Applicative Bidirectional Programming with Lenses

A bidirectional transformation is a pair of mappings between source and view data objects, one in each direction. When the view is modified, the source is updated accordingly with respect to some laws. One way to reduce the development and maintenance effort of bidirectional transformations is to have specialized languages in which the resulting programs are bidirectional by construction---giving rise to the paradigm of bidirectional programming. In this paper, we develop a framework for applicative-style and higher-order bidirectional programming, in which we can write bidirectional transformations as unidirectional programs in standard functional languages, opening up access to the bundle of language features previously only available to conventional unidirectional languages. Our framework essentially bridges two very different approaches of bidirectional programming, namely the lens framework and Voigtlander’s semantic bidirectionalization, creating a new programming style that is able to bag benefits from both

Towards modular compilers for effects

Compilers are traditionally factorised into a number of separate phases, such as parsing, type checking, code generation, etc. However, there is another potential factorisation that has received comparatively little attention: the treatment of separate language features, such as mutable state, input/output, exceptions, concurrency and so forth. In this article we focus on the problem of modular compilation, in which the aim is to develop compilers for separate language features independently, which can then be combined as required. We summarise our progress to date, issues that have arisen, and further wor

The constrained-monad problem

In Haskell, there are many data types that would form monads were it not for the presence of type-class constraints on the operations onthat data type. This is a frustrating problem in practice, because there is a considerable amount of support and infrastructure for monads that these data types cannot use. Using several examples,we show that a monadic computation can be restructured into a normal form such that the standard monad class can be used. The technique is not specific to monads, and we show how it can also be applied to other structures, such as applicative functors. One significant use case for this technique is domain-specific languages,where it is often desirable to compile a deep embedding of a computation to some other language, which requires restricting the types that can appear in that computation

Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment

Introduction: Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization. Responses of cancer patients to radiotherapy depend in part on the intrinsic radiosensitivity of the tumor cells. Thus, promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients. Methods: Mammary tumor cells were treated by a 16-base phosphodiester-linked oligonucleotide homologous to the telomere G-rich sequence TTAGGG (T-oligo: GGTTAGGTGTAGGTTT) or a control-oligo (the partial complement, TAACCCTAACCCTAAC) followed by IR. The inhibition of tumor cell growth in vitro was assessed by cell counting and clonogenic cell survival assay. The tumorigenesis of tumor cells after various treatments was measured by tumor growth in mice. The mechanism underlying the radiosensitization by T-oligo was explored by immunofluorescent determination of phosphorylated histone H2AX ($\gamma$H2AX) foci, $\beta$-galactosidase staining, comet and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assays. The efficacy of the combined treatment was assessed in a spontaneous murine mammary tumor model. Results: Pretreatment of tumor cells with T-oligo for 24 hours in vitro enhanced both senescence and apoptosis of irradiated tumor cells and reduced clonogenic potential. Radiosensitization by T-oligo was associated with increased formation and/or delayed resolution of $\gamma$H2AX DNA damage foci and fragmented DNA. T-oligo also caused radiosensitization in two in vivo mammary tumor models. Indeed, combined T-oligo and IR-treatment in vivo led to a substantial reduction in tumor growth. Of further significance, treatment with T-oligo and IR led to synergistic inhibition of the growth of spontaneous mammary carcinomas. Despite these profound antitumor properties, T-oligo and IR caused no detectable side effects under our experimental conditions. Conclusions: Pretreatment with T-oligo sensitizes mammary tumor cells to radiation in both in vitro and in vivo settings with minimal or no normal tissue side effects

Chronic psychosocial and financial burden accelerates 5-year telomere shortening: findings from the Coronary Artery Risk Development in Young Adults Study.

