CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza virus pathogenicity in vivo

Human infections with influenza viruses exhibit mild to severe clinical outcomes as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin domain family 5 member A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of proinflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes. Infection of bone marrow-derived macrophages from CLEC5A-deficient mice showed reduced levels of tumor necrosis factor alpha (TNF-α) and IP-10 but elevated alpha interferon (IFN-α) compared to those of wild-type mice. The heightened type I IFN response in the macrophages of CLEC5A-deficient mice was associated with upregulated TLR3 mRNA after treatment with double-stranded RNA. Upon lethal challenges with a recombinant H5N1 virus, CLEC5A-deficient mice showed reduced levels of proinflammatory cytokines, decreased immune cell infiltration in the lungs, and improved survival compared to the wild-type mice, despite comparable viral loads noted throughout the course of infection. The survival difference was more prominent at a lower dose of inoculum. Our results suggest that CLEC5A-mediated enhancement of the inflammatory response in myeloid cells contributes to influenza pathogenicity in vivo and may be considered a therapeutic target in combination with effective antivirals. Well-orchestrated host responses together with effective viral clearance are critical for optimal clinical outcome after influenza infections.published_or_final_versio

Evaluation of the late life disability instrument in the lifestyle interventions and independence for elders pilot (LIFE-P) study

Background: The late life disability instrument (LLDI) was developed to assess limitations in instrumental and management roles using a small and restricted sample. In this paper we examine the measurement properties of the LLDI using data from the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study.Methods: LIFE-P participants, aged 70-89 years, were at elevated risk of disability. The 424 participants were enrolled at the Cooper Institute, Stanford University, University of Pittsburgh, and Wake Forest University. Physical activity and successful aging health education interventions were compared after 12-months of follow-up. Using factor analysis, we determined whether the LLDI's factor structure was comparable with that reported previously. We further examined how each item related to measured disability using item response theory (IRT).Results: The factor structure for the limitation domain within the LLDI in the LIFE-P study did not corroborate previous findings. However, the factor structure using the abbreviated version was supported. Social and personal role factors were identified. IRT analysis revealed that each item in the social role factor provided a similar level of information, whereas the items in the personal role factor tended to provide different levels of information.Conclusions: Within the context of community-based clinical intervention research in aged populations, an abbreviated version of the LLDI performed better than the full 16-item version. In addition, the personal subscale would benefit from additional research using IRT.Trial registration: The protocol of LIFE-P is consistent with the principles of the Declaration of Helsinki and is registered at http://www.ClinicalTrials.gov (registration # NCT00116194). © 2010 Hsu et al; licensee BioMed Central Ltd

The rolling problem: overview and challenges

In the present paper we give a historical account -ranging from classical to modern results- of the problem of rolling two Riemannian manifolds one on the other, with the restrictions that they cannot instantaneously slip or spin one with respect to the other. On the way we show how this problem has profited from the development of intrinsic Riemannian geometry, from geometric control theory and sub-Riemannian geometry. We also mention how other areas -such as robotics and interpolation theory- have employed the rolling model.Comment: 20 page

Risk, Unexpected Uncertainty, and Estimation Uncertainty: Bayesian Learning in Unstable Settings

Recently, evidence has emerged that humans approach learning using Bayesian updating rather than (model-free) reinforcement algorithms in a six-arm restless bandit problem. Here, we investigate what this implies for human appreciation of uncertainty. In our task, a Bayesian learner distinguishes three equally salient levels of uncertainty. First, the Bayesian perceives irreducible uncertainty or risk: even knowing the payoff probabilities of a given arm, the outcome remains uncertain. Second, there is (parameter) estimation uncertainty or ambiguity: payoff probabilities are unknown and need to be estimated. Third, the outcome probabilities of the arms change: the sudden jumps are referred to as unexpected uncertainty. We document how the three levels of uncertainty evolved during the course of our experiment and how it affected the learning rate. We then zoom in on estimation uncertainty, which has been suggested to be a driving force in exploration, in spite of evidence of widespread aversion to ambiguity. Our data corroborate the latter. We discuss neural evidence that foreshadowed the ability of humans to distinguish between the three levels of uncertainty. Finally, we investigate the boundaries of human capacity to implement Bayesian learning. We repeat the experiment with different instructions, reflecting varying levels of structural uncertainty. Under this fourth notion of uncertainty, choices were no better explained by Bayesian updating than by (model-free) reinforcement learning. Exit questionnaires revealed that participants remained unaware of the presence of unexpected uncertainty and failed to acquire the right model with which to implement Bayesian updating

Immune reconstitution inflammatory syndrome presenting as chylothorax in a patient with HIV and Mycobacterium tuberculosis coinfection: a case report

