Control of the innate immune response by the mevalonate pathway.

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1ß that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

Preclinical studies of targeted therapies for CD20-positive B lymphoid malignancies by Ofatumumab conjugated with auristatin.

Utilization of antibodies to deliver highly potent cytotoxic agents to corresponding antigen-overexpressed tumor cells is a clinically validated therapeutic strategy. Ofatumumab (OFA, trade name Arzerra) is a fully human CD20-specific antibody that is active against CD20-positive B-cell lymphoma/chronic lymphocytic leukemia cells. In order to further enhance the anticancer effect of OFA, anti-CD20 OFA has been conjugated with highly cytotoxic monomethyl auristatin E (MMAE) through a cathepsin-B-cleavable valine-citrulline (vc) dipeptide linkage to form OFA-vcMMAE and the anti-tumor activity of OFA-vcMMAE against CD20-positive B lymphoma cells are then evaluated in vitro and in vivo. As a result, conjugation of OFA with MMAE has kept the initial effector functional activities of OFA such as binding affinity, complement-dependent cytotoxicity (CDC) as well as antibody-dependent cell-mediated cytotoxicity (ADCC). In addition, the conjugation of MMAE significantly improved the cytotoxic activity of OFA against CD20-positive cells (i.e., Raji, Daudi and WIL2-S cells) but not against CD20-negative K562 cells. On the other hand, OFA-vcMMAE was modulated from the CD20-positive cell surface and then entered the lysosomes by receptor-mediated endocytosis, underwent proteolytic degradation and released active drug MMAE to induce apoptotic cell death through a caspase-3-like protease-dependent pathway. Surprisingly, OFA-vcMMAE completely inhibited the growth of CD20-positive Daudi and Ramos lymphoma xenografts in vivo, and exhibited greater anti-tumor activity than unconjugated OFA, suggesting that the anti-tumor activity of anti-CD20 antibody can be enhanced by conjugation with MMAE. In the near future, this new approach might be used as a clinical treatment of CD20-positive B lymphoid malignancies.

Migration within China and from China to the USA: the effects of migration networks, selectivity, and the rural political economy in Fujian Province.

This paper tests a new strategy for simultaneously studying internal migration within, and international migration from, China. Our theoretical discussion draws on ideas from migration-networks theory and studies of the transition to a market-oriented economy. Data collection is modelled on the Mexican Migration Project. We find that education is more important in initiating internal migration than international migration. Second, although the role of migration networks at a community level seems similar to that for Mexico-USA migration, the networks at a family level show a different pattern. Third, there is evidence that internal and international migration are competing options. Finally, we find that individuals with cadres (public officials) in the family are less likely to undertake internal migration, but more likely to participate in international migration, a finding that highlights the continuing significance of the cadres in coastal rural China.

Chinese Immigrant Entrepreneurship in the United States: Temporal and Spatial Dimensions.

Focusing on transnational entrepreneurship and immigrant businesses in new destinations, this paper studies entrepreneurship of Chinese immigrants in the U.S. using data from three surveys. In the analysis of transnational connections, we focus on the temporal dimension that links pre-migration and post-migration business activities. Results from logistic models reveal that the prospect of being self-employed among Chinese immigrants is significantly enhanced if they are from households in China with business backgrounds. This finding highlights the fact that transnational entrepreneurship is embedded in the multi-stranded connections between the immigrant sending and receiving societies. In the second part of the paper, sequence analysis is used to describe and classify business trajectories in traditional and new immigrant destinations. The results establish that while it may take a longer time for immigrants to achieve business ownership in new destinations than in traditional destinations, new immigrant destinations increase the chance of business expansion from one business to multiple businesses. These findings indicate a transition in immigrant entrepreneurs' business models. Businesses in traditional destinations mainly follow a survival strategy, while those in new destinations are adopting models that are akin to mainstream business operations, which gives rise to more opportunities for socioeconomic mobility.

Control of antiviral innate immune response by protein geranylgeranylation.

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.

Efficient Payload Delivery by a Bispecific Antibody-Drug Conjugate Targeting HER2 and CD63.

