Introduction

Asset management, a distinctive sector within the financial services industry, centers on an agency relationship between a client and an individual manager or firm appointed to manage the client\u27s investment portfolio. Additionally, in many jurisdictions asset managers are subject to a technically complex set of regulatory requirements, which differ across jurisdictions. This book is the only comparative analysis of the law of asset manager liability in the major European jurisdictions, the United States, and Canada, with chapters written by specialists from the relevant jurisdictions plus a comprehensive chapter covering the relevant European law, in particular the MiFID directive. The book\u27s coverage is limited to relationships that pertain to individual portfolios of securities, as opposed to collective investment schemes such as mutual funds and UCITs. A central focus is how regulation interacts with civil liability, whether based on breaches of duties imposed by general law (such as breach of fiduciary duty and duties of care) or on breaches of duties imposed by regulation itself. The Introduction, co-authored by the book\u27s co-editors, situates the country-by-country materials within the broader context of questions about regulatory design and effectiveness. These include whether regulation and liability should be understood as substitutes for each other or as necessary complements; differences in the style of regulation; the role of industry-based self-regulation; and the impact of mandated disclosure of information by asset managers

Clec12a Is an Inhibitory Receptor for Uric Acid Crystals that Regulates Inflammation in Response to Cell Death

SummaryRecognition of cell death by the innate immune system triggers inflammatory responses. However, how these reactions are regulated is not well understood. Here, we identify the inhibitory C-type lectin receptor Clec12a as a specific receptor for dead cells. Both human and mouse Clec12a could physically sense uric acid crystals (monosodium urate, MSU), which are key danger signals for cell-death-induced immunity. Clec12a inhibited inflammatory responses to MSU in vitro, and Clec12a-deficient mice exhibited hyperinflammatory responses after being challenged with MSU or necrotic cells and after radiation-induced thymocyte killing in vivo. Thus, we identified a negative regulatory MSU receptor that controls noninfectious inflammation in response to cell death that has implications for autoimmunity and inflammatory disease

Generation of ordered protein assemblies using rigid three-body fusion

Protein nanomaterial design is an emerging discipline with applications in medicine and beyond. A longstanding design approach uses genetic fusion to join protein homo-oligomer subunits via α-helical linkers to form more complex symmetric assemblies, but this method is hampered by linker flexibility and a dearth of geometric solutions. Here, we describe a general computational method that performs rigid three-body fusion of homo-oligomer and spacer building blocks to generate user-defined architectures, while at the same time significantly increasing the number of geometric solutions over typical symmetric fusion. The fusion junctions are then optimized using Rosetta to minimize flexibility. We apply this method to design and test 92 dihedral symmetric protein assemblies from a set of designed homo-dimers and repeat protein building blocks. Experimental validation by native mass spectrometry, small angle X-ray scattering, and negative-stain single-particle electron microscopy confirms the assembly states for 11 designs. Most of these assemblies are constructed from DARPins (designed ankyrin repeat proteins), anchored on one end by α-helical fusion and on the other by a designed homo-dimer interface, and we explored their use for cryo-EM structure determination by incorporating DARPin variants selected to bind targets of interest. Although the target resolution was limited by preferred orientation effects, small scaffold size, and the low-order symmetry of these dihedral scaffolds, we found that the dual anchoring strategy reduced the flexibility of the target-DARPIN complex with respect to the overall assembly, suggesting that multipoint anchoring of binding domains could contribute to cryo-EM structure determination of small proteins

Generation of ordered protein assemblies using rigid three-body fusion

Protein nanomaterial design is an emerging discipline with applications in medicine and beyond. A longstanding design approach uses genetic fusion to join protein homo-oligomer subunits via α-helical linkers to form more complex symmetric assemblies, but this method is hampered by linker flexibility and a dearth of geometric solutions. Here, we describe a general computational method that performs rigid three-body fusion of homo-oligomer and spacer building blocks to generate user-defined architectures, while at the same time significantly increasing the number of geometric solutions over typical symmetric fusion. The fusion junctions are then optimized using Rosetta to minimize flexibility. We apply this method to design and test 92 dihedral symmetric protein assemblies from a set of designed homo-dimers and repeat protein building blocks. Experimental validation by native mass spectrometry, small angle X-ray scattering, and negative-stain single-particle electron microscopy confirms the assembly states for 11 designs. Most of these assemblies are constructed from DARPins (designed ankyrin repeat proteins), anchored on one end by α-helical fusion and on the other by a designed homo-dimer interface, and we explored their use for cryo-EM structure determination by incorporating DARPin variants selected to bind targets of interest. Although the target resolution was limited by preferred orientation effects, small scaffold size, and the low-order symmetry of these dihedral scaffolds, we found that the dual anchoring strategy reduced the flexibility of the target-DARPIN complex with respect to the overall assembly, suggesting that multipoint anchoring of binding domains could contribute to cryo-EM structure determination of small proteins

