The Co-occurrence of Two Delimiters: An Investigation of Mandarin Chinese Resultatives

Department of Chinese and Bilingual StudiesRefereed conference pape

A figure's final location must be identifiable: Localizer distribution in Chinese motion expressions

Proceedings of the 37th Annual Meeting of the Berkeley Linguistics Society (2013), pp. 242-25

Structural and Functional Characterization of the FadR Regulatory Protein from Vibrio alginolyticus

The structure of Vibrio cholerae FadR (VcFadR) complexed with the ligand oleoyl-CoA suggests an additional ligand-binding site. However, the fatty acid metabolism and its regulation is poorly addressed in Vibrio alginolyticus, a species closely-related to V. cholerae. Here, we show crystal structures of V. alginolyticus FadR (ValFadR) alone and its complex with the palmitoyl-CoA, a long-chain fatty acyl ligand different from the oleoyl-CoA occupied by VcFadR. Structural comparison indicates that both VcFadR and ValFadR consistently have an additional ligand-binding site (called site 2), which leads to more dramatic conformational-change of DNA-binding domain than that of the E. coli FadR (EcFadR). Isothermal titration calorimetry (ITC) analyses defines that the ligand-binding pattern of ValFadR (2:1) is distinct from that of EcFadR (1:1). Together with surface plasmon resonance (SPR), electrophoresis mobility shift assay (EMSA) demonstrates that ValFadR binds fabA, an important gene of unsaturated fatty acid (UFA) synthesis. The removal of fadR from V. cholerae attenuates fabA transcription and results in the unbalance of UFA/SFA incorporated into membrane phospholipids. Genetic complementation of the mutant version of fadR (Δ42, 136-177) lacking site 2 cannot restore the defective phenotypes of ΔfadR while the wild-type fadR gene and addition of exogenous oleate can restore them. Mice experiments reveals that VcFadR and its site 2 have roles in bacterial colonizing. Together, the results might represent an additional example that illustrates the Vibrio FadR-mediated lipid regulation and its role in pathogenesis

Adapting and developing an academic and community practice collaborative care model for metastatic breast cancer care (Project ADAPT): Protocol for an implementation science-based study

BACKGROUND: Metastatic breast cancer (MBC) remains incurable despite significant treatment advances. Coordinating care for patients with MBC can be challenging given the various treatment options, available clinical trials, and frequent need for ancillary services. To optimize MBC care, we designed a project for adapting and developing an academic and community practice collaborative care model for MBC care (Project ADAPT), based on the Ending Metastatic Breast Cancer for Everyone (EMBRACE) program developed at Dana Farber Cancer Institute. OBJECTIVE: We aim to describe the implementation science-based study design and innovative components of Project ADAPT. METHODS: Project ADAPT uses the Dynamic Adaptation Process informed by the Exploration, Preparation, Implementation, Sustainment framework. Washington University School of Medicine (WUSM) partnered with 3 community hospitals in the St. Louis region covering rural and urban settings. The exploration and preparation phases provide patient and provider feedback on current referral practices to finalize the approach for the implementation phase. At the implementation phase, we will enroll patients with MBC at these 3 community sites to evaluate potential collaborative care at WUSM and assess the impact of this collaborative care model on referral satisfaction and acceptability for patients with MBC and their providers. Patients may then return to their community site for care or continue to receive part of their care at WUSM. We are incorporating virtual and digital health strategies to improve MBC care coordination in order to minimize patient burden. RESULTS: The exploration phase is ongoing. As of August 2021, we have recruited 21 patient and provider participants to complete surveys of the current collaborative care process at WUSM. Using a 2-tailed paired t test, 44 patients (including 10 patients from the exploration phase) and 32 oncologists are required to detect an effect size of 0.5 with 80% power at a level of significance of .05. Throughout this phase and in preparation for the implementation phase, we have iteratively updated and refined our surveys for the implementation phase based on testing of our data collection instruments. Our partner sites are in various stages of the single institutional review board (IRB) approval process. We have ongoing engagement with all partner sites, which has helped solidify our participant recruitment strategies and design patient-friendly recruitment materials. In addition, we have included a patient advocate on the research team. Members of the research team have launched a single IRB Support Network at WUSM to create a repository of the single IRB procedures in order to streamline the partner site onboarding process and facilitate enhanced collaboration across institutions. CONCLUSIONS: With this robust model, we expect that patients with MBC will receive optimal care regardless of geographical location and the model will improve patient and provider experiences when navigating the health system. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35736

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC

E3 Ligase Activity of XIAP RING Domain Is Required for XIAP-Mediated Cancer Cell Migration, but Not for Its RhoGDI Binding Activity

Although an increased expression level of XIAP is associated with cancer cell metastasis, the underlying molecular mechanisms remain largely unexplored. To verify the specific structural basis of XIAP for regulation of cancer cell migration, we introduced different XIAP domains into XIAP−/− HCT116 cells, and found that reconstitutive expression of full length HA-XIAP and HA-XIAP ΔBIR, both of which have intact RING domain, restored β-Actin expression, actin polymerization and cancer cell motility. Whereas introduction of HA-XIAP ΔRING or H467A mutant, which abolished its E3 ligase function, did not show obvious restoration, demonstrating that E3 ligase activity of XIAP RING domain played a crucial role of XIAP in regulation of cancer cell motility. Moreover, RING domain rather than BIR domain was required for interaction with RhoGDI independent on its E3 ligase activity. To sum up, our present studies found that role of XIAP in regulating cellular motility was uncoupled from its caspase-inhibitory properties, but related to physical interaction between RhoGDI and its RING domain. Although E3 ligase activity of RING domain contributed to cell migration, it was not involved in RhoGDI binding nor its ubiquitinational modification