To translate, or not to translate: viral and host mRNA regulation by interferon-stimulated genes.

Type I interferon (IFN) is one of the first lines of cellular defense against viral pathogens. As a result of IFN signaling, a wide array of IFN-stimulated gene (ISG) products is upregulated to target different stages of the viral life cycle. We review recent findings implicating a subset of ISGs in translational regulation of viral and host mRNAs. Translation inhibition is mediated either by binding to viral RNA or by disrupting physiological interactions or levels of the translation complex components. In addition, many of these ISGs localize to translationally silent cytoplasmic granules, such as stress granules and processing bodies, and intersect with the microRNA (miRNA)-mediated silencing pathway to regulate translation of cellular mRNAs

GelSlim: A High-Resolution, Compact, Robust, and Calibrated Tactile-sensing Finger

This work describes the development of a high-resolution tactile-sensing finger for robot grasping. This finger, inspired by previous GelSight sensing techniques, features an integration that is slimmer, more robust, and with more homogeneous output than previous vision-based tactile sensors. To achieve a compact integration, we redesign the optical path from illumination source to camera by combining light guides and an arrangement of mirror reflections. We parameterize the optical path with geometric design variables and describe the tradeoffs between the finger thickness, the depth of field of the camera, and the size of the tactile sensing area. The sensor sustains the wear from continuous use -- and abuse -- in grasping tasks by combining tougher materials for the compliant soft gel, a textured fabric skin, a structurally rigid body, and a calibration process that maintains homogeneous illumination and contrast of the tactile images during use. Finally, we evaluate the sensor's durability along four metrics that track the signal quality during more than 3000 grasping experiments.Comment: RA-L Pre-print. 8 page

Environmental Scanning for Customer Complaint Identification in Social Media

Social media provides a platform for dissatisfied and frustrated customers to discuss matters of common concerns and share experiences about products and services. While listening to and learning from customer has long been recognized as an important marketing charge, how to identify customer complaints on social media is a nontrivial task. Customer complaint messages are highly distributed on social media, while non-complaint messages are unspecific and topically diverse. It is costly and time consuming to manually label a large number of customer complaint messages (positive examples) and non-complaint messages (negative examples) for training classification systems. Nevertheless, it is relatively easy to obtain large volumes of unlabeled content on social media. In this paper, we propose a partially supervised learning approach to automatically extract high quality positive and negative examples from an unlabeled dataset. The empirical evaluation suggested that the proposed approach generally outperforms the benchmark techniques and exhibits more stable performance

When a Wife is a Visitor: Mainland Chinese Marriage Migration, Citizenship, and Activism in Hong Kong

This dissertation investigates contemporary Hong Kong-China cross-border marriages. In particular, it focuses on the family life and the complexity of politics, power, and agency in mainland Chinese migrant wives’ individual and collective experiences of rights and belonging in Hong Kong. The women in question are allowed to live temporarily in Hong Kong as “visitors” by utilizing family visit permits which must be periodically renewed in mainland China. These women are denied -- or have highly restricted -- social rights and public resources during their transitional stay in Hong Kong while awaiting formal immigration approval. Based on anthropological participant observation-based research in Hong Kong and Guangdong Province, China, in 2011-2012 and in the summers of 2008, 2009, and 2010, this dissertation examines the migrant wives’ cross-border living conditions, the difficulties they face during the periodic permit renewal process, the impact of a visitor immigration status on their experience of living in Hong Kong, and how this situation prompts them and their Hong Kong husbands and families to engage in political organizing to claim rights. Against the backdrop of Hong Kong’s expanded public space for activism, migrant wives develop political consciousness and transform themselves into “citizen-like” subjects by learning to express the idea of claiming rights and gaining a positive sense of political subjectivity in relation to the state despite their “visitor” status. In contrast to the state’s formalistic definitions of local vs. non-local/visitor, migrant wives and their families strive to redefine such meanings in their own terms. They emphasize the wives’ familial relationships and their participation in social activities through which their “local” status and ties to Hong Kong are substantively expressed. Migrant wives’ political and subjective experiences suggest that citizenship is best understood as a process that is negotiated through the efforts of individuals and collective groups to redefine its terms and conditions, but this process is shaped by larger sociopolitical conditions. This dissertation illustrates productive ways to bring together questions of non-citizens’ political organizing and intimate domestic life relationships to illuminate a practice-oriented perspective of citizenship, and to enrich analyses of subjective and cultural aspects of citizenship

ZAP's stress granule localization is correlated with its antiviral activity and induced by virus replication.

Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection ZAP is targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP's antiviral activity correlates with SG localization, and what molecular cues are required to induce this localization event. Here, we use Sindbis virus (SINV) as a model infection and find that ZAP's localization to SGs can be transient. Sometimes no apparent viral infection follows ZAP SG localization but ZAP SG localization always precedes accumulation of SINV non-structural protein, suggesting virus replication processes trigger SG formation and ZAP recruitment. Data from single-molecule RNA FISH corroborates this finding as the majority of cells with ZAP localization in SGs contain low levels of viral RNA. Furthermore, ZAP recruitment to SGs occurred in ZAP-expressing cells when co-cultured with cells replicating full-length SINV, but not when co-cultured with cells replicating a SINV replicon. ZAP recruitment to SGs is functionally important as a panel of alanine ZAP mutants indicate that the anti-SINV activity is correlated with ZAP's ability to localize to SGs. As ZAP is a central component of the cellular antiviral programs, these data provide further evidence that SGs are an important cytoplasmic antiviral hub. These findings provide insight into how antiviral components are regulated upon virus infection to inhibit virus spread

Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion.

