Safe functional reactive programming through dependent types

Functional Reactive Programming (FRP) is an approach to reactive programming where systems are structured as networks of functions operating on signals. FRP is based on the synchronous dataflow paradigm and supports both 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. Statically guaranteeing correctness properties of programs is an attractive proposition. This is true in particular for typical application domains for reactive programming such as embedded systems. To that end, many existing reactive languages have type systems or other static checks that guarantee domain-specific properties, such as feedback loops always being well-formed. However, they are limited in their capabilities to support dynamism and higher-order data-flow compared with FRP. Thus, the onus of ensuring such properties of FRP programs has so far been on the programmer as established static techniques do not suffice. In this paper, we show how dependent types allow this concern to be addressed. We present an implementation of FRP embedded in the dependently-typed language Agda, leveraging the type system of the host language to craft a domain-specific (dependent) type system for FRP. The implementation constitutes a discrete, operational semantics of FRP, and as it passes the Agda type, coverage, and termination checks, we know the operational semantics is total, which means our type system is safe

Aerosol climate feedback due to decadal increases in Southern Hemisphere wind speeds

Observations indicate that the westerly jet in the Southern Hemisphere troposphere is accelerating. Using a global aerosol model we estimate that the increase in wind speed of 0.45 + /- 0.2 m s(-1) decade(-1) at 50-65 degrees S since the early 1980s caused a higher sea spray flux, resulting in an increase of cloud condensation nucleus concentrations of more than 85% in some regions, and of 22% on average between 50 and 65 degrees S. These fractional increases are similar in magnitude to the decreases over many northern hemisphere land areas due to changes in air pollution over the same period. The change in cloud drop concentrations causes an increase in cloud reflectivity and a summertime radiative forcing between at 50 and 65 degrees S comparable in magnitude but acting against that from greenhouse gas forcing over the same time period, and thus represents a substantial negative climate feedback. However, recovery of Antarctic ozone depletion in the next two decades will likely cause a fall in wind speeds, a decrease in cloud drop concentration and a correspondingly weaker cloud feedback

In Situ Activation and Heterologous Production of a Cryptic Lantibiotic from an African Plant Ant-Derived Saccharopolyspora Species.

Most clinical antibiotics are derived from actinomycete natural products discovered at least 60 years ago. However, the repeated rediscovery of known compounds led the pharmaceutical industry to largely discard microbial natural products (NPs) as a source of new chemical diversity. Recent advances in genome sequencing have revealed that these organisms have the potential to make many more NPs than previously thought. Approaches to unlock NP biosynthesis by genetic manipulation of strains, by the application of chemical genetics, or by microbial cocultivation have resulted in the identification of new antibacterial compounds. Concomitantly, intensive exploration of coevolved ecological niches, such as insect-microbe defensive symbioses, has revealed these to be a rich source of chemical novelty. Here, we report the new lanthipeptide antibiotic kyamicin, which was generated through the activation of a cryptic biosynthetic gene cluster identified by genome mining Saccharopolyspora species found in the obligate domatium-dwelling ant Tetraponera penzigi of the ant plant Vachellia drepanolobium Transcriptional activation of this silent gene cluster was achieved by ectopic expression of a pathway-specific activator under the control of a constitutive promoter. Subsequently, a heterologous production platform was developed which enabled the purification of kyamicin for structural characterization and bioactivity determination. This strategy was also successful for the production of lantibiotics from other genera, paving the way for a synthetic heterologous expression platform for the discovery of lanthipeptides that are not detected under laboratory conditions or that are new to nature.IMPORTANCE The discovery of novel antibiotics to tackle the growing threat of antimicrobial resistance is impeded by difficulties in accessing the full biosynthetic potential of microorganisms. The development of new tools to unlock the biosynthesis of cryptic bacterial natural products will greatly increase the repertoire of natural product scaffolds. Here, we report a strategy for the ectopic expression of pathway-specific positive regulators that can be rapidly applied to activate the biosynthesis of cryptic lanthipeptide biosynthetic gene clusters. This allowed the discovery of a new lanthipeptide antibiotic directly from the native host and via heterologous expression

Comparison of Satellite Observations of Nitrogen Dioxide to Surface Monitor Nitrogen Dioxide Concentration

