Further phenotypic characterization of the primitive lineage− CD34+CD38−CD90+CD45RA− hematopoietic stem cell/progenitor cell sub-population isolated from cord blood, mobilized peripheral blood and patients with chronic myelogenous leukemia

The most primitive hematopoietic stem cell (HSC)/progenitor cell (PC) population reported to date is characterized as being Lin−CD34+CD38−CD90+CD45R. We have a long-standing interest in comparing the characteristics of hematopoietic progenitor cell populations enriched from normal subjects and patients with chronic myelogenous leukemia (CML). In order to investigate further purification of HSCs and for potential targetable differences between the very primitive normal and CML stem/PCs, we have phenotypically compared the normal and CML Lin−CD34+CD38−CD90+CD45RA− HSC/PC populations. The additional antigens analyzed were HLA-DR, the receptor tyrosine kinases c-kit and Tie2, the interleukin-3 cytokine receptor, CD33 and the activation antigen CD69, the latter of which was recently reported to be selectively elevated in cell lines expressing the Bcr-Abl tyrosine kinase. Notably, we found a strikingly low percentage of cells from the HSC/PC sub-population isolated from CML patients that were found to express the c-kit receptor (<1%) compared with the percentages of HSC/PCs expressing the c-kitR isolated from umbilical cord blood (50%) and mobilized peripheral blood (10%). Surprisingly, Tie2 receptor expression within the HSC/PC subset was extremely low from both normal and CML samples. Using in vivo transplantation studies, we provide evidence that HLA-DR, c-kitR, Tie2 and IL-3R may not be suitable markers for further partitioning of HSCs from the Lin−CD34+CD38−CD90+CD45RA− sub-population

Abnormal Intracellular Accumulation and Extracellular Aβ Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders

<div><h3>Background</h3><p>It has been shown that amyloid ß (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount.</p> <h3>Methodology/Principal Findings</h3><p>In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Aβ load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Aβ load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly N-terminally truncated. Increased intraneuronal accumulation of Aβ_17–40/42 in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aβ_1–40/42 detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques.</p> <h3>Conclusions/Significance</h3><p>The higher prevalence of excessive Aβ accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.</p> </div

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C

Guideline for Load and Resistance Assessment of Existing European Railway Bridges : Advices on the use of advanced methods

The bridge assessment in many aspects is very similar to the bridge design. The same basic principles lie at the heart of the process. Nevertheless, an important difference lies in the fact that when a bridge is being designed, an element of conservatism is generally a good thing that can be achieved with very little additional costs. When a bridge is being assessed, it is important to avoid unnecessarily conservative measures because of the financial implications that may follow the decision of ratingthe bridge as deficient. Therefore, the design codes (e.g. EC codes) may not always be appropriate for assessment of existing bridges and some additional recommendations or guidelines are required that will lead to less conservative assessment of theirs load carrying capacity. Such guidelines have been already proposed for assessment of highway bridges in Europe. However, there is a lack of this type of documents that can be applied for the assessment of railway bridges. The present "Guideline for Load and Resistance Assessment of Existing European Railway Bridges - advices on the use of advanced methods" is providing guidance and recommendations for applying the most advanced and beneficial methods, models and tools for assessing the load carrying capacity of existing railway bridges. This includes systematized step-level assessment methodology, advanced safety formats (e.g. probabilistic or simplified probabilistic) refined structural analysis (e.g. non-linear or plastic, dynamic considering train-bridge interaction), better models of loads and resistance parameters (e.g. probabilistic and/or based on the results of measurements) and methods for incorporation of the results form monitoring and on-site testing (e.g. Bayesian updating). Basis for the "Guideline for Load and Resistance Assessment of Existing EuropeanRailway Bridges - advices on the use of advanced methods" is the research work carried out in the work package WP4 of the Sustainable Bridges project combined with the best practical experience and know-how of all the partners involved. The research activities within the work package WP4 have been carried out in the following five groups: − Loads and dynamic effects, with focus on train loads and dynamics (Deliverables D4.3, also referred as SB 4.3 Dynamic (2007), or just SB4.3 (2007)); − Safety and probabilistic modelling (Deliverables D4.4, also referred as SB4.4Safety (2007), or just SB4.4 (2007)); − Concrete bridges, with focus on non-linear analysis (Deliverables D4.5, also referred as SB4.5 Concrete (2007), or just SB4.5 (2007)); − Metal bridges, with focus on riveted bridges (Deliverables D4.6, also referredas SB4.6 Metal (2007), or just SB4.6 (2007)); − Masonry arch bridges including soil/structure interaction (Deliverables D4.7,also referred as SB4.7 Masonry (2007), or just SB4.7 (2007)). The results of these activities are reported in corresponding Background Documents (Deliverables) listed above within parenthesis. The main results from the research activities performed and the know-how of all the partners in the specific areas of bridge assessment are tried to be presented in this Sustainable Bridges SB-LRA 2007-11-30 6 (428) Guideline in such a way that the target reader of the Guideline, a structural engineer experienced in assessment of railway bridges, is able to apply them in the everyday practice, without necessity of searching for several specific scientific publications. Nevertheless, in some cases it has been necessary to refer to public available literature and Background Documents prepared in the Sustainable Bridges project. The present Guideline has been prepared aiming to follow somehow the structure of the EC codes and it is divided into 10 chapters and 12 Annexes concerning: − Assessment procedure (Chapter 2); − Requirements, safety formats and limit states (Chapter 3, Annexes 3.1-3.7); − Basic information for bridge assessment (Chapter 4); − Load and dynamic effects (Chapter 5, Annex 5.1); − Concrete bridges (Chapter 6); − Metal bridges (Chapter 7, Annex 7.1); − Masonry arch bridges (Chapter 8, Annexes 8.1 and 8.2); − Foundations and transition zones (Chapter 9); − Improvement of assessment using information from testing and monitoring (Chapter 10, Annex 10.1). In most of the topics related to railway bridges assessment the Guideline uses the current state-of-the-art knowledge and the presently best practice. Nevertheless, in many subjects it propose the use of original methods and models that have been developed, obtained or systematized due to research performed within one of the five groups of work package WP4.EU, FP6, Sjätte ramprogrammetTIP3-CT-2003-001653Sustainable Bridges - Assessment for Future Traffic Demands and Longer Live

