced arthritis (CIA). The proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) induce SYN expression in mouse synovial fibroblasts. Cultivation of mouse synovial fibroblasts with IL-1β activates mitogen-activated protein kinases, including extra-cellular signal-regulated kinase (Erk), JNK (c-Jun N-terminal kinase), and p38, while only Erk-specific inhibitor blocks IL-1β-induced SYN expression. Expression of transcription factor ETS1 further enhances IL-1β-induced SYN expression. The dominant negative ETS1 mutant lacking the transcription activation domain inhibits SYN expression in a dose-dependent manner. The activation of both Erk1/2 and ETS1 is increased in the CIA synovial fibroblasts. Inhibition of Erk activation reduces ETS1 phosphorylation and SYN expression. Our data indicate that the proinflammatory cytokines IL-1β and TNF-α induce the overgrowth of synovial cells by upregulating SYN expression via the Erk1/-ETS1 pathway. These molecules or pathways could therefore be potential targets for the treatment of RA

Learning prediction function of prior measures for statistical inverse problems of partial differential equations

In this paper, we view the statistical inverse problems of partial differential equations (PDEs) as PDE-constrained regression and focus on learning the prediction function of the prior probability measures. From this perspective, we propose general generalization bounds for learning infinite-dimensionally defined prior measures in the style of the probability approximately correct Bayesian learning theory. The theoretical framework is rigorously defined on infinite-dimensional separable function space, which makes the theories intimately connected to the usual infinite-dimensional Bayesian inverse approach. Inspired by the concept of $\alpha$-differential privacy, a generalized condition (containing the usual Gaussian measures employed widely in the statistical inverse problems of PDEs) has been proposed, which allows the learned prior measures to depend on the measured data (the prediction function with measured data as input and the prior measure as output can be introduced). After illustrating the general theories, the specific settings of linear and nonlinear problems have been given and can be easily casted into our general theories to obtain concrete generalization bounds. Based on the obtained generalization bounds, infinite-dimensionally well-defined practical algorithms are formulated. Finally, numerical examples of the backward diffusion and Darcy flow problems are provided to demonstrate the potential applications of the proposed approach in learning the prediction function of the prior probability measures.Comment: 57 page

Infection of mesangial cells with HIV and SIV: Identification of GPR1 as a coreceptor

Infection of mesangial cells with HIV and SIV: Identification of GPR1 as a coreceptor.BackgroundMesangial cells are an important component of the glomerulus. Dysfunction of mesangial cells is thought to be involved in the development of human immunodeficiency virus type 1 (HIV-1)-associated nephropathy (HIVAN). HIVAN is a structural renal failure frequently observed in patients with acquired immune deficiency syndrome. However, the susceptibility of mesangial cells to HIV-1 is disputable. More than ten G protein-coupled receptors, including chemokine receptors, have been shown to act as HIV-1 coreceptors that determine the susceptibilities of cells to HIV-1 strains with specific cell tropisms.MethodsWe examined the susceptibility of mesangial cells to various HIV-1, HIV type 2 (HIV-2) and simian immunodeficiency virus (SIV) strains. Expression of CD4 and HIV/SIV coreceptors was examined by Western blotting and polymerase chain reaction.ResultsMesangial cells were found to be susceptible to HIV-1 variant and mutants that infect brain-derived cells, but highly resistant to T-tropic (X4), M-tropic (R5) or dual-tropic (X4R5) HIV-1 strains. In addition, mesangial cells were also susceptible to HIV-2 and SIV strains that infect the brain-derived cells. Among HIV/SIV coreceptors we tested, the expression of GPR1 mRNA was detected in mesangial cells. Expression of CD4 mRNA and protein was also detected in them. Mesangial cells and GPR1-transduced CD4-positive cells showed similar susceptibilities to the HIV-1 variant and mutants and HIV-2 and SIV strains.ConclusionsCD4 and GPR1 mRNAs were detected in mesangial cells. Mesangial cells were susceptible to HIV/SIV strains that use GPR1 as a coreceptor. Our findings suggest that an orphan G protein-coupled receptor, GPR1, is a coreceptor expressed in mesangial cells. It remains to be investigated whether the interaction of mesangial cells with specific HIV-1 strains through GPR1 plays a role in the development of HIVAN

