Chen Chen

Increased airway smooth muscle contractility and the development of airway hyperresponsiveness are cardinal features of asthma, but the signaling pathways that promote these changes are poorly understood. Tyrosine phosphorylation is tightly regulated by the opposing actions of protein tyrosine kinases and phosphatases, but little is known about whether tyrosine phosphatases influence AHR. Here, we demonstrate that genetic inactivation of receptor-like protein tyrosine phosphatase J, which encodes CD148, protected mice from the development of increased AHR in two different asthma models. Surprisingly, CD148 deficiency minimally affected the inflammatory response to allergen, but significantly altered baseline pulmonary resistance. Mice specifically lacking CD148 in smooth muscle had decreased AHR, and the frequency of calcium oscillations in CD148-deficient ASM was substantially attenuated, suggesting that signaling pathway alterations may underlie ASM contractility. Biochemical analysis of CD148-deficient ASM revealed hyper-phosphorylation of the C-terminal inhibitory tyrosine of SRC family kinases, implicating CD148 as a critical positive regulator of SFK signaling in ASM. The effect of CD148 deficiency on ASM contractility could be mimicked by treatment of both mouse trachea and human bronchi with specific SFK inhibitors. Our studies identify CD148 and the SFKs it regulates in ASM as potential targets for the treatment of AHR.

Exaggerated contraction of airway smooth muscle is the major cause of symptoms in asthma, but the mechanisms that prevent exaggerated contraction are incompletely understood. Here, we showed that integrin α 9β 1on airway smooth muscle localizes the polyamine catabolizing enzyme spermidine/spermine N 1-acetyltransferase in close proximity to the lipid kinase PIP5K1γ. As PIP5K1γ is the major source of PIP2 in airway smooth muscle and its activity is regulated by higher-order polyamines, this interaction inhibited IP3-dependent airway smooth muscle contraction. Mice lacking integrin α 9β 1 in smooth muscle had increased airway responsiveness in vivo, and loss or inhibition of integrin α 9β 1 increased in vitro airway narrowing and airway smooth muscle contraction in murine and human airways. Contraction was enhanced in control airways by the higher-order polyamine spermine or by cell-permeable PIP2, but these interventions had no effect on airways lacking integrin α 9β 1 or treated with integrin α 9β 1-blocking antibodies. Enhancement of SSAT activity or knockdown of PIP5K1γ inhibited airway contraction, but only in the presence of functional integrin α 9β 1. Therefore, integrin α 9β 1 appears to serve as a brake on airway smooth muscle contraction by recruiting SSAT, which facilitates local catabolism of polyamines and thereby inhibits PIP5K1γ. Targeting key components of this pathway could thus lead to new treatment strategies for asthma.

We report the design and characterization of a CMOS pixel direct charge sensor, Topmetal-II-, fabricated in a standard 0.35 μm CMOS Integrated Circuit process. The sensor utilizes exposed metal patches on top of each pixel to directly collect charge. Each pixel contains a low-noise charge-sensitive preamplifier to establish the analog signal and a discriminator with tunable threshold to generate hits. The analog signal from each pixel is accessible through time-shared multiplexing over the entire array. Hits are read out digitally through a column-based priority logic structure. Tests show that the sensor achieved a <15e- analog noise and a 200e- minimum threshold for digital readout per pixel. The sensor is capable of detecting both electrons and ions drifting in gas. These characteristics enable its use as the charge readout device in future Time Projection Chambers without gaseous gain mechanism, which has unique advantages in low background and low rate-density experiments.

Previous research has consistently demonstrated the importance of parents' expectations and adolescents' expectations on adolescents' academic achievement. Less is known, however, about the reciprocal relationships among these constructs. To address this issue, we analyzed two waves of data from the National Education Longitudinal Study of 1988 using longitudinal cross-lagged path models. The sample consisted of 14,376 students. Results indicated that there was a reciprocal relationship between parents' expectations and adolescents' expectations. Moreover, there was a reciprocal relationship between expectations and adolescents' academic achievement. Multiple-group analyses of gender and ethnicity revealed that the effects of parents' expectations on students' expectations were stronger among males than among females. With respect to ethnic differences, the effects of adolescents' expectations were weakest on parents' expectations among African Americans as compared to the other ethnic groups. Implications of these findings are discussed. © 2010 The Author.

Legal Judgment Prediction (LJP) is a typical application of Artificial Intelligence in the intelligent judiciary. Current research primarily focuses on automatically predicting law articles, charges, and terms of penalty based on the fact description of cases. However, existing methods for LJP have limitations, such as neglecting document structure and ignoring case similarities. We propose a novel framework called Graph Contrastive Learning with Augmentation (GCLA) for legal judgment prediction to address these issues. GCLA constructs trainable document-level graphs for fact description, capturing local and global context through sentence-level subgraphs. Graph augmentation enhances robustness. We introduce a comparison case relation perspective, using graph contrastive learning to model case-text label relationships effectively. Experimental results on real-world datasets demonstrate the competitive performance of GCLA.