Nitrogen dioxide is one of the U. S. EPA s criteria pollutants, and one of the main ingredients needed for the production of ground-level ozone. Both ozone and nitrogen dioxide cause severe public health problems. Existing satellites have begun to produce observational data sets for nitrogen dioxide. Under NASAs Earth Science Applications Program, we examined the relationship between satellite observations and surface monitor observations of this air pollutant to examine if the satellite data can be used to facilitate a more capable and integrated observing network. This report provides a comparison of satellite tropospheric column nitrogen dioxide to surface monitor nitrogen dioxide concentration for the period from September 1996 through August 1997 at more than 300 individual locations in the continental US. We found that the spatial resolution and observation time of the satellite did not capture the variability of this pollutant as measured at ground level. The tools and processes developed to conduct this study will be applied to the analysis of advanced satellite observations. One advanced instrument has significantly better spatial resolution than the measurements studied here and operates with an afternoon overpass time, providing a more representative distribution for once-per-day sampling of this photochemically active atmospheric constituent

Quantitative analysis of high-resolution microendoscopic images for diagnosis of neoplasia in patients with Barrett’s esophagus

Background and Aims: Previous studies show that microendoscopic images can be interpreted visually to identify the presence of neoplasia in patients with Barrett’s esophagus (BE), but this approach is subjective and requires clinical expertise. This study describes an approach for quantitative image analysis of microendoscopic images to identify neoplastic lesions in patients with BE. Methods: Images were acquired from 230 sites from 58 patients by using a fiberoptic high-resolution microendoscope during standard endoscopic procedures. Images were analyzed by a fully automated image processing algorithm, which automatically selected a region of interest and calculated quantitative image features. Image features were used to develop an algorithm to identify the presence of neoplasia; results were compared with a histopathology diagnosis. Results: A sequential classification algorithm that used image features related to glandular and cellular morphology resulted in a sensitivity of 84% and a specificity of 85%. Applying the algorithm to an independent validation set resulted in a sensitivity of 88% and a specificity of 85%. Conclusions: This pilot study demonstrates that automated analysis of microendoscopic images can provide an objective, quantitative framework to assist clinicians in evaluating esophageal lesions from patients with BE. (Clinical trial registration number: NCT01384227 and NCT02018367.

The HERMIT in the machine: a plugin for the interactive transformation of GHC core language programs

The importance of reasoning about and refactoring programs is a central tenet of functional programming. Yet our compilers and development toolchains only provide rudimentary support for these tasks. This paper introduces a programmatic and compiler-centric interface that facilitates refactoring and equational reasoning. To develop our ideas, we have implemented HERMIT, a toolkit enabling informal but systematic transformation of Haskell programs from inside the Glasgow Haskell Compiler’s optimization pipeline. With HERMIT, users can experiment with optimizations and equational reasoning, while the tedious heavy lifting of performing the actual transformations is done for them. HERMIT provides a transformation API that can be used to build higher-level rewrite tools. One use-case is prototyping new optimizations as clients of this API before being committed to the GHC toolchain. We describe a HERMIT application - a read-eval-print shell for performing transformations using HERMIT. We also demonstrate using this shell to prototype an optimization on a specific example, and report our initial experiences and remaining challenges

Quantitative Analysis of High-Resolution Microendoscopic Images for Diagnosis of Esophageal Squamous Cell Carcinomaﾠ

Background & Aims: High-resolution microendoscopy is an optical imaging technique with the potential to improve the accuracy of endoscopic screening for esophageal squamous neoplasia. Although these microscopic images can be interpreted readily by trained personnel, quantitative image analysis software could facilitate the use of this technology in low-resource settings. In this study, we developed and evaluated quantitative image analysis criteria for the evaluation of neoplastic and non-neoplastic squamous esophageal mucosa. Methods: We performed an image analysis of 177 patients undergoing standard upper endoscopy for screening or surveillance of esophageal squamous neoplasia, using high-resolution microendoscopy, at 2 hospitals in China and at 1 hospital in the United States from May 2010 to October 2012. Biopsy specimens were collected from imaged sites (n = 375), and a consensus diagnosis was provided by 2 expert gastrointestinal pathologists and used as the standard. Results: Quantitative information from the high-resolution images was used to develop an algorithm to identify high-grade squamous dysplasia or invasive squamous cell cancer, based on histopathology findings. Optimal performance was obtained using the mean nuclear area as the basis for classification, resulting in sensitivities and specificities of 93% and 92% in the training set, 87% and 97% in the test set, and 84% and 95% in an independent validation set, respectively. Conclusions: High-resolution microendoscopy with quantitative image analysis can aid in the identification of esophageal squamous neoplasia. Use of software-based image guides may overcome issues of training and expertise in low-resource settings, allowing for widespread use of these optical biopsy technologies

