Functional reactive programming, refactored

Functional Reactive Programming (FRP) has come to mean many things. Yet, scratch the surface of the multitude of realisations, and there is great commonality between them. This paper investigates this commonality, turning it into a mathematically coherent and practical FRP realisation that allows us to express the functionality of many existing FRP systems and beyond by providing a minimal FRP core parameterised on a monad. We give proofs for our theoretical claims and we have verified the practical side by benchmarking a set of existing, non-trivial Yampa applications running on top of our new system with very good results

Potential L-Type Voltage-Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models

Drotaverine is considered as an inhibitor of cyclic-3′,5′-nucleotide-phophodiesterase (PDE) enzymes. However, published receptor binding data supports the potential Ltype Voltage Operated Calcium Channel (L-VOCC) blocking effect of drotaverine too. Hence, in this work we are focusing on the potential L-VOCC blocking effect of drotaverine using L-VOCC associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction. It was found that drotaverine, like the L-VOCC blockers nifedipine or diltiazem, inhibited the KCl-induced inward Ca2+- induced contraction in a concentration dependent fashion. The PDE-inhibitor theophylline had no effect on the KCl-evoked contractions indicating its lack of inhibition on inward Ca2+ flow. Drotaverine was also tested on the L-VOCC mediated resting Ca2+ refill model. In this model the extracellular Ca2+ enters the cells to replenish the emptied intracellular Ca2+ stores. Drotaverine and L-VOCC blocker reference molecules inhibited the Ca2+ replenishment of Ca2+ depleted preparations detected by agonist-induced contractions in post Ca2+ replenishment Ca2+ free medium. Theophylline didn’t modify the Ca2+ store replenishment following contraction. It seems that drotaverine but not theophylline inhibit the inward Ca2+ flux. Addition of CaCl2 to Ca2+ free medium containing the agonist, induced inward Ca2+ flow and subsequent contraction of Ca2+ depleted tracheal preparations. Drotaverine similar to the L-VOCC blockers, inhibited inward Ca2+ flow and blunted the slope of CaCl2-induced contraction in agonist containing Ca2+ free medium withCa2+ depleted tracheal preparations. These results show that drotaverine behaves like L-VOCC blockers but unlike PDE inhibitors using L-VOCC associated in vitro experimental models

Keeping calm in the face of change: towards optimisation of FRP by reasoning about change

Functional Reactive Programming (FRP) is an approach to reactive programming where systems are structured as networks of functions operating on signals (time-varying values). FRP is based on the synchronous data-flow paradigm and supports both (an approximation to) continuous-time and discrete-time signals (hybrid systems).What sets FRP apart from most other languages for similar applications is its support for systems with dynamic structure and for higher-order reactive constructs. This paper contributes towards advancing the state of the art of FRP implementation by studying the notion of signal change and change propagation in a setting of structurally dynamic networks of n-ary signal functions operating on mixed continuous-time and discrete-time signals. We first define an ideal denotational semantics (time is truly continuous) for this kind of FRP, along with temporal properties, expressed in temporal logic, of signals and signal functions pertaining to change and change propagation. Using this framework, we then show how to reason about change; specifically, we identify and justify a number of possible optimisations, such as avoiding recomputation of unchanging values. Note that due to structural dynamism, and the fact that the output of a signal function may change because time is passing even if the input is unchanging, the problem is significantly more complex than standard change propagation in networks with static structure

Comprehensive DNA Methylation Analysis Reveals a Common Ten-Gene Methylation Signature in Colorectal Adenomas and Carcinomas

Microarray analysis of promoter hypermethylation provides insight into the role and extent of DNA methylation in the development of colorectal cancer (CRC) and may be co-monitored with the appearance of driver mutations. Colonic biopsy samples were obtained endoscopically from 10 normal, 23 adenoma (17 low-grade (LGD) and 6 high-grade dysplasia (HGD)), and 8 ulcerative colitis (UC) patients (4 active and 4 inactive). CRC samples were obtained from 24 patients (17 primary, 7 metastatic (MCRC)), 7 of them with synchronous LGD. Field effects were analyzed in tissues 1 cm (n = 5) and 10 cm (n = 5) from the margin of CRC. Tissue materials were studied for DNA methylation status using a 96 gene panel and for KRAS and BRAF mutations. Expression levels were assayed using whole genomic mRNA arrays. SFRP1 was further examined by immunohistochemistry. HT29 cells were treated with 5-aza-2' deoxycytidine to analyze the reversal possibility of DNA methylation. More than 85% of tumor samples showed hypermethylation in 10 genes (SFRP1, SST, BNC1, MAL, SLIT2, SFRP2, SLIT3, ALDH1A3, TMEFF2, WIF1), whereas the frequency of examined mutations were below 25%. These genes distinguished precancerous and cancerous lesions from inflamed and healthy tissue. The mRNA alterations that might be caused by systematic methylation could be partly reversed by demethylation treatment. Systematic changes in methylation patterns were observed early in CRC carcinogenesis, occuring in precursor lesions and CRC. Thus we conclude that DNA hypermethylation is an early and systematic event in colorectal carcinogenesis, and it could be potentially reversed by systematic demethylation therapy, but it would need more in vitro and in vivo experiments to support this theory

