Toward automated document reformatting: A SGML markup system

A SGML markup system is presented. One major obstacle for the SGML to gain more application is the prohibitively high cost of the markup process. The system we are to present adopts an incremental design approach. This approach helps to ``divide and conquer` each specific problem encountered during the markup process and ensures that the system converges to a almost-fully automated markup system. The major software components of the system are described. Some selective algorithms are also introduced

Advanced information science and object-oriented technology for information management applications

The role of the military has been undergoing rapid change since the fall of the Berlin Wall. The kinds of missions the US military has been asked to participate in have often fallen into the category of {open_quotes}Military Operations Other Than War{close_quotes} and those involving military responses have been more of a surgical nature directed against different kinds of threats, like rogue states or in response to terrorist actions. As a result, the requirements on the military planner and analyst have also had to change dramatically. For example, preparing response options now requires rapid turnaround and a highly flexible simulation capability. This in turn requires that the planner or analyst have access to sophisticated information science and simulation technologies. In this paper, we shall discuss how advanced information science and object-oriented technologies can be used in advanced information management applications. We shall also discuss how these technologies and tools can be applied to DoD applications by presenting examples with a system developed at Argonne, the Dynamic Information Architecture System (DIAS). DIAS has been developed to exploit advanced information science and simulation technologies to provide tools for future planners and analysts

Proteomics reveals distinct mechanisms regulating the release of cytokines and alarmins during pyroptosis

A major pathway for proinflammatory protein release by macrophages is inflammasome-mediated pyroptotic cell death. As conventional secretion, unconventional secretion, and cell death are executed simultaneously, however, the cellular mechanisms regulating this complex paracrine program remain incompletely understood. Here, we devise a quantitative proteomics strategy to define the cellular exit route for each protein by pharmacological and genetic dissection of cellular checkpoints regulating protein release. We report the release of hundreds of proteins during pyroptosis, predominantly due to cell lysis. They comprise constitutively expressed and transcriptionally induced proteins derived from the cytoplasm and specific intracellular organelles. Many low-molecular-weight proteins including the cytokine interleukin-1b, alarmins, and lysosomal-cargo proteins exit cells in the absence of cell lysis. Cytokines and alarmins are released in an endoplasmic reticulum (ER)-Golgi-dependent manner as free proteins rather than by extracellular vesicles. Our work provides an experimental framework for the dissection of cellular exit pathways and a resource for pyroptotic protein release

Resonance Raman investigations of the symmetric stretching mode of I3- anions in α and β phases of di-bis(ethylenedithio)tetrathiafulvalene tri-iodide

The resonance Raman spectra of I3- anions in the organic superconductor β-(BEDT-TTF)2I3 [BEDT-TTF represents bis(ethylenedithio)tetrathiafulvalene] were studied and discussed in comparison with the nonsuperconducting phase of α-(BEDT-TTF)2I3. In both modifications at low temperature a splitting of the Raman mode assigned to the symmetric stretching mode of the I3- anions was discovered. The splitting of this mode in the β-(BEDT-TTF)2I3 crystals is related to the commensurate superstructure developed below 125 K in contradiction to the α phase where the splitting is related to a crystal-field effect. It is shown that an electronic excitation of the β-phase crystals by laser light can induce a structural transformation at least in a thin layer of the surface. This transformation is observed by a disappearance of the splitting of the symmetric stretching mode. The structural change can be related to a transformation from the commensurate superstructure with a superconducting transition temperature Tc=1.3 K into a more ordered and symmetric structure which becomes superconducting at Tc=8.1 K

A stable superconducting state at 8K and ambient pressure in αt-(BEDT-TTF)2I3

We report bulk superconductivity at 8 K and ambient pressure in crystals of α t (BEDT-TTF)2I3. In contrast to the earlier observed metastable superconducting state at 8 K in crystals of β-(BEDT-TTF)2I3 here the superconducting state is stable and the crystals can be prepared by tempering α-(BEDT-TTF)2I3 above 70 °C for several days. ac-susceptibility measurements show that the observed superconducting state at 8 K is a bulk property of the crystals. Resistivity measurements indicate a sharp superconducting transition at 8 K with an onset temperature of about 9 K. The upper critical fields Hc2 at 1.3 K lie between 3 and 11 T depending on the direction of the magnetic field with respect to the crystal axes. ESR- as well as NMR-measurements indicate a total transformation of the α-phase crystals into the new superconducting α t -crystals after tempering

Expression Quantitative Trait Locus Mapping in Pulmonary Arterial Hypertension.

Expression quantitative trait loci (eQTL) can provide a link between disease susceptibility variants discovered by genetic association studies and biology. To date, eQTL mapping studies have been primarily conducted in healthy individuals from population-based cohorts. Genetic effects have been known to be context-specific and vary with changing environmental stimuli. We conducted a transcriptome- and genome-wide eQTL mapping study in a cohort of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) using RNA sequencing (RNAseq) data from whole blood. We sought confirmation from three published population-based eQTL studies, including the GTEx Project, and followed up potentially novel eQTL not observed in the general population. In total, we identified 2314 eQTL of which 90% were cis-acting and 75% were confirmed by at least one of the published studies. While we observed a higher GWAS trait colocalization rate among confirmed eQTL, colocalisation rate of novel eQTL reported for lung-related phenotypes was twice as high as that of confirmed eQTL. Functional enrichment analysis of genes with novel eQTL in PAH highlighted immune-related processes, a suspected contributor to PAH. These potentially novel eQTL specific to or active in PAH could be useful in understanding genetic risk factors for other diseases that share common mechanisms with PAH

The Medical Action Ontology: A tool for annotating and analyzing treatments and clinical management of human disease.

BACKGROUND: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions. METHODS: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology. FINDINGS: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases. CONCLUSIONS: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO). FUNDING: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04

Tumor-Derived Lactic Acid Modulates Activation and Metabolic Status of Draining Lymph Node Stroma

Communication between tumors and the stroma of tumor-draining lymph nodes (TDLN) exists before metastasis arises, altering the structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRC), the dominant stromal population of lymph nodes, has revealed that FRCs in TDLNs are reprogrammed. However, the tumor-derived factors driving the changes in FRCs remain to be identified. Taking an unbiased approach, we have shown herein that lactic acid (LA), a metabolite released by cancer cells, was not only secreted by B16.F10 and 4T1 tumors in high amounts, but also that it was enriched in TDLNs. LA supported an upregulation of Podoplanin (Pdpn) and Thy1 and downregulation of IL7 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we found that tumor-derived LA altered mitochondrial function of FRCs in TDLNs. Thus, our results demonstrate a mechanism by which a tumor-derived metabolite connected with a low pH environment modulates the function of fibroblasts in TDLNs. How lymph node function is perturbed to support cancer metastases remains unclear. The authors show that tumor-derived LA drains to lymph nodes where it modulates the function of lymph node stromal cells, prior to metastatic colonization

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention