Chin-Wei 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.

Integrins are transmembrane heterodimeric receptors that contribute to diverse biological functions and play critical roles in many human diseases. Studies using integrin subunit knockout mice and inhibitory antibodies have identified important roles for nearly every integrin heterodimer and led to the development of a number of potentially useful therapeutics. One notable exception is the α v β 1 integrin. α v and β 1 subunits are individually present in numerous dimer pairs, making it challenging to infer specific roles for α v β 1 by genetic inactivation of individual subunits, and α v β 1 complex-specific blocking antibodies do not yet exist. We therefore developed a potent and highly specific small-molecule inhibitor of α v β 1 to probe the function of this understudied integrin. We found that α v β 1, which is highly expressed on activated fibroblasts, directly binds to the latency-associated peptide of transforming growth factor-β 1 and mediates TGFb1 activation. Therapeutic delivery of this α v β 1 inhibitor attenuated bleomycin-induced pulmonary fibrosis and carbon tetrachloride-induced liver fibrosis, suggesting that drugs based on this lead compound could be broadly useful for treatment of diseases characterized by excessive tissue fibrosis.

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.

© The Author 2017.Topological Weyl semimetal, a new state of quantum matter, has sparked enormous research interest recently. Possessing unique Weyl fermions in the bulk and Fermi arcs on the surface, TWSs offer a rare platform for realizing many exotic physical phenomena. TWSs can be classified into type-I that respect Lorentz symmetry and type-II that do not. Here, we directly visualize the electronic structure of MoTe 2, a recently proposed type-II TWS. Using angle-resolved photoemission spectroscopy, we unravel the unique surface Fermi arcs, in good agreement with our ab initio calculations that have nontrivial topological nature. Our work not only leads to new understandings of the unusual properties discovered in this family of compounds, but also allows for the further exploration of exotic properties and practical applications of type-II TWSs, as well as the interplay between superconductivity and their topological order.

This study examined risk and protection for adolescent problem behavior and depressive symptomatology in an average-risk sample of 11th graders. Using a socioecological perspective, we aggregated risk factors for adolescent problem behavior and depressed mood by 3 social contexts: i.e., family and peer contexts, and a context comprising the most important nonparental adult in respondents' lives. Protective factors associated with these 3 contexts were also included in the analyses. We tested separate models for predicting problem behaviors and depressive symptoms; the models demonstrated divergent validity. Risk and protective factors accounted for 49% of the variance in problem behavior and 49% in depressive symptoms. Tests of interactions between risk-aggregates and protective factors yielded several significant cross-context buffering effects in the problem behavior model, but none in the depressive symptoms model. Parents' and VIP's perceived sanctions buffered adolescents against high risk for problem behavior emanating from the peer context. Additionally, perceived peers' sanctions buffered youths against risk emanating from each of the 3 contexts.

Objectives: The aim of the current study was to differentiate between neural activity that represents neural anomalies that are responsible for persistent developmental stuttering from the activity that is a result of compensating for stuttering. This was done by investigating alterations to the intrinsic functional architecture of speech-language processes of patients with PDS before and after a short-term intervention. Methods: The resting-state functional connectivity and cortical thickness were examined before and after the intervention. The structural data were used to validate the functional results. Fifteen stuttering patients who received intervention, 13 stuttering patients who did not receive intervention, and 13 fluent controls participated. Results: Before the intervention, both groups of PDS patients showed significant RSFC and cortical thickness reductions in the left pars-opercularis and RSFC increases in the cerebellum, as compared to fluent controls. The intervention was effective in reducing stuttering in PDS- patients and lowering their RSFC in the cerebellum to the level of fluent controls. The intervention effect was specific to the PDS-group. The intervention did not change RSFC and cortical thickness in the left PO, which remained at its preintervention level. Conclusions: The results suggest that the left PO is a locus where the intrinsic functional architecture of speech-language processes is altered in PDS patients, suggesting an etiologic role of this region in PDS. The cerebellum showed intervention-induced neural reorganization, suggesting a compensatory response when stuttering occurs. Copyright © 2012 by AAN Enterprises, Inc.

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.

As part of a larger program of research on the nature of adolescents' relationships with very important nonparental adulis, a community sample of 243 eleventh graders was surveyed, and a subgroup of 55 adolescents and their VIPs were interviewed about the nature and quality of their relationships. Results showed that adolescent-VIP relationships were a normative component of adolescent development, not a result of problems in adolescents' lives; adolescent-VIP relationships were generally of high quality ; there were significant differences between kin and nonkin VIPs in terms of the duration of relationships and frequency of contact, but not in the quality of relationships; and VIPs whom, adolescents designated as extremely important were distinguished from other VIPs in terms of providing a higher level of social support and a higher frequency of contact. Theoretical and practical implications of these findings are discussed.

