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Autoimmune liver diseases (AILDs) are life-threatening chronic liver diseases, mainly including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and AIH–PBC overlap syndrome (OS), which are difficult to distinguish clinically at early stages. This study aimed to establish model to achieve the purpose of the diagnosis of AIH/PBC OS in a noninvasive way. A total of 201 AILDs patients were included in this retrospective study who underwent liver biopsy during January 2011 to December 2020. Serological factors significantly associated with OS were determined by the univariate analysis. Two multivariate models based on these factors were constructed to predict the diagnosis of AIH/PBC OS using logistic regression and random forest analysis. The results showed that immunoglobulins G and M had significant importance in both models. In logistic regression model, anti-Sp100, anti-Ro-52, anti-SSA, or antinuclear antibody positivity were risk factors for OS. In random forest model, activated partial thromboplastin time and ɑ-fetoprotein level were important. To distinguish PBC and OS, the sensitivity and specificity of logistic regression model were 0.889 and 0.727, respectively, and the sensitivity and specificity of random forest model were 0.944 and 0.818, respectively. In conclusion, we established two predictive models for the diagnosis of AIH/PBC OS in a noninvasive method and they showed better performance than Paris criteria for the definition of AIH/PBC OS.

Purpose: To evaluate the shielding effect of lead aprons (LAs) on peripheral radiation doses outside the applicator of electron beams from a linear accelerator. Methods: Out‐of‐field radiation doses of 4‐, 6‐, 8‐, 10‐, 12‐, and 15‐MeV electron beams from an Elekta Synergy linear accelerator (linac) were measured by thermoluminescence dosimeters (TLD) at different depths (0, 0.5, 1.0, and 2.0 cm) and distances from the applicator edge (0–58 cm) in a water‐equivalent slab phantom with a different number of layers of LA shielding (0–5 layers). Measurements were performed by 6 × 6, 10 × 10, 14 × 14, and 20 × 20‐cm2 applicators at a gantry and collimator angle of 0°. The out‐of‐field radiation dose profiles were normalized to the maximum dose of every energy and measuring depth. Results: The out‐of‐field radiation doses (beyond 3 cm away from the field edge) decreased with an increase in the number of LA layers and distance away from the central beam axis (CAX). After shielding with the LA, the out‐of‐field doses decreased by up to approximately 99% compared with the no shielding group. For 4‐MeV electron beams, there was a peak at 24.5 cm from the CAX, which weakened with an increasing number of LA layers. Conclusion: The shielding effect of the LA varied for a different number of LA layers as well as different depths and distances away from the CAX. Four LA layers were sufficient for shielding out‐of‐field doses of 4–15‐MeV electron beams. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ca(1 − x) Sr x Cu3Ti4O12 ceramics are synthesized by sol–gel process. [•] Positron annihilation lifetime spectra is used to investigate the defects of samples. [•] Nonlinear and dielectric properties are controlled by density and defects of samples. [Copyright &y& Elsevier]

STIM1- and Orai1-mediated store-operated Ca 2+ entry (SOCE) constitutes the major Ca 2+ influx in almost all electrically non-excitable cells. However, little is known about the spatiotemporal organization at the elementary level. Here, we developed Orai1-tethered or palmitoylated biosensor GCaMP6f to report subplasmalemmal Ca 2+ signals. We visualized spontaneous discrete and long-lasting transients ('Ca 2+ glows') arising from STIM1-Orai1 in invading melanoma cells. Ca 2+ glows occurred preferentially in single invadopodia and at sites near the cell periphery under resting conditions. Re-addition of external Ca 2+ after store depletion elicited spatially synchronous Ca 2+ glows, followed by high-rate discharge of asynchronous local events. Knockout of STIM1 or expression of the dominant-negative Orai1-E106A mutant markedly decreased Ca 2+ glow frequency, diminished global SOCE and attenuated invadopodial formation. Functionally, invadopodial Ca 2+ glows provided high Ca 2+ microdomains to locally activate Ca 2+ /calmodulin-dependent Pyk2 (also known as PTK2B), which initiates the SOCE-Pyk2-Src signaling cascade required for invasion. Overall, the discovery of elemental Ca 2+ signals of SOCE not only unveils a previously unappreciated gating mode of STIM1-Orai1 channels in situ , but also underscores a critical role of the spatiotemporal dynamics of SOCE in orchestrating complex cell behaviors such as invasion. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Inhibitory molecules associated with CNS myelin, such as myelin-associated glycoprotein (MAG), represent major obstacles to axonal regeneration following CNS injury. Our laboratory has shown that elevating levels of intracellular cAMP, via application of the nonhydrolyzable analog dibutyryl cAMP (dbcAMP), can block the inhibitory effects of MAG and myelin. We have also shown that elevation of cAMP results in upregulation of arginase I and increased polyamine synthesis. Treatment with putrescine or spermidine blocks myelin-mediated inhibition of neurite outgrowth, but the mechanism underlying this effect has not yet been elucidated. Here we show that cyclin-dependent kinase 5 (Cdk5) is required for dbcAMP and putrescine to overcome MAG-mediated inhibition. The ability of dbcAMP and putrescine to overcome inhibition by MAG is abolished in the presence of roscovitine, a Cdk inhibitor that has greater selectivity for Cdk5, and expression of dominant negative Cdk5 abolishes the ability of dbcAMP or putrescine to enhance neurite outgrowth in the presence of MAG. Importantly, dbcAMP and putrescine increase expression of p35, the neuron-specific activator of Cdk5, and rat DRG neurons transduced with HSV overexpressing p35 can overcome inhibition by MAG. The upregulation of p35 by putrescine is also reflected in increased localization of p35 to neurites and growth cones. Last, we show that putrescine upregulates p35 expression by serving as a substrate for hypusine modification of eIF5A, and that this hypusination is necessary for putrescine's ability to overcome inhibition by MAG. Our findings reveal a previously unknown mechanism by which polyamines may encourage regeneration after CNS injury., (Copyright © 2016 the authors 0270-6474/16/363079-13$15.00/0.)

Adult spinal axons do not spontaneously regenerate after injury. However, if the peripheral branch of dorsal root ganglion neurons is lesioned before lesioning the central branch of the same neurons in the dorsal column, these central axons will regenerate and, if cultured, are not inhibited from extending neurites by myelin-associated inhibitors of regeneration such as myelin-associated glycoprotein (MAG). This effect can be mimicked by elevating cAMP and is transcription dependent. The ability of cAMP to overcome inhibition by MAG in culture involves the upregulation of the enzyme arginase I (Arg I) and subsequent increase in synthesis of polyamines such as putrescine. Now we show that a peripheral lesion also induces an increase in Arg I expression and synthesis of polyamines. We also show that the conditioning lesion effect in overcoming inhibition by MAG is initially dependent on ongoing polyamine synthesis but, with time after lesion, becomes independent of ongoing synthesis. However, if synthesis of polyamines is blocked in vivo the early phase of good growth after a conditioning lesion is completely blocked and the later phase of growth, when ongoing polyamine synthesis is not required during culture, is attenuated. We also show that putrescine must be converted to spermidine both in culture and in vivo to overcome inhibition by MAG and that spermidine can promote optic nerve regeneration in vivo. These results suggest that spermidine could be a useful tool in promoting CNS axon regeneration after injury.