The host responds to virus infection by activating type I interferon (IFN) signaling leading to expression of IFN-stimulated genes (ISGs). Dysregulation of the IFN response results in inflammatory diseases and chronic infections. In this study, we demonstrate that IFN regulatory factor 2 (IRF2), an ISG and a negative regulator of IFN signaling, influences alphavirus neuroinvasion and pathogenesis. A Sindbis virus strain that in wild-type (WT) mice only causes disease when injected into the brain leads to lethal encephalitis in Irf2-/- mice after peripheral inoculation. Irf2-/- mice fail to control virus replication and recruit immune infiltrates into the brain. Reduced B cells and virus-specific IgG are observed in the Irf2-/- mouse brains despite the presence of peripheral neutralizing antibodies, suggesting a defect in B cell trafficking to the central nervous system (CNS). B cell-deficient μMT mice are significantly more susceptible to viral infection, yet WT B cells and serum are unable to rescue the Irf2-/- mice. Collectively, our data demonstrate that proper localization of B cells and local production of antibodies in the CNS are required for protection. The work advances our understanding of host mechanisms that affect viral neuroinvasion and their contribution to immunity against CNS infections

A functional correlate of severity in alternating hemiplegia of childhood

OBJECTIVE: Mutations in ATP1A3, the gene that encodes the α3 subunit of the Na(+)/K(+) ATPase, are the primary cause of alternating hemiplegia of childhood (AHC). Correlations between different mutations and AHC severity were recently reported, with E815K identified in severe and D801N and G947R in milder cases. This study aims to explore the molecular pathological mechanisms in AHC and to identify functional correlates for mutations associated with different levels of disease severity. METHODS: Human wild type ATP1A3, and E815K, D801N and G947R mutants were expressed in Xenopus laevis oocytes and Na(+)/K(+) ATPase function measured. Structural homology models of the human α3 subunit containing AHC mutations were created. RESULTS: The AHC mutations examined all showed similar levels of reduction in forward cycling. Wild type forward cycling was reduced by coexpression with any mutant, indicating dominant negative interactions. Proton transport was measured and found to be selectively impaired only in E815K. Homology modeling showed that D801 and G947 lie within or near known cation binding sites while E815 is more distal. Despite its effect on proton transport, E815K was also distant from the proposed proton transport route. INTERPRETATION: Loss of forward cycling and dominant negativity are common and likely necessary pathomechanisms for AHC. In addition, loss of proton transport correlated with severity of AHC. D801N and G947R are likely to directly disrupt normal Na(+)/K(+) binding while E815K may disrupt forward cycling and proton transport via allosteric mechanisms yet to be elucidated

Detecting Multiple Change Points in Piecewise Constant Hazard Functions

The National Cancer Institute (NCI) suggests a sudden reduction in prostate cancer mortality rates, likely due to highly successful treatments and screening methods for early diagnosis. We are interested in understanding the impact of medical breakthroughs, treatments, or interventions, on the survival experience for a population. For this purpose, estimating the underlying hazard function, with possible time change points, would be of substantial interest, as it will provide a general picture of the survival trend and when this trend is disrupted. Increasing attention has been given to testing the assumption of a constant failure rate against a failure rate that changes at a single point in time. We expand the set of alternatives to allow for the consideration of multiple change-points, and propose a model selection algorithm using sequential testing for the piecewise constant hazard model. These methods are data driven and allow us to estimate not only the number of change points in the hazard function but where those changes occur. Such an analysis allows for better understanding of how changing medical practice affects the survival experience for a patient population. We test for change points in prostate cancer mortality rates using the NCI Surveillance, Epidemiology,and End Results dataset

Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice

Reverse cholesterol transport (RCT) refers to the mobilization of cholesterol on HDL particles (HDL-C) from extravascular tissues to plasma, ultimately for fecal excretion. Little is known about how HDL-C leaves peripheral tissues to reach plasma. We first used 2 models of disrupted lymphatic drainage from skin — 1 surgical and the other genetic — to quantitatively track RCT following injection of [3H]-cholesterol–loaded macrophages upstream of blocked or absent lymphatic vessels. Macrophage RCT was markedly impaired in both models, even at sites with a leaky vasculature. Inhibited RCT was downstream of cholesterol efflux from macrophages, since macrophage efflux of a fluorescent cholesterol analog (BODIPY-cholesterol) was not altered by impaired lymphatic drainage. We next addressed whether RCT was mediated by lymphatic vessels from the aortic wall by loading the aortae of donor atherosclerotic Apoe-deficient mice with [2H]6-labeled cholesterol and surgically transplanting these aortae into recipient Apoe-deficient mice that were treated with anti-VEGFR3 antibody to block lymphatic regrowth or with control antibody to allow such regrowth. [2H]-Cholesterol was retained in aortae of anti–VEGFR3-treated mice. Thus, the lymphatic vessel route is critical for RCT from multiple tissues, including the aortic wall. These results suggest that supporting lymphatic transport function may facilitate cholesterol clearance in therapies aimed at reversing atherosclerosis