Guideline for Load and Resistance Assessment of Existing European Railway Bridges : Advices on the use of advanced methods

The bridge assessment in many aspects is very similar to the bridge design. The same basic principles lie at the heart of the process. Nevertheless, an important difference lies in the fact that when a bridge is being designed, an element of conservatism is generally a good thing that can be achieved with very little additional costs. When a bridge is being assessed, it is important to avoid unnecessarily conservative measures because of the financial implications that may follow the decision of ratingthe bridge as deficient. Therefore, the design codes (e.g. EC codes) may not always be appropriate for assessment of existing bridges and some additional recommendations or guidelines are required that will lead to less conservative assessment of theirs load carrying capacity. Such guidelines have been already proposed for assessment of highway bridges in Europe. However, there is a lack of this type of documents that can be applied for the assessment of railway bridges. The present "Guideline for Load and Resistance Assessment of Existing European Railway Bridges - advices on the use of advanced methods" is providing guidance and recommendations for applying the most advanced and beneficial methods, models and tools for assessing the load carrying capacity of existing railway bridges. This includes systematized step-level assessment methodology, advanced safety formats (e.g. probabilistic or simplified probabilistic) refined structural analysis (e.g. non-linear or plastic, dynamic considering train-bridge interaction), better models of loads and resistance parameters (e.g. probabilistic and/or based on the results of measurements) and methods for incorporation of the results form monitoring and on-site testing (e.g. Bayesian updating). Basis for the "Guideline for Load and Resistance Assessment of Existing EuropeanRailway Bridges - advices on the use of advanced methods" is the research work carried out in the work package WP4 of the Sustainable Bridges project combined with the best practical experience and know-how of all the partners involved. The research activities within the work package WP4 have been carried out in the following five groups: − Loads and dynamic effects, with focus on train loads and dynamics (Deliverables D4.3, also referred as SB 4.3 Dynamic (2007), or just SB4.3 (2007)); − Safety and probabilistic modelling (Deliverables D4.4, also referred as SB4.4Safety (2007), or just SB4.4 (2007)); − Concrete bridges, with focus on non-linear analysis (Deliverables D4.5, also referred as SB4.5 Concrete (2007), or just SB4.5 (2007)); − Metal bridges, with focus on riveted bridges (Deliverables D4.6, also referredas SB4.6 Metal (2007), or just SB4.6 (2007)); − Masonry arch bridges including soil/structure interaction (Deliverables D4.7,also referred as SB4.7 Masonry (2007), or just SB4.7 (2007)). The results of these activities are reported in corresponding Background Documents (Deliverables) listed above within parenthesis. The main results from the research activities performed and the know-how of all the partners in the specific areas of bridge assessment are tried to be presented in this Sustainable Bridges SB-LRA 2007-11-30 6 (428) Guideline in such a way that the target reader of the Guideline, a structural engineer experienced in assessment of railway bridges, is able to apply them in the everyday practice, without necessity of searching for several specific scientific publications. Nevertheless, in some cases it has been necessary to refer to public available literature and Background Documents prepared in the Sustainable Bridges project. The present Guideline has been prepared aiming to follow somehow the structure of the EC codes and it is divided into 10 chapters and 12 Annexes concerning: − Assessment procedure (Chapter 2); − Requirements, safety formats and limit states (Chapter 3, Annexes 3.1-3.7); − Basic information for bridge assessment (Chapter 4); − Load and dynamic effects (Chapter 5, Annex 5.1); − Concrete bridges (Chapter 6); − Metal bridges (Chapter 7, Annex 7.1); − Masonry arch bridges (Chapter 8, Annexes 8.1 and 8.2); − Foundations and transition zones (Chapter 9); − Improvement of assessment using information from testing and monitoring (Chapter 10, Annex 10.1). In most of the topics related to railway bridges assessment the Guideline uses the current state-of-the-art knowledge and the presently best practice. Nevertheless, in many subjects it propose the use of original methods and models that have been developed, obtained or systematized due to research performed within one of the five groups of work package WP4.EU, FP6, Sjätte ramprogrammetTIP3-CT-2003-001653Sustainable Bridges - Assessment for Future Traffic Demands and Longer Live

On the Risk of Misbehaving RPKI Authorities

The RPKI is a new security infrastructure that relies on trusted authorities to prevent some of the most devastating attacks on interdomain routing. The threat model for the RPKI supposes that authorities are trusted and routing is under attack. Here we discuss the risks that arise when this threat model is flipped: when RPKI authorities are faulty, misconfigured, compromised, or compelled to misbehave. We show how design decisions that elegantly address the vulnerabilities in the original threat model have unexpected side effects in this flipped threat model. In particular, we show new targeted attacks that allow RPKI authorities, under certain conditions, to limit access to IP prefixes, and discuss the risk that transient RPKI faults can take IP prefixes offline. Our results suggest promising directions for future research, and have implications on the design of security architectures that are appropriate for the untrusted and error-prone Internet