<p>Abstract</p> <p>Background</p> <p>Patients with human immunodeficiency virus (HIV) infection are at risk for <it>Mycobacterium tuberculosis </it>(TB) coinfection. The advent of antiretroviral therapy restores immunity in HIV-infected patients, but predisposes patients to immune reconstitution inflammatory syndrome (IRIS).</p> <p>Case Presentation</p> <p>A 25-year-old HIV-infected male presented with fever, productive cough, and body weight loss for 2 months. His CD4 cell count was 11 cells/μl and HIV-1 viral load was 315,939 copies/ml. Antituberculosis therapy was initiated after the diagnosis of pulmonary TB. One week after antituberculosis therapy, antiretroviral therapy was started. However, multiple mediastinal lymphadenopathies and chylothorax developed. Adequate drainage of the chylothorax, suspension of antiretroviral therapy, and continued antituberculosis therapy resulted in successful treatment and good outcome.</p> <p>Conclusions</p> <p>Chylothorax is a rare manifestation of TB-associated IRIS in HIV-infected patients. Careful monitoring for development of IRIS during treatment of HIV-TB coinfection is essential to minimize the associated morbidity and mortality.</p

Retargeted adenoviruses for radiation-guided gene delivery

The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber-modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment

Gate-tunable black phosphorus spin valve with nanosecond spin lifetimes

Two-dimensional materials offer new opportunities for both fundamental science and technological applications, by exploiting the electron spin. While graphene is very promising for spin communication due to its extraordinary electron mobility, the lack of a band gap restricts its prospects for semiconducting spin devices such as spin diodes and bipolar spin transistors. The recent emergence of 2D semiconductors could help overcome this basic challenge. In this letter we report the first important step towards making 2D semiconductor spin devices. We have fabricated a spin valve based on ultra-thin (5 nm) semiconducting black phosphorus (bP), and established fundamental spin properties of this spin channel material which supports all electrical spin injection, transport, precession and detection up to room temperature (RT). Inserting a few layers of boron nitride between the ferromagnetic electrodes and bP alleviates the notorious conductivity mismatch problem and allows efficient electrical spin injection into an n-type bP. In the non-local spin valve geometry we measure Hanle spin precession and observe spin relaxation times as high as 4 ns, with spin relaxation lengths exceeding 6 um. Our experimental results are in a very good agreement with first-principles calculations and demonstrate that Elliott-Yafet spin relaxation mechanism is dominant. We also demonstrate that spin transport in ultra-thin bP depends strongly on the charge carrier concentration, and can be manipulated by the electric field effect

interPopula: a Python API to access the HapMap Project dataset

<p>Abstract</p> <p>Background</p> <p>The HapMap project is a publicly available catalogue of common genetic variants that occur in humans, currently including several million SNPs across 1115 individuals spanning 11 different populations. This important database does not provide any programmatic access to the dataset, furthermore no standard relational database interface is provided.</p> <p>Results</p> <p>interPopula is a Python API to access the HapMap dataset. interPopula provides integration facilities with both the Python ecology of software (e.g. Biopython and matplotlib) and other relevant human population datasets (e.g. Ensembl gene annotation and UCSC Known Genes). A set of guidelines and code examples to address possible inconsistencies across heterogeneous data sources is also provided.</p> <p>Conclusions</p> <p>interPopula is a straightforward and flexible Python API that facilitates the construction of scripts and applications that require access to the HapMap dataset.</p

Expression, purification and characterization of the Lily symptomless virus coat protein from Lanzhou Isolate

Background: Lily symptomless virus (LSV) is widespread in many countries where lily are grown or planted, and causes severe economic losses in terms of quantity and quality of flower and bulb production. To study the structure-function relationship of coat protein (CP) of LSV, to investigate antigenic relationships between coat protein subunits or intact virons, and to prepare specific antibodies against LSV, substantial amounts of CP protein are needed. Results: Thus, full-length cDNA of LSV coat protein was synthesized and amplified by RT-PCR from RNA isolated from LSV Lanzhou isolate. The extended 33.6 kDa CP was cloned and expressed prokaryoticly and then purified by Ni-ion affinity chromatography. Its identity and antigenicity of recombinant CP were identified on Western-blotting by using the prepared anti-LSV antibodies. Conclusions: The results indicate that fusion CP maintains its native antigenicity and specificity, providing a good source of antigen in preparation of LSV related antibodies. Detailed structural analysis of a pure recombinant CP should allow a better understanding of its role in cell attachment and LSV tropism. This investigation to LSV should provide some specific antibodies and aid to development a detection system for LSV diagnostics and epidemiologic surveys