Leukocyte telomere length, a marker of immune system function, is sensitive to exposures such as psychosocial stressors and health-maintaining behaviors. Past research has determined that stress experienced in adulthood is associated with shorter telomere length, but is limited to mostly cross-sectional reports. We test whether repeated reports of chronic psychosocial and financial burden is associated with telomere length change over a 5-year period (years 15 and 20) from 969 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a longitudinal, population-based cohort, ages 18-30 at time of recruitment in 1985. We further examine whether multisystem resiliency, comprised of social connections, health-maintaining behaviors, and psychological resources, mitigates the effects of repeated burden on telomere attrition over 5 years. Our results indicate that adults with high chronic burden do not show decreased telomere length over the 5-year period. However, these effects do vary by level of resiliency, as regression results revealed a significant interaction between chronic burden and multisystem resiliency. For individuals with high repeated chronic burden and low multisystem resiliency (1 SD below the mean), there was a significant 5-year shortening in telomere length, whereas no significant relationships between chronic burden and attrition were evident for those at moderate and higher levels of resiliency. These effects apply similarly across the three components of resiliency. Results imply that interventions should focus on establishing strong social connections, psychological resources, and health-maintaining behaviors when attempting to ameliorate stress-related decline in telomere length among at-risk individuals

Needle & knot : binder boilerplate tied up

To lighten the burden of programming language mechanization, many approaches have been developed that tackle the substantial boilerplate which arises from variable binders. Unfortunately, the existing approaches are limited in scope. They typically do not support complex binding forms (such as multi-binders) that arise in more advanced languages, or they do not tackle the boilerplate due to mentioning variables and binders in relations. As a consequence, the human mechanizer is still unnecessarily burdened with binder boilerplate and discouraged from taking on richer languages. This paper presents Knot, a new approach that substantially extends the support for binder boilerplate. Knot is a highly expressive language for natural and concise specification of syntax with binders. Its meta-theory constructively guarantees the coverage of a considerable amount of binder boilerplate for well-formed specifications, including that for well-scoping of terms and context lookups. Knot also comes with a code generator, Needle, that specializes the generic boilerplate for convenient embedding in COQ and provides a tactic library for automatically discharging proof obligations that frequently come up in proofs of weakening and substitution lemmas of type-systems. Our evaluation shows, that Needle & Knot significantly reduce the size of language mechanizations (by 40% in our case study). Moreover, as far as we know, Knot enables the most concise mechanization of the POPLmark Challenge (1a + 2a) and is two-thirds the size of the next smallest. Finally, Knot allows us to mechanize for instance dependentlytyped languages, which is notoriously challenging because of dependent contexts and mutually-recursive sorts with variables

ATP-dependent chromatin remodeling shapes the DNA replication landscape.

The eukaryotic DNA replication machinery must traverse every nucleosome in the genome during S phase. As nucleosomes are generally inhibitory to DNA-dependent processes, chromatin structure must undergo extensive reorganization to facilitate DNA synthesis. However, the identity of chromatin-remodeling factors involved in replication and how they affect DNA synthesis is largely unknown. Here we show that two highly conserved ATP-dependent chromatin-remodeling complexes in Saccharomyces cerevisiae, Isw2 and Ino80, function in parallel to promote replication fork progression. As a result, Isw2 and Ino80 have especially important roles for replication of late-replicating regions during periods of replication stress. Both Isw2 and Ino80 complexes are enriched at sites of replication, suggesting that these complexes act directly to promote fork progression. These findings identify ATP-dependent chromatin-remodeling complexes that promote DNA replication and define a specific stage of replication that requires remodeling for normal function

Rad51 Polymerization Reveals a New Chromatin Remodeling Mechanism

Rad51 protein is a well known protagonist of homologous recombination in eukaryotic cells. Rad51 polymerization on single-stranded DNA and its role in presynaptic filament formation have been extensively documented. Rad51 polymerizes also on double-stranded DNA but the significance of this filament formation remains unclear. We explored the behavior of Saccharomyces cerevisiae Rad51 on dsDNA and the influence of nucleosomes on Rad51 polymerization mechanism to investigate its putative role in chromatin accessibility to recombination machinery. We combined biochemical approaches, transmission electron microscopy (TEM) and atomic force microscopy (AFM) for analysis of the effects of the Rad51 filament on chromatinized templates. Quantitative analyses clearly demonstrated the occurrence of chromatin remodeling during nucleoprotein filament formation. During Rad51 polymerization, recombinase proteins moved all the nucleosomal arrays in front of the progressing filament. This polymerization process had a powerful remodeling effect, as Rad51 destabilized the nucleosomes along considerable stretches of DNA. Similar behavior was observed with RecA. Thus, recombinase polymerization is a powerful mechanism of chromatin remodeling. These remarkable features open up new possibilities for understanding DNA recombination and reveal new types of ATP-dependent chromatin dynamics

SS18 Together with Animal-Specific Factors Defines Human BAF-Type SWI/SNF Complexes

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