Sport and British Jewish identity

This article examines the relationship between sport and Jewish identity. The experiences of Jewish people have rarely been considered in previous sport-related research which has typically focused on ‘Black’ and South Asian individuals, sports clubs, and organisations. Drawing on data generated from interviews ( n = 20) and focus groups ( n = 2) with individuals based in one British city, this article explores how their Jewish identity was informed, and shaped by, different sports activities and spaces. This study’s participants were quick to correct the idea that sport was alien to Jewish culture and did not accept the stereotype that ‘Jews don’t play sport’. The limited historical research on sport and Jewish people and the ongoing debates around Jewish identity are noted before exploring the role of religion and the suggestion that Jewish participation in sport is affected by the Shabbat (sabbath). Participants discussed how sports clubs acted as spaces for the expression and re/affirmation of their Jewish identity, before they reflected on the threats posed to the wider Jewish community by secularism, assimilation, and antisemitism. The article concludes by discussing how the sporting experiences of the study’s British Jewish participants compare with the experiences of individuals from other ethnic minority communities

Promoter Hypermethylation-Related Reduced Somatostatin Production Promotes Uncontrolled Cell Proliferation in Colorectal Cancer.

BACKGROUND: Somatostatin (SST) has anti-proliferative and pro-apoptotic effects. Our aims were to analyze and compare the SST expression during normal aging and colorectal carcinogenesis at mRNA and protein levels. Furthermore, we tested the methylation status of SST in biopsy samples, and the cell growth inhibitory effect of the SST analogue octreotide in human colorectal adenocarcinoma cell line. METHODS: Colonic samples were collected from healthy children (n1 = 6), healthy adults (n2 = 41) and colorectal cancer patients (CRCs) (n3 = 34) for SST mRNA expression analysis, using HGU133 Plus2.0 microarrays. Results were validated both on original (n1 = 6; n2 = 6; n3 = 6) and independent samples ((n1 = 6; n2 = 6; n3 = 6) by real-time PCR. SST expressing cells were detected by immunohistochemistry on colonic biopsy samples (n1 = 14; n2 = 20; n3 = 23). The effect of octreotide on cell growth was tested on Caco-2 cell line. SST methylation percentage in biopsy samples (n1 = 5; n2 = 5; n3 = 9) was defined using methylation-sensitive restriction enzyme digestion. RESULTS: In case of normal aging SST mRNA expression did not alter, but decreased in cancer (p<0.05). The ratio of SST immunoreactive cells was significantly higher in children (0.70%+/-0.79%) compared to CRC (0%+/-0%) (p<0.05). Octreotide significantly increased the proportion of apoptotic Caco-2 cells. SST showed significantly higher methylation level in tumor samples (30.2%+/-11.6%) compared to healthy young individuals (3.5%+/-1.9%) (p<0.05). CONCLUSIONS: In cancerous colonic mucosa the reduced SST production may contribute to the uncontrolled cell proliferation. Our observation that in colon cancer cells octreotide significantly enhanced cell death and attenuated cell proliferation suggests that SST may act as a regulator of epithelial cell kinetics. The inhibition of SST expression in CRC can be epigenetically regulated by promoter hypermethylation

Direct peptide bioconjugation/PEGylation at tyrosine with linear and branched polymeric diazonium salts

Direct polymer conjugation at peptide tyrosine residues is described. In this study Tyr residues of both leucine enkephalin and salmon calcitonin (sCT) were targeted using appropriate diazonium salt-terminated linear monomethoxy poly(ethylene glycol)s (mPEGs) and poly(mPEG) methacrylate prepared by atom transfer radical polymerization. Judicious choice of the reaction conditions-pH, stoichiometry, and chemical structure of diazonium salt-led to a high degree of site-specificity in the conjugation reaction, even in the presence of competitive peptide amino acid targets such as histidine, lysines, and N-terminal amine. In vitro studies showed that conjugation of mPEG 2000 to sCT did not affect the peptide's ability to increase intracellular cAMP induced in T47D human breast cancer cells bearing sCT receptors. Preliminary in vivo investigation showed preserved ability to reduce [Ca 2+] plasma levels by mPEG 2000-sCT conjugate in rat animal models. © 2012 American Chemical Society

Active/Passive, ‘Diminished’/‘Beautiful’, ‘Light’ from Above and Below: Rereading Shekhinah’s Sexual Desire in Zohar al Shir ha-Shirim (Song of Songs)

In Zohar al Shir ha-Shirim, the Zohar’s reading of Song of Songs, Shekhinah, echoing themes associated with the Shulamite of the biblical text, consistently initiates cosmic union. Sexual desire in the zoharic texts is a form of capital necessary to facilitate sefirotic intercourse, although scholarly readings of the zoharic corpus often identify Shekhinah as a passive receptacle. This, however, is only true if the endemic contradictions within the texts are glossed over. In Song of Songs, the Shulamite’s sexual ‘initiative’ is core. This was not lost on the author(s) of Zohar al Shir ha-Shirim, who, in struggling to explain Shekhinah’s sefirotic role in line with the erotics of Song of Songs, inescapably echoed the ‘depatriarchalizing’ themes of the biblical text. As this article demonstrates, in Zohar al Shir ha-Shirim, Shekhinah is active and repeatedly encourages and frustrates cosmic sexual intercourse. Zohar al Shir ha-Shirim shows that it is possible to reread Shekhinah’s role beyond the androcentrism of the authors as well as scholarly assumptions about her passivity

Some psychosocial and cultural factors in the Arab-Israeli conflict: a review of the literature

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66497/2/10.1177_002200277201600210.pd