Identification of direction in gene networks from expression and methylation

Background: Reverse-engineering gene regulatory networks from expression data is difficult, especially without temporal measurements or interventional experiments. In particular, the causal direction of an edge is generally not statistically identifiable, i.e., cannot be inferred as a statistical parameter, even from an unlimited amount of non-time series observational mRNA expression data. Some additional evidence is required and high-throughput methylation data can viewed as a natural multifactorial gene perturbation experiment. Results: We introduce IDEM (Identifying Direction from Expression and Methylation), a method for identifying the causal direction of edges by combining DNA methylation and mRNA transcription data. We describe the circumstances under which edge directions become identifiable and experiments with both real and synthetic data demonstrate that the accuracy of IDEM for inferring both edge placement and edge direction in gene regulatory networks is significantly improved relative to other methods. Conclusion: Reverse-engineering directed gene regulatory networks from static observational data becomes feasible by exploiting the context provided by high-throughput DNA methylation data. An implementation of the algorithm described is available at http://code.google.com/p/idem/

Litigating the Carceral Soundscape

Sound has always been a material issue in prisons, whether it be in connection with sonic surveillance, the “silent cell,” or the insistence of sound (excessive noise, counter-carceral music making). This article asks: How and when does the carceral soundscape become a litigable issue? Our article opens with a discussion of the challenges involved in attempting to study the sonic ambiance of the penitentiary through the medium of written documents and proposes a methodology of “sensing between the lines” by way of a solution. It goes on to analyze the “moral architecture” at the foundation of the modern prison in an effort to excavate the sonic dimensions of incarceration in the context of a system that was designed with silence at its core. Solitude and silence were presumed to have an “emancipatory effect” on the prisoner by attuning the carceral subject to “the inner voice of conscience” through forced withdrawal from the distractions of the senses. The next part considers the ways that, despite attempts to manage sound, its insistence has resisted these forms of control. It presents solitary confinement as a crucial site to explore the ways in which enforced silence, as an organizing principle, has undergone several contortions that gave rise to alternative rationales such as “structured intervention,” yet has persisted. The article then explores how this enduring silence has figured in the contemporary case law, alongside other forms of acoustic violence, such as excessive noise and sonic resistance to the conditions of incarceration on the part of prison inmates (e.g., rapping to beat the rap). While some cases describe the experience of the prison as one of unbearable silence, others describe it as noise without respite. This research highlights the ways that sound in prison has remained an important site of discipline and contestation that reverberates through the case law, yet without being appreciated adequately by the courts. The article concludes with observations about the ways that probing the role of sound in the logic of incarceration can complement litigation efforts that question carceral logics

SOAR: Improved Indexing for Approximate Nearest Neighbor Search

This paper introduces SOAR: Spilling with Orthogonality-Amplified Residuals, a novel data indexing technique for approximate nearest neighbor (ANN) search. SOAR extends upon previous approaches to ANN search, such as spill trees, that utilize multiple redundant representations while partitioning the data to reduce the probability of missing a nearest neighbor during search. Rather than training and computing these redundant representations independently, however, SOAR uses an orthogonality-amplified residual loss, which optimizes each representation to compensate for cases where other representations perform poorly. This drastically improves the overall index quality, resulting in state-of-the-art ANN benchmark performance while maintaining fast indexing times and low memory consumption

The olive-branch dating of the Santorini eruption

The date of the volcanic eruption of Santorini that caused extensive damage toMinoan Crete has been controversial since the 1980s. Some have placed the event in the late seventeenth century BC. Others have made the case for a younger date of around 1500 BC. A recent contribution to that controversy has been the dating of an olive tree branch preserved within the volcanic ash fall on Santorini. In this debate feature Paolo Cherubini and colleagues argue that the olive tree dating (which supports the older chronology) is unreliable on a number of grounds. There follows a response from the authors of that dating, and comments from other specialists, with a closing reply from Cherubini and his tea

The impact of the introduction of new recognition criteria for overwork-related cardiovascular and cerebrovascular diseases: a cross-country comparison

Cardiovascular and cerebrovascular diseases (CVDs) related to overwork are common in Asia, as is death from overwork, known as karoshi. Japan was the first country in the world to introduce criteria for recognizing overwork-related CVDs in 1961. Taiwan followed Japan in putting in place new policies and then updating these in 2010. We aimed to investigate the effect of introducing the new criteria for recognizing overwork-related CVDs in both countries. We defined the baseline period as the 5 years before launch of the new criteria, then collected data to 5 years after the new criteria. We applied a Poisson regression model to analyze the longitudinal change in rates of overwork-related CVDs before and after, adjusting for indicators of working conditions. Implementation of the new criteria was associated with a 2.58-fold increase in the rate of overwork-related CVDs (p-value < 0.05). However, the examined policy framework in Taiwan still appears to miss a substantial number of cases compared to that are captured by a similar policy framework used to capture overwork-related CVD rates in Japan by a factor of 0.42 (p-value < 0.05). Accordingly, we make a case for enhancements of Taiwan’s system for reporting and recognizing overwork-related diseases and deaths

Roles of DNA polymerase I in leading and lagging-strand replication defined by a high-resolution mutation footprint of ColE1 plasmid replication

DNA polymerase I (pol I) processes RNA primers during lagging-strand synthesis and fills small gaps during DNA repair reactions. However, it is unclear how pol I and pol III work together during replication and repair or how extensive pol I processing of Okazaki fragments is in vivo. Here, we address these questions by analyzing pol I mutations generated through error-prone replication of ColE1 plasmids. The data were obtained by direct sequencing, allowing an accurate determination of the mutation spectrum and distribution. Pol I’s mutational footprint suggests: (i) during leading-strand replication pol I is gradually replaced by pol III over at least 1.3 kb; (ii) pol I processing of Okazaki fragments is limited to ∼20 nt and (iii) the size of Okazaki fragments is short (∼250 nt). While based on ColE1 plasmid replication, our findings are likely relevant to other pol I replicative processes such as chromosomal replication and DNA repair, which differ from ColE1 replication mostly at the recruitment steps. This mutation footprinting approach should help establish the role of other prokaryotic or eukaryotic polymerases in vivo, and provides a tool to investigate how sequence topology, DNA damage, or interactions with protein partners may affect the function of individual DNA polymerases

The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD+-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a β-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates β-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of β-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of β−catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in β−catenin-driven malignancies