Theory of ω-languages. II: A study of various models of ω-type generation and recognition

ω-languages are sets consisting of ω-length strings; ω-automata are recognition devicesfor ω-languages. In a previous paper the basic notions of ω-grammars, ω-context-free languages (ω-CFL's), and ω-pushdown automata (ω-PDA's) were first defined and studied. In this paper various modes of ω-type generation are introduced and the effect of certain restrictions on the derivations in ω-grammars is investigated. Several distinct models of recognition in ω-PDA's are considered, giving rise to a hierarchy of subfamilies of the ω-CFL's. The relations among these subfamilies are established and characterizations for each family are derived. Non-leftmost derivations in ω-CFG's are studied and it is shown that leftmost generation in ω-CFG's is strictly more powerful than non-leftmost generation

Formats of Winning Strategies for Six Types of Pushdown Games

The solution of parity games over pushdown graphs (Walukiewicz '96) was the first step towards an effective theory of infinite-state games. It was shown that winning strategies for pushdown games can be implemented again as pushdown automata. We continue this study and investigate the connection between game presentations and winning strategies in altogether six cases of game arenas, among them realtime pushdown systems, visibly pushdown systems, and counter systems. In four cases we show by a uniform proof method that we obtain strategies implementable by the same type of pushdown machine as given in the game arena. We prove that for the two remaining cases this correspondence fails. In the conclusion we address the question of an abstract criterion that explains the results

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

‘Multi-Epitope-Targeted’ Immune-Specific Therapy for a Multiple Sclerosis-Like Disease via Engineered Multi-Epitope Protein Is Superior to Peptides

Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents. Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells). Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents. Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases

Validation of the Body Concealment Scale for Scleroderma (BCSS): Replication in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort

© 2016 Elsevier Ltd Body concealment is an important component of appearance distress for individuals with disfiguring conditions, including scleroderma. The objective was to replicate the validation study of the Body Concealment Scale for Scleroderma (BCSS) among 897 scleroderma patients. The factor structure of the BCSS was evaluated using confirmatory factor analysis and the Multiple-Indicator Multiple-Cause model examined differential item functioning of SWAP items for sex and age. Internal consistency reliability was assessed via Cronbach's alpha. Construct validity was assessed by comparing the BCSS with a measure of body image distress and measures of mental health and pain intensity. Results replicated the original validation study, where a bifactor model provided the best fit. The BCSS demonstrated strong internal consistency reliability and construct validity. Findings further support the BCSS as a valid measure of body concealment in scleroderma and provide new evidence that scores can be compared and combined across sexes and ages

Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance

Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non-Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2-5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (∼0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load synaptic protein turnover places on individual neurons is very substantial

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A 50,000-year record of lake-level variations and overflow from Owens Lake, eastern California, USA

A continuous lake-level curve was constructed for Owens Lake, eastern California by integrating lake-core data and shoreline geomorphology with new wind-wave and sediment entrainment modeling of lake-core sedimentology. This effort enabled refinement of the overflow history and development of a better understanding of the effects of regional and global climate variability on lake levels of the paleo-Owens River system during the last 50,000 years. The elevations of stratigraphic sites, plus lake bottom and spillway positions were corrected for vertical tectonic deformation using a differential fault-block model to estimate the absolute hydrologic change of the watershed-lake system. New results include 14C dating of mollusk shells in shoreline deposits, plus post-IR-IRSL dating of a suite of five beach ridges and OSL dating of spillway alluvial and deltaic deposits in deep boreholes. Geotechnical data show the overflow area is an entrenched channel that had erodible sills composed of unconsolidated fluvial-deltaic and alluvial sediment at elevations of ∼1113–1165 m above mean sea level. Owens Lake spilled most of the time at or near minimum sill levels, controlled by a bedrock sill at ∼1113 m. Nine major transgressions at ∼40.0, 38.7, 23.3, 19.3, 15.6, 13.8, 12.8, 11.6, and 10.6 ka reached levels ∼10–45 m above the bedrock sill. Several major regressions at or below the bedrock sill from 36.9 to 28.5 ka, and at ∼17.8, 12.9, and 10.4–8.8 ka indicate little to no overflow during these times. The latest period of overflow occurred ∼10–20 m above the bedrock sill from ∼8.4 to 6.4 ka that was followed by closed basin conditions after ∼6.4 ka. Previous lake core age-depth models were revised by accounting for sediment compaction and using no reservoir correction for open basin conditions, thereby reducing discrepancies between Owens Lake shoreline and lake-core proxy records. The integrated analysis provides a continuous 50 ka lake-level record of hydroclimate variability along the south-central Sierra Nevada that is consistent with other shoreline and speleothem records in the southwestern U.S