PD-L1 Dependent Immunogenic Landscape in Hot Lung Adenocarcinomas Identified by Transcriptome Analysis

Background: Lung cancer is the most frequent cause of cancer-related deaths worldwide. The clinical development of immune checkpoint blockade has dramatically changed the treatment paradigm for patients with lung cancer. Yet, an improved understanding of PD-1/PD-L1 checkpoint blockade- responsive biology is warranted. Methods: We aimed to identify the landscape of immune cell infiltration in primary lung adenocarcinoma (LUAD) in the context of tumoral PD-L1 expression and the extent of immune infiltration ("hot" vs. "cold" phenotype). The study comprises LUAD cases (n = 138) with "hot" (≥150 lymphocytes/HPF) and "cold" (<150 lymphocytes/HPF) tumor immune phenotype and positive (>50%) and negative (<1%) tumor PD-L1 expression, respectively. Tumor samples were immunohistochemically analyzed for expression of PD-L1, CD4, and CD8, and further investigated by transcriptome analysis. Results: Gene set enrichment analysis defined complement, IL-JAK-STAT signaling, KRAS signaling, inflammatory response, TNF-alpha signaling, interferon-gamma response, interferon-alpha response, and allograft rejection as significantly upregulated pathways in the PD-L1-positive hot subgroup. Additionally, we demonstrated that STAT1 is upregulated in the PD-L1-positive hot subgroup and KIT in the PD-L1-negative hot subgroup. Conclusion: The presented study illustrates novel aspects of PD-L1 regulation, with potential biological relevance, as well as relevance for immunotherapy response stratification

Design of an Attitude Dynamics and Control Subsystem for a medium Earth orbit satellite

The Department of Defense has a continuing need for satellite communications to satisfy the demand for information exchange for strategic, operations, and tactical warfighters. There is currently a transition planning effort to develop a satellite communications architecture for the 2007-2010 time frame. During this time all three current communication satellite systems; UFO, DSCS, and MILSTAR, are expected to degrade rapidly. As part of the transition planning effort, the U.S. Navy was tasked to form a Mobile Users Study to establish a framework for completing the detailed requirements and engineering work needed to develop the UHF/Mobile User transition plan. Then, as part of the Navy effort, the Naval Postgraduate School's Astronautical Engineering class SE-61 under Professor Brij Agrawal's guidance designed a proposed medium Earth orbit communications satellite. This thesis is a design of the Attitude Dynamics and Control Subsystem for the subject medium Earth MUS communications satellite. The thesis describes and explores the five major steps in designing an Attitude Dynamics and Control Subsystem and focuses on key ADCS related areas that are peculilar to a MEO satellite as compared to a GEO satellite.http://archive.org/details/designofattitude00buscLieutenant, United States NavyApproved for public release; distribution is unlimited

Summary and Conclusions

status: publishe

Introduction

Asset management, a distinctive sector within the financial services industry, centers on an agency relationship between a client and an individual manager or firm appointed to manage the client\u27s investment portfolio. Additionally, in many jurisdictions asset managers are subject to a technically complex set of regulatory requirements, which differ across jurisdictions. This book is the only comparative analysis of the law of asset manager liability in the major European jurisdictions, the United States, and Canada, with chapters written by specialists from the relevant jurisdictions plus a comprehensive chapter covering the relevant European law, in particular the MiFID directive. The book\u27s coverage is limited to relationships that pertain to individual portfolios of securities, as opposed to collective investment schemes such as mutual funds and UCITs. A central focus is how regulation interacts with civil liability, whether based on breaches of duties imposed by general law (such as breach of fiduciary duty and duties of care) or on breaches of duties imposed by regulation itself. The Introduction, co-authored by the book\u27s co-editors, situates the country-by-country materials within the broader context of questions about regulatory design and effectiveness. These include whether regulation and liability should be understood as substitutes for each other or as necessary complements; differences in the style of regulation; the role of industry-based self-regulation; and the impact of mandated disclosure of information by asset managers