Antibody-drug conjugates (ADC) are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake, and degradation in tumor cells. Efficient internalization and routing to lysosomes where proteolysis can take place is therefore essential. For many cell surface proteins and carbohydrate structures on tumor cells, however, the magnitude of these processes is insufficient to allow for an effective ADC approach. We hypothesized that we could overcome this limitation by enhancing lysosomal ADC delivery via a bispecific antibody (bsAb) approach, in which one binding domain would provide tumor specificity, whereas the other binding domain would facilitate targeting to the lysosomal compartment. We therefore designed a bsAb in which one binding arm specifically targeted CD63, a protein that is described to shuttle between the plasma membrane and intracellular compartments, and combined it in a bsAb with a HER2 binding arm, which was selected as model antigen for tumor-specific binding. The resulting bsHER2xCD63his demonstrated strong binding, internalization and lysosomal accumulation in HER2-positive tumor cells, and minimal internalization into HER2-negative cells. By conjugating bsHER2xCD63his to the microtubule-disrupting agent duostatin-3, we were able to demonstrate potent cytotoxicity of bsHER2xCD63his-ADC against HER2-positive tumors, which was not observed with monovalent HER2- and CD63-specific ADCs. Our data demonstrate, for the first time, that intracellular trafficking of ADCs can be improved using a bsAb approach that targets the lysosomal membrane protein CD63 and provide a rationale for the development of novel bsADCs that combine tumor-specific targeting with targeting of rapidly internalizing antigens. Mol Cancer Ther; 15(11); 2688-97. ©2016 AACR.

Emergent ghettos: black neighborhoods in New York and Chicago, 1880-1940.

This article studies in detail the settlement patterns of blacks in the urban North from before the Great Migration and through 1940, focusing on the cases of New York and Chicago. It relies on new and rarely used data sources, including census geocoded microdata from the 1880 census (allowing segregation patterns and processes to be studied at any geographic scale) and census data for 1900-1940 aggregated to enumeration districts. It is shown that blacks were unusually highly isolated in 1880 given their small share of the total population and that segregation reached high levels in both cities earlier than previously reported. Regarding sources of racial separation, neither higher class standing nor northern birth had much effect on whether blacks lived within or outside black neighborhoods in 1880 or 1940, and it is concluded that the processes that created large black ghettos were already in place several decades before 1940.

High turnover of tissue factor enables efficient intracellular delivery of antibody-drug conjugates.

Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR- and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach.

Emigration from China in Comparative Perspective.

Comparative research on international migration has increasingly focused on immigrant integration rather than the process of emigration. By investigating the different streams of Chinese migration to the United States and Europe, as well as the different stages of Chinese migration to the U.S., this study examines the way in which both receiving and sending contexts combine to shape the process of emigration. Using data from a 2002-2003 survey of emigration from China's Fujian Province, we demonstrate that under restrictive exit and entry policies and high barriers to migration (i.e., clandestine migration from Fuzhou to the U.S.), resources such as migrant social capital, political capital (cadre resources), and human capital all play a crucial role in the emigration process. However, the roles of these resources in the migration process are limited when migration barriers are sufficiently low and when local governments adopt proactive policies promoting emigration (i.e., legal migration from Mingxi to Europe). Comparisons over time suggest that the importance of migrant social capital, political capital, and human capital has strongly persisted for Fuzhou-US emigration, as a result of tightening exit and entry policies. Despite these marked differences between Fuzhou and Mingxi emigration, the results also point to two general processes that are highly consistent across settings and over time-the cumulative causation of migration and the advantage conferred by traditional positional power (cadre status).

Cumulative causation, market transition, and emigration from China.

This article reports findings from a recent survey of international migration from China's Fujian Province to the United States. Using the ethnosurvey approach developed in the Mexican Migration Project, the authors conducted surveys in migrant-sending communities in China as well as in destination communities in New York City. Hypotheses are derived from the international migration literature and the market transition debate. The results are generally consistent with hypotheses derived from cumulative causation of migration; however, geographical location creates some differences in migration patterns to the United States. In China as in Mexico, the existence of migration networks increases the propensity of migration for others in the community. In contrast to the Mexican case, among Chinese immigrants, having a previously migrated household member increases the propensity of other household members to migrate only after the debt for previous migration is paid off. In step with market transition theory, the authors also find that political power influences the migration experience from the coastal Fujian Province.