Low-Cost High-Resolution Microendoscopy for the Detection of Esophageal Squamous Cell Neoplasia: An International Trial

Background & Aims: Esophageal squamous cell neoplasia has a high mortality rate as a result of late detection. In high-risk regions such as China, screening is performed by Lugol’s chromoendoscopy (LCE). LCE has low specificity, resulting in unnecessary tissue biopsy with a subsequent increase in procedure cost and risk. The purpose of this study was to evaluate the accuracy of a novel, low-cost, high-resolution microendoscope (HRME) as an adjunct to LCE. Methods: In this prospective trial, 147 consecutive high-risk patients were enrolled from 2 US and 2 Chinese tertiary centers. Three expert and 4 novice endoscopists performed white-light endoscopy followed by LCE and HRME. All optical images were compared with the gold standard of histopathology. Results: By using a per-biopsy analysis, the sensitivity of LCE vs LCE + HRME was 96% vs 91% (P = .0832), specificity was 48% vs 88% (P < .001), positive predictive value was 22% vs 45% (P < .0001), negative predictive value was 98% vs 98% (P = .3551), and overall accuracy was 57% vs 90% (P < .001), respectively. By using a per-patient analysis, the sensitivity of LCE vs LCE + HRME was 100% vs 95% (P = .16), specificity was 29% vs 79% (P < .001), positive predictive value was 32% vs 60%, 100% vs 98%, and accuracy was 47% vs 83% (P < .001). With the use of HRME, 136 biopsies (60%; 95% confidence interval, 53%–66%) could have been spared, and 55 patients (48%; 95% confidence interval, 38%–57%) could have been spared any biopsy. Conclusions: In this trial, HRME improved the accuracy of LCE for esophageal squamous cell neoplasia screening and surveillance. HRME may be a cost-effective optical biopsy adjunct to LCE, potentially reducing unnecessary biopsies and facilitating real-time decision making in globally underserved regions. ClinicalTrials.gov, NCT 01384708

Contrasting Habitat Use and Population Dynamics of Reef Manta Rays Within the Nusa Penida Marine Protected Area, Indonesia

Manta rays (Mobula spp.) are highly valued in nature-based tourism globally. In Indonesia, although manta rays are protected, critical information is lacking on their habitat use, population dynamics and movements. We investigate the population structure and residency patterns of reef manta rays (Mobula alfredi) in the Nusa Penida Marine Protected Area (MPA). From photo-identification data logged by citizen scientists and trained observers (mantamatcher.org), we identified 624 reef manta rays from 5,913 sightings (January 2012–April 2018) based on their unique ventral coloration patterns. Year-round records were collected from two shallow (&lt;20 m) reefs – Manta Bay (MB; n = 3,029 sightings) and Manta Point (MP; n = 3,058) – that are used frequently by tourism operators. Maximum likelihood techniques and a Markov movement analysis were used to model residency patterns and movement between these sites within the MPA. Manta rays at MB were predominantly male (64%, n = 261 individuals), with immature males (14%, n = 59) being sighted most frequently (39%, n = 1,170). In contrast, few immature individuals were sighted at MP (6%, n = 28), and they were sighted on few occasions (2%, n = 45), while mature female manta rays comprised 26% (n = 127) of the MP community and were the most frequently sighted (48%, n = 1,413). Lagged identification rates indicated high site fidelity at each location. However, 44% (n = 278) of individuals moved between the two sites and cumulative discovery curves showed a continued recruitment of individuals over the 6 years of the study. In addition, the behaviors displayed by the manta rays differed markedly between the two sites: MB appears to be a foraging ground, especially for juveniles, and potentially a nursery, while MP is used mainly for cleaning and courtship, indicating a social and reproductive site. Reproductive behavior coincided with the peak annual sightings in May. To prevent disturbance to this threatened species by tourism, regulations for the number of boats and interactions, especially during key reproductive times should be considered. Further, strict fishing regulation in the area is recommended as fishing gear entanglement was identified as a threat to this population