Why Do Woodpeckers Resist Head Impact Injury: A Biomechanical Investigation

Head injury is a leading cause of morbidity and death in both industrialized and developing countries. It is estimated that brain injuries account for 15% of the burden of fatalities and disabilities, and represent the leading cause of death in young adults. Brain injury may be caused by an impact or a sudden change in the linear and/or angular velocity of the head. However, the woodpecker does not experience any head injury at the high speed of 6–7 m/s with a deceleration of 1000 g when it drums a tree trunk. It is still not known how woodpeckers protect their brain from impact injury. In order to investigate this, two synchronous high-speed video systems were used to observe the pecking process, and the force sensor was used to measure the peck force. The mechanical properties and macro/micro morphological structure in woodpecker's head were investigated using a mechanical testing system and micro-CT scanning. Finite element (FE) models of the woodpecker's head were established to study the dynamic intracranial responses. The result showed that macro/micro morphology of cranial bone and beak can be recognized as a major contributor to non-impact-injuries. This biomechanical analysis makes it possible to visualize events during woodpecker pecking and may inspire new approaches to prevention and treatment of human head injury

Augmentation of Pulmonary Epithelial Cell IL-8 Expression and Permeability by Pre-B-cell Colony Enhancing Factor

© 2008 Li et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Regulation of hepatic autophagy by stress‐sensing transcription factor CREBH

Autophagy, a lysosomal degradative pathway in response to nutrient limitation, plays an important regulatory role in lipid homeostasis upon energy demands. Here, we demonstrated that the endoplasmic reticulum–tethered, stress‐sensing transcription factor cAMP‐responsive element‐binding protein, hepatic‐specific (CREBH) functions as a major transcriptional regulator of hepatic autophagy and lysosomal biogenesis in response to nutritional or circadian signals. CREBH deficiency led to decreased hepatic autophagic activities and increased hepatic lipid accumulation upon starvation. Under unfed or during energy‐demanding phases of the circadian cycle, CREBH is activated to drive expression of the genes encoding the key enzymes or regulators in autophagosome formation or autophagic process, including microtubule‐associated protein IB‐light chain 3, autophagy‐related protein (ATG)7, ATG2b, and autophagosome formation Unc‐51 like kinase 1, and the genes encoding functions in lysosomal biogenesis and homeostasis. Upon nutrient starvation, CREBH regulates and interacts with peroxisome proliferator–activated receptor α (PPARα) and PPARγ coactivator 1α to synergistically drive expression of the key autophagy genes and transcription factor EB, a master regulator of lysosomal biogenesis. Furthermore, CREBH regulates rhythmic expression of the key autophagy genes in the liver in a circadian‐dependent manner. In summary, we identified CREBH as a key transcriptional regulator of hepatic autophagy and lysosomal biogenesis for the purpose of maintaining hepatic lipid homeostasis under nutritional stress or circadian oscillation.—Kim, H., Williams, D., Qiu, Y., Song, Z., Yang, Z., Kimler, V., Goldberg, A., Zhang, R., Yang, Z., Chen, X., Wang, L., Fang, D., Lin, J. D., Zhang, K. Regulation of hepatic autophagy by stress‐sensing transcription factor CREBH. FASEB J. 33, 7896–7914 (2019). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154423/1/fsb2fj201802528r-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154423/2/fsb2fj201802528r.pd

Regional Cerebral Blood Flow in Mania: Assessment Using 320-Slice Computed Tomography

Objectives: While evidence that episodes of mania in bipolar I are associated with changes in bioenergetic and regional cerebral blood flow (rCBF) and cerebral blood flow velocity (rCBFV), both the regions and the extent of these changes have not yet been defined. Therefore, we determined the pattern of regional cerebral perfusion mania patients and using patients with major depressive disorder (MDD) as positive controls and healthy participants as negative controls.Methods: Twenty participants with mania, together with 22 MDD patients and 24 healthy volunteers, were recruited for this study. On all participants, Transcranial Doppler (TCD) was conducted to measure rCBFV parameters, 320-slice CT was conducted to measure rCBF in the different cerebral artery regions, and hematological parameters were assessed. ANOVA and Pearson's tests were used for the statistical analysis.Results: Our data indicated that rCBF in the medial temporal lobe and hippocampus, especially in the left medial temporal lobe and the right hippocampus, was increased in the mania group compared with the control and MDD groups (p < 0.01). In contrast, rCBF in the medial temporal lobe and hippocampus was decreased in the depression group (p < 0.01) compared with healthy controls. In addition, values of rCBFV in the bilateral internal carotid arteries (ICAs) and middle cerebral arteries (MCA) were increased in mania (p < 0.01) in comparison to the MDD group. Whole blood viscosity and hematocrit as well as red blood cell sedimentation rate remained unchanged in all group (p > 0.05).Conclusions: In mania, rCBF is increased in the medial temporal lobe and hippocampus, with a corresponding increase in rCBFV in the same regions

Toll‐like receptor‐mediated IRE1α activation as a therapeutic target for inflammatory arthritis

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