On Fast Large-Scale Program Analysis in Datalog

Designing and crafting a static program analysis is challenging due to the complexity of the task at hand. Among the challenges are modelling the semantics of the input language, finding suitable abstractions for the analysis, and handwriting efficient code for the analysis in a traditional imperative language such as C++. Hence, the development of static program analysis tools is costly in terms of development time and resources for real world languages. To overcome, or at least alleviate the costs of developing a static program analysis, Datalog has been proposed as a domain specific language (DSL).With Datalog, a designer expresses a static program analysis in the form of a logical specification. While a domain specific language approach aids in the ease of development of program analyses, it is commonly accepted that such an approach has worse runtime performance than handcrafted static analysis tools. In this work, we introduce a new program synthesis methodology for Datalog specifications to produce highly efficient monolithic C++ analyzers. The synthesis technique requires the re-interpretation of the semi-naïve evaluation as a scaffolding for translation using partial evaluation. To achieve high-performance, we employ staged compilation techniques and specialize the underlying relational data structures for a given Datalog specification. Experimentation on benchmarks for large-scale program analysis validates the superior performance of our approach over available Datalog tools and demonstrates our competitiveness with state-of-the-art handcrafted tools

Clinical Outcomes After Four-Level Anterior Cervical Discectomy and Fusion.

Study Design: Retrospective cohort study. Objectives: Anterior cervical discectomy and fusion (ACDF) demonstrates reliable improvement in neurologic symptoms associated with anterior compression of the cervical spine. There is a paucity of data on outcomes following 4-level ACDFs. The purpose of this study was to evaluate clinical outcomes for patients undergoing 4-level ACDF. Methods: All 4-level ACDFs with at least 1-year clinical follow-up were identified. Clinical outcomes, including fusion rates, neurologic outcomes, and reoperation rates were determined. Results: Retrospective review of our institutional database revealed 25 patients who underwent 4-level ACDF with at least 1-year clinical follow-up. Average age was 57.5 years (range 38.2-75.0 years); 14 (56%) were male, and average body mass index was 30.2 kg/m Conclusions: Review of our institution\u27s experience demonstrated a low rate of revision cervical surgery for any reason of 8% at mean 19 months follow-up, and neurological examinations consistently improved, despite a high rate of radiographic nonunion (31%)

Quantitative Coding and Complexity Theory of Compact Metric Spaces

Specifying a computational problem requires fixing encodings for input and output: encoding graphs as adjacency matrices, characters as integers, integers as bit strings, and vice versa. For such discrete data, the actual encoding is usually straightforward and/or complexity-theoretically inessential (up to polynomial time, say); but concerning continuous data, already real numbers naturally suggest various encodings with very different computational properties. With respect to qualitative computability, Kreitz and Weihrauch (1985) had identified ADMISSIBILITY as crucial property for 'reasonable' encodings over the Cantor space of infinite binary sequences, so-called representations [doi:10.1007/11780342_48]: For (precisely) these does the sometimes so-called MAIN THEOREM apply, characterizing continuity of functions in terms of continuous realizers. We rephrase qualitative admissibility as continuity of both the representation and its multivalued inverse, adopting from [doi:10.4115/jla.2013.5.7] a notion of sequential continuity for multifunctions. This suggests its quantitative refinement as criterion for representations suitable for complexity investigations. Higher-type complexity is captured by replacing Cantor's as ground space with Baire or any other (compact) ULTRAmetric space: a quantitative counterpart to equilogical spaces in computability [doi:10.1016/j.tcs.2003.11.012]

Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of meier-gorlin syndrome

Mutations in ORC1, ORC4, ORC6, CDT1, and CDC6, which encode proteins required for DNA replication origin licensing, cause Meier-Gorlin syndrome (MGS), a disorder conferring microcephaly, primordial dwarfism, underdeveloped ears, and skeletal abnormalities. Mutations in ATR, which also functions during replication, can cause Seckel syndrome, a clinically related disorder. These findings suggest that impaired DNA replication could underlie the developmental defects characteristic of these disorders. Here, we show that although origin licensing capacity is impaired in all patient cells with mutations in origin licensing component proteins, this does not correlate with the rate of progression through S phase. Thus, the replicative capacity in MGS patient cells does not correlate with clinical manifestation. However, ORC1-deficient cells from MGS patients and siRNA-mediated depletion of origin licensing proteins also have impaired centrosome and centriole copy number. As a novel and unexpected finding, we show that they also display a striking defect in the rate of formation of primary cilia. We demonstrate that this impacts sonic hedgehog signalling in ORC1-deficient primary fibroblasts. Additionally, reduced growth factor-dependent signaling via primary cilia affects the kinetics of cell cycle progression following cell cycle exit and re-entry, highlighting an unexpected mechanism whereby origin licensing components can influence cell cycle progression. Finally, using a cell-based model, we show that defects in cilia function impair chondroinduction. Our findings raise the possibility that a reduced efficiency in forming cilia could contribute to the clinical features of MGS, particularly the bone development abnormalities, and could provide a new dimension for considering developmental impacts of licensing deficiency

Language, Life, Limits

In the context of second-order polynomial-time computability, we prove that there is no general function space construction. We proceed to identify restrictions on the domain or the codomain that do provide a function space with polynomial-time function evaluation containing all polynomial-time computable functions of that type. As side results we show that a polynomial-time counterpart to admissibility of a representation is not a suitable criterion for natural representations, and that the Weihrauch degrees embed into the polynomial-time Weihrauch degrees

MCM2 - a promising marker for premalignant lesions of the lung: a cohort study

BACKGROUND: Because cells progressing to cancer must proliferate, marker proteins specific to proliferating cells may permit detection of premalignant lesions. Here we compared the sensitivities of a classic proliferation marker, Ki-67, with a new proliferation marker, MCM2, in 41 bronchial biopsy specimens representing normal mucosa, metaplasia, dysplasia, and carcinoma in situ. METHODS: Parallel sections were stained with antibodies against MCM2 and Ki-67, and the frequencies of staining were independently measured by two investigators. Differences were evaluated statistically using the two-sided correlated samples t-test and Wilcoxon rank sum test. RESULTS: For each of the 41 specimens, the average frequency of staining by anti-MCM2 (39%) was significantly (p < 0.001) greater than by anti-Ki-67 (16%). In metaplastic lesions anti-MCM2 frequently detected cells near the epithelial surface, while anti-Ki-67 did not. CONCLUSIONS: We conclude that MCM2 is detectable in 2-3 times more proliferating premalignant lung cells than is Ki-67. The promise of MCM2 as a sensitive marker for premalignant lung cells is enhanced by the fact that it is present in cells at the surface of metaplastic lung lesions, which are more likely to be exfoliated into sputum. Future studies will determine if use of anti-MCM2 makes possible sufficiently early detection to significantly enhance lung cancer survival rates

DNA replication licensing and cell cycle kinetics of oligodendroglial tumours

The convergence point of growth-signalling pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes (pre-RCs), resulting in chromatin being ‘licensed’ for DNA replication in the subsequent S phase. The Mcm2–7 complex is a core constituent of the pre-RC, whose recruitment to replication origins is dependent on the Cdt1 loading factor. Geminin is a potent inhibitor of the initiation of DNA replication by preventing Mcm2–7 assembly at origins via its interaction with Cdt1, ensuring genomic integrity through suppression of re-initiation events in S phase. Here we investigate the regulation of Ki67, Mcm2, p21, caspase 3 and Geminin in a series of 55 oligodendrogliomas to provide an integrated picture of how cellular proliferation and programmed cell death are dysregulated in these tumours. Geminin does not behave as an inhibitor of cell proliferation, its labelling index rising with increasing growth fraction as defined by Ki67 or Mcm2 expression. Geminin is expressed in a higher proportion of cells in higher grade tumours (P<0.001) and shows a strong correlation to proliferation and replication licensing (P<0.01), but not apoptosis. Increasing tumour anaplasia is not associated with loss of Geminin. Importantly, the G1 phase of the proliferative cell cycle, as assessed by the Geminin/Ki67 ratio, shortens with increasing anaplasia, providing new potential algorithms for prognostic assessment. Origin licensing proteins thus provide powerful novel tools for assessment of tumour cell cycle kinetics in routinely processed surgical biopsy material

Formal reasoning about modules, reuse, and their correctness

We present a formalisation of modules that are correct, and (correctly) reusable in the sense that composition of modules preserves both correctness and reusability. We also introduce a calculus for formally reasoning about the construction of such modules