The initial singularity of ultrastiff perfect fluid spacetimes without symmetries

We consider the Einstein equations coupled to an ultrastiff perfect fluid and prove the existence of a family of solutions with an initial singularity whose structure is that of explicit isotropic models. This family of solutions is `generic' in the sense that it depends on as many free functions as a general solution, i.e., without imposing any symmetry assumptions, of the Einstein-Euler equations. The method we use is a that of a Fuchsian reduction.Comment: 16 pages, journal versio

Combining in Silico Tools with Multicriteria Analysis for Alternatives Assessment of Hazardous Chemicals: A Case Study of Decabromodiphenyl Ether Alternatives

Alternatives assessment is applied for minimizing the risk of unintentionally replacing a hazardous chemical with another hazardous chemical. Central challenges are the diversity of properties to consider and the lack of high-quality experimental data. To address this, a novel alternatives assessment procedure was developed based on in silico data and multicriteria decision analysis (MCDA) methods. As a case study, 16 alternatives to the flame retardant decabromodiphenyl ether were considered. The hazard properties included persistence (P), bioaccumulation potential (B), toxicities (T), and mobility in water (M). Databases were consulted and 2866 experimental data points were collected for the target chemicals; however, these were mostly replicate data points for some hazard criteria for a subset of alternatives. Therefore, in silico data and three MCDA strategies were tested including heat mapping, multiattribute utility theory (MAUT), and Elimination Et Choix Traduisant la REalit\ue9 (ELECTRE III). The heat map clearly showed that none of the target chemicals are hazard-free, whereas MAUT and ELECTRE III agreed on ranking the "least worst" choices. This study identified several challenges and the complexity in the alternatives assessment processes motivating more case studies combining in silico and MCDA approaches

Collision Dynamics and Solvation of Water Molecules in a Liquid Methanol Film

Environmental molecular beam experiments are used to examine water interactions with liquid methanol films at temperatures from 170 K to 190 K. We find that water molecules with 0.32 eV incident kinetic energy are efficiently trapped by the liquid methanol. The scattering process is characterized by an efficient loss of energy to surface modes with a minor component of the incident beam that is inelastically scattered. Thermal desorption of water molecules has a well characterized Arrhenius form with an activation energy of 0.47{\pm}0.11 eV and pre-exponential factor of 4.6 {\times} 10^(15{\pm}3) s^(-1). We also observe a temperature dependent incorporation of incident water into the methanol layer. The implication for fundamental studies and environmental applications is that even an alcohol as simple as methanol can exhibit complex and temperature dependent surfactant behavior.Comment: 8 pages, 5 figure

Gene expression signatures in childhood acute leukemias are largely unique and distinct from those of normal tissues and other malignancies

<p>Abstract</p> <p>Background</p> <p>Childhood leukemia is characterized by the presence of balanced chromosomal translocations or by other structural or numerical chromosomal changes. It is well know that leukemias with specific molecular abnormalities display profoundly different global gene expression profiles. However, it is largely unknown whether such subtype-specific leukemic signatures are unique or if they are active also in non-hematopoietic normal tissues or in other human cancer types.</p> <p>Methods</p> <p>Using gene set enrichment analysis, we systematically explored whether the transcriptional programs in childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML) were significantly similar to those in different flow-sorted subpopulations of normal hematopoietic cells (n = 8), normal non-hematopoietic tissues (n = 22) or human cancer tissues (n = 13).</p> <p>Results</p> <p>This study revealed that e.g., the t(12;21) [<it>ETV6-RUNX1</it>] subtype of ALL and the t(15;17) [<it>PML-RARA</it>] subtype of AML had transcriptional programs similar to those in normal Pro-B cells and promyelocytes, respectively. Moreover, the 11q23/<it>MLL </it>subtype of ALL showed similarities with non-hematopoietic tissues. Strikingly however, most of the transcriptional programs in the other leukemic subtypes lacked significant similarity to ~100 gene sets derived from normal and malignant tissues.</p> <p>Conclusions</p> <p>This study demonstrates, for the first time, that the expression profiles of childhood leukemia are largely unique, with limited similarities to transcriptional programs active in normal hematopoietic cells, non-hematopoietic normal tissues or the most common forms of human cancer. In addition to providing important pathogenetic insights, these findings should facilitate the identification of candidate genes or transcriptional programs that can be used as unique targets in leukemia.</p

Frequent CXCR4 tropism of HIV-1 subtype A and CRF02_AG during late-stage disease - indication of an evolving epidemic in West Africa

<p>Abstract</p> <p>Background</p> <p>HIV-1 is one of the fastest evolving pathogens, and is distinguished by geographic and genetic variants that have been classified into different subtypes and circulating recombinant forms (CRFs). Early in infection the primary coreceptor is CCR5, but during disease course CXCR4-using HIV-1 populations may emerge. This has been correlated with accelerated disease progression in HIV-1 subtype B. Basic knowledge of HIV-1 coreceptor tropism is important due to the recent introduction of coreceptor antagonists in antiretroviral therapy, and subtype-specific differences regarding how frequently HIV-1 CXCR4-using populations appear in late-stage disease need to be further investigated. To study how frequently CXCR4-using populations appear in late-stage disease among HIV-1 subtype A and CRF02_AG, we evaluated the accuracy of a recombinant virus phenotypic assay for these subtypes, and used it to determine the HIV-1 coreceptor tropism of plasma samples collected during late-stage disease in Guinea-Bissau. We also performed a genotypic analysis and investigated subtype-specific differences in the appearance of CXCR4 tropism late in disease.</p> <p>Results</p> <p>We found that the recombinant virus phenotypic assay accurately predicted HIV-1 coreceptor tropism of subtype A and CRF02_AG. Over the study period (1997-2007), we found an increasing and generally high frequency of CXCR4 tropism (86%) in CRF02_AG. By sequence analysis of the V3 region of our samples we developed a novel genotypic rule for predicting CXCR4 tropism in CRF02_AG, based on the combined criteria of the total number of charged amino acids and net charge. This rule had higher sensitivity than previously described genotypic rules and may be useful for development of future genotypic tools for this CRF. Finally, we conducted a literature analysis, combining data of 498 individuals in late-stage disease, and found high amounts of CXCR4 tropism for all major HIV-1 subtypes (60-77%), except for subtype C (15%).</p> <p>Conclusions</p> <p>The increase in CXCR4 tropism over time suggests an evolving epidemic of CRF02_AG. The results of the literature analysis demonstrate the need for further studies investigating subtype-specific emergence for CXCR4-tropism; this may be particularly important due to the introduction of CCR5-antagonists in HIV treatment regimens.</p

The goliath project: Towards an internationally harmonised approach for testing metabolism disrupting compounds

Copyright © 2020 by the authors. The purpose of this project report is to introduce the European “GOLIATH” project, a new research project which addresses one of the most urgent regulatory needs in the testing of endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as “metabolism disrupting compounds” (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the world’s first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption—hepatocytes, pancreatic endocrine cells, myocytes and adipocytes—and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development

Toxicological Profile of Ultrapure 2,2 ',3,4,4 ',5,5 '-Heptachlorbiphenyl (PCB 180) in Adult Rats

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