© 2013, Springer-Verlag Berlin Heidelberg.Overweight and obesity are rapidly becoming a central public health challenge around the world. Previous studies have suggested that elevated Body Mass Index might be associated with structural changes in both gray and white matter, but this association is still not well understood. The present study aimed to investigate the relationship between BMI and brain structure with a relatively large sample of young adults in a small age range. Voxel-based morphometry results showed significant negative correlations between BMI and gray-matter volumes in the midcingulate cortex, left orbital frontal cortex, and left ventromedial prefrontal cortex. There was also a significant negative correlation between BMI and white matter integrity as indexed by fractional anisotropy in bilateral cingulum. Further tractography analysis showed a significant negative correlation between BMI and the number of fibers passing the MCC region. Regression analysis showed that gray matter and white matter in these regions both contributed to the variance of BMI. These results remained significant even when analysis was restricted to the subjects with normal weights. Finally, we found that decision-making ability mediated the association between the structure of the MCC and BMI. These results shed light on the structural neural basis of weight variations.

Cardiac Arrest leads to a global hypoxic-ischemic injury in the brain leading to a poor neurological outcome. Understanding the mechanisms of functional disruption in various regions of the brain may be essential for the development of improved diagnostic and therapeutic solutions. Using controlled laboratory experiment with animal models of CA, our primary focus here is on understanding the functional changes in the thalamus and the cortex, associated with the injury and acute recovery upon resuscitation. Specifically, to study the changes in thalamocortical synchrony through these periods, we acquired local field potentials from the ventroposterior lateral nucleus of the thalamus and the forelimb somatosensory cortex in rats after asphyxial CA. Band-specific relative Hilbert phases were used to analyze synchrony between the LFPs. We observed that the CA induced global ischemia changes the local phase-relationships by introducing a phase-lag in both the thalamus and the cortex, while the synchrony between the two regions is nearly completely lost after CA. © 2013 IEEE.

Using the ER-fMRI technique, the present study was designed to investigate the neural substrates of language switching among second-language learners. Twelve Chinese college students who were learning English were scanned when they performed language switching tasks. Compared to non-switching conditions, language switching elicited greater activation in the right superior prefrontal cortex, left middle and superior frontal cortex, and right middle cingulum and caudate. When the direction of switching was considered, forward switching, but not backward switching, activated several brain regions related to executive functions relative to non-switching conditions. These results suggest that neural correlates of language switching differ depending on the direction of the switch and that there does not seem to be a specific brain area acting as a "language switch". © 2006.

There are great individual differences in learning abilities, but their neural bases, especially among normal populations, are not well understood. Using functional magnetic resonance imaging and a training paradigm, the present study investigated individual differences in cerebral asymmetry in fusiform regions when processing a new writing system and their correlation to subsequent visual character learning. Twelve Chinese adults underwent a 2-week training to learn 120 Korean characters and they were scanned before and after the training. Results showed that left-hemispheric dominance during the pretraining task was predictive of better posttraining performance. These results have significant implications for our understanding of the neural basis of language learning, especially in terms of individual differences. © 2006 Massachusetts Institute of Technology.

Existing cognitive and neural imaging studies have suggested a frontoparietal network of multiple, cooperative components for verbal working memory. We used functional MRI to investigate whether this neural network is also involved in the processing of second language by nonfluent bilinguals. Twelve native Chinese speakers who had limited English proficiency were scanned while performing working memory tasks in Chinese and English. They were asked to make judgment continuously whether the word presented on the screen was semantically related to another word presented two words earlier. On a different task, they were asked to make judgment whether the target word rhymed with the other word. A naming and judgment task in each language was adopted to control for the visual process, initial lexical process, and motor responses. Behavioral data showed that subjects performed better at tasks in their native language than in English. Imaging results showed that all working memory tasks in both L1 and L2 elicited a very similar pattern of left-hemisphere-dominated activation in the dorsolateral prefrontal cortex, pars opercularis region, pars triangularis region, precentral cortex, and parietal lobule. Consistent with the behavioral data, the volume of activation in the left opercularis region, left parietal lobule, and right precentral region was greater for L2 than for L1. These results suggest that working memory in L1 and L2 is mediated by a unitary neural system, which is capable of recruiting surrounding cortical resources to meet the increased computational demand caused by low L2 proficiency. © 2004 Elsevier Inc. All rights reserved.