Structure of FcRY, an avian immunoglobulin receptor related to mammalian mannose receptors, and its complex with IgY

Fc receptors transport maternal antibodies across epithelial cell barriers to passively immunize newborns. FcRY, the functional counterpart of mammalian FcRn (a major histocompatibility complex homolog), transfers IgY across the avian yolk sac, and represents a new class of Fc receptor related to the mammalian mannose receptor family. FcRY and FcRn bind immunoglobulins at pH ≤6.5, but not pH ≥7, allowing receptor–ligand association inside intracellular vesicles and release at the pH of blood. We obtained structures of monomeric and dimeric FcRY and an FcRY–IgY complex and explored FcRY's pH-dependent binding mechanism using electron cryomicroscopy (cryoEM) and small-angle X-ray scattering. The cryoEM structure of FcRY at pH 6 revealed a compact double-ring “head,” in which the N-terminal cysteine-rich and fibronectin II domains were folded back to contact C-type lectin-like domains 1–6, and a “tail” comprising C-type lectin-like domains 7–8. Conformational changes at pH 8 created a more elongated structure that cannot bind IgY. CryoEM reconstruction of FcRY dimers at pH 6 and small-angle X-ray scattering analysis at both pH values confirmed both structures. The cryoEM structure of the FcRY–IgY revealed symmetric binding of two FcRY heads to the dimeric FcY, each head contacting the CH4 domain of one FcY chain. FcRY shares structural properties with mannose receptor family members, including a head and tail domain organization, multimerization that may regulate ligand binding, and pH-dependent conformational changes. Our results facilitate understanding of immune recognition by the structurally related mannose receptor family and comparison of diverse methods of Ig transport across evolution

Schizophrenia trials in China: a survey

OBJECTIVE: China's biomedical research activity is increasing and this literature is becoming more accessible online. Our aim was to survey all randomized control schizophrenia trials (RCTs) in one Chinese bibliographic database. METHOD: Chinese Academic Journals was electronically searched for RCTs and all relevant citations were also sought on PubMed to ascertain global accessibility. RESULTS: The search identified 3275 records, of which 982 were RCTs relevant to schizophrenia. A total of 71% (699) could be found by using English phrases. All the main body of text of the 982 papers was in Mandarin. On average, these trials involved about 100 people, with interventions and outcome measures familiar to schizophrenia trialists worldwide. Four of the 982 records (<1%) were identified on PubMed. CONCLUSION: Those undertaking systematic reviews should search the Chinese literature for relevant material. Failing to do this will leave the results of systematic reviews prone to random error or bias, or both

Acute Effects of Fine Particulate Air Pollution on Cardiac Arrhythmia: The APACR Study

Background: The mechanisms underlying the relationship between particulate matter (PM) air pollution and cardiac disease are not fully understood

Yttrium-90 Radioembolization in Patients with Hepatocellular Carcinoma Who have Previously Received Sorafenib

Purpose: Yttrium-90 radioembolization (RE) is a locoregional therapy option for hepatocellular carcinoma (HCC). Sorafenib is a multikinase inhibitor used in HCC that can potentially affect the efficacy of RE by altering tumor vascularity or suppressing post-irradiation angiogenesis. The safety and efficacy of sorafenib followed by RE has not been previously reported. Materials and Methods: Patients with HCC who received RE after sorafenib were included in this retrospective review. Overall survival, toxicity, and maximal radiographic response and necrosis criteria were examined. Results: Ten patients (15 RE administrations) fit the inclusion criteria. All were Barcelona Clinic Liver Cancer (BCLC) stage C. Median follow-up was 16.5 weeks. Median overall survival and radiographic progression-free survival were 30 and 28 weeks, respectively. Significant differences in overall survival were seen based on Child-Pugh class (p = 0.002) and radiographic response (p = 0.009). Three patients had partial response, six had stable disease, and one had progressive disease. Grade 1 or 2 acute fatigue, anorexia, and abdominal pain were common. Three patients had Grade 3 ascites in the setting of disease progression. Two patients had Grade 3 biochemical toxicity. One patient was sufficiently downstaged following RE and sorafenib to receive a partial hepatectomy. Conclusion: Yttrium-90 RE in patients with HCC who have received sorafenib demonstrate acceptable toxicity and rates of radiographic response. However, the overall survival is lower than that reported in the literature on RE alone or sorafenib alone. This may be due in part to more patients in this study having advanced disease compared to these other study populations. Larger prospective studies are needed to determine whether the combination of RE and sorafenib is superior to either therapy alone

VASP Activation via the Gα13/RhoA/PKA Pathway Mediates Cucurbitacin-B-Induced Actin Aggregation and Cofilin-Actin Rod Formation

Cucurbitacin B (CuB), a potent antineoplastic agent of cucurbitacin triterpenoids, induces rapid disruption of actin cytoskeleton and aberrant cell cycle inhibiting carcinogenesis. However, the underlying molecular mechanism of such anticancer effects remains incompletely understood. In this study, we showed that CuB treatment rapidly induced vasodilator-stimulated phosphoprotein (VASP) phosphorylation (i.e. activation) at the Ser157 residue and generated VASP clumps which were co-localized with amorphous actin aggregates prior to the formation of highly-ordered cofilin-actin rods in melanoma cells. Knockdown of VASP or inhibition of VASP activation using PKA-specific inhibitor H89 suppressed CuB-induced VASP activation, actin aggregation and cofilin-actin rod formation. The VASP activation was mediated by cAMP-independent PKA activation as CuB decreased the levels of cAMP while MDL12330A, an inhibitor of adenylyl cyclase, had weak effect on VASP activation. Knockdown of either Gα13 or RhoA not only suppressed VASP activation, but also ameliorated CuB-induced actin aggregation and abrogated cofilin-actin rod formation. Collectively, our studies highlighted that the CuB-induced actin aggregation and cofilin-actin rod formation was mediated via the Gα13/RhoA/PKA/VASP pathway

A structured representation for parallel algorithm design on multicomputers

Traditionally, parallel algorithms have been designed by brute force methods and fine-tuned on each architecture to achieve high performance. Rather than studying the design case by case, a systematic approach is proposed. A notation is first developed. Using this notation, most of the frequently used scientific and engineering applications can be presented by simple formulas. The formulas constitute the structured representation of the corresponding applications. The structured representation is simple, adequate and easy to understand. They also contain sufficient information about uneven allocation and communication latency degradations. With the structured representation, applications can be compared, classified and partitioned. Some of the basic building blocks, called computation models, of frequently used applications are identified and studied. Most applications are combinations of some computation models. The structured representation relates general applications to computation models. Studying computation models leads to a guideline for efficient parallel algorithm design for general applications. 6 refs., 7 figs

FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4- induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification

Global Power Counting Analysis On Probing Electroweak Symmetry Breaking Mechanism At High Energy Colliders

We develop a precise power counting rule (a generalization of Weinberg's counting method for the nonlinear sigma model) for the electroweak theories formulated by chiral Lagrangians. Then we estimate the contributions of ``all'' next-to-leading order (NLO) bosonic operators to the amplitudes of the relevant scattering processes which can be measured at high energy colliders, such as the LHC and future Linear Colliders. Based upon these results, we globally classify the sensitivities of testing all NLO bosonic operators for probing the electroweak symmetry breaking mechanism at high energy colliders.Comment: Version Published in Physics Letters B. Latex, 12 pages, minor typos correcte

All inkjet-printed graphene-based conductive patterns for wearable e-textile applications

© 2017 The Royal Society of Chemistry. Inkjet printing of graphene inks is considered to be very promising for wearable e-textile applications as benefits of both inkjet printing and extra-ordinary electronic, optical and mechanical properties of graphene can be exploited. However, the common problem associated with inkjet printing of conductive inks on textiles is the difficulty to print a continuous conductive path on a rough and porous textile surface. Here we report inkjet printing of an organic nanoparticle based surface pre-treatment onto textiles to enable all inkjet-printed graphene e-textiles for the first time. The functionalized organic nanoparticles present a hydrophobic breathable coating on textiles. Subsequent inkjet printing of a continuous conductive electrical path onto the pre-treated coating reduced the sheet resistance of graphene-based printed e-textiles by three orders of magnitude from 1.09 × 106 Ω sq-1 to 2.14 × 103 Ω sq-1 compared with untreated textiles. We present several examples of how this finding opens up opportunities for real world applications of printed, low cost and environmentally friendly graphene wearable e-textiles