Recursive types and bounded quantification are prominent features in many modern programming languages, such as Java, C#, Scala, or TypeScript. Unfortunately, the interaction between recursive types, bounded quantification, and subtyping has shown to be problematic in the past. Consequently, defining a simple foundational calculus that combines those features and has desirable properties, such as decidability, transitivity of subtyping, conservativity, and a sound and complete algorithmic formulation, has been a long-time challenge.

This paper shows how to extend $F_{\le}$ with iso-recursive types in a new calculus called $F_{\le}^{\mu}$. $F_{\le}$ is a well-known polymorphic calculus with bounded quantification. In $F_{\le}^{\mu}$, we add iso-recursive types and correspondingly extend the subtyping relation with iso-recursive subtyping using the recently proposed nominal unfolding rules. In addition, we use so-called structural folding/unfolding rules for typing iso-recursive expressions, inspired by the structural unfolding rule proposed by Abadi et al. (1996). The structural rules add expressive power to the more conventional folding/unfolding rules in the literature, and they enable additional applications. We present several results, including: type soundness; transitivity; the conservativity of $F_{\le}^{\mu}$ over $F_{\le}$; and a sound and complete algorithmic formulation of $F_{\le}^{\mu}$. We study two variants of $F_{\le}^{\mu}$. The first one uses an extension of the $\textrm{kernel}~F_{\le}$ (a well-known decidable variant of $F_{\le}$). This extension accepts equivalent rather than equal bounds and is shown to preserve decidable subtyping. The second variant employs the $\textrm{full}~F_{\le}$ rule for bounded quantification and has undecidable subtyping. Moreover, we also study an extension of the kernel version of $F_{\le}^{\mu}$, called $F_{\le\ge}^{\mu\wedge}$, with a form of intersection types and lower bounded quantification. All the properties from the kernel version of $F_{\le}^{\mu}$ are preserved in $F_{\le\ge}^{\mu\wedge}$. All the results in this paper have been formalized in the Coq theorem prover.

To meet the development needs of aeroengines for high thrust-to-weight ratios and fuel-air ratios, a high temperature rise triple-swirler main combustor was designed with a total fuel-air ratio of 0.037, utilising advanced technologies including staged combustion, multi-point injection and multi-inclined hole cooling. Fluent software was used to conduct numerical simulations under both takeoff and idle conditions, thereby obtaining the distribution characteristics of the velocity and temperature fields within the combustor, as well as the generation of pollutants. The simulation results indicate that under takeoff conditions, the high temperature rise triple-swirler combustor achieves a total pressure loss coefficient of less than 6% and a combustion efficiency exceeding 99%. Under takeoff conditions, the OTDF and RTDF values are 0.144 and 0.0738, respectively. The mole fraction of NOx emissions is 3,700ppm, while the mole fraction of soot emissions is 2.55×10−5ppm. Under idle conditions, the triple-swirler combustor maintains a total pressure loss coefficient of less than 6% and a combustion efficiency greater than 99.9%. The OTDF and RTDF values are 0.131 and 0.0624, respectively. The mole fractions of CO and UHC emissions are both 0×10−32ppm at the calculation limit of Fluent software.

The rising demand for air traffic will inevitably result in a surge in both the number and complexity of flight conflicts, necessitating intelligent strategies for conflict resolution. This study addresses the critical challenges of scalability and real-time performance in multi-aircraft flight conflict resolution by proposing a comprehensive method that integrates a priority ranking mechanism with a conflict resolution model based on the Markov decision process (MDP). Within this framework, the proximity between aircraft in a multi-aircraft conflict set is dynamically assessed to establish a conflict resolution ranking mechanism. The problem of multi-aircraft conflict resolution is formalised through the MDP, encompassing the design of state space, discrete action space and reward function, with the transition function implemented via simulation prediction using model-free methods. To address the positional uncertainty of aircraft in real-time scenarios, the conflict detection mechanism introduces the aircraft’s positional error. A deep reinforcement learning (DRL) environment is constructed incorporating actual airspace structures and traffic densities, leveraging the Actor Critic using Kronecker-factored Trust Region (ACKTR) algorithm to determine resolution actions. The experimental results indicate that with 20–30 aircraft in the airspace, the success rate can reach 94% for the training set and 85% for the test set. Furthermore, this study analyses the impact of varying aircraft numbers on the success rate within a specific airspace scenario. The outcomes of this research provide valuable insights for the automation of flight conflict resolution.

Background: Cerebral venous thrombosis (CVT)most commonly affects younger women. Diagnosis may be delayed due to its distinct presentation and demographic profile compared to other stroke types. Methods: We examined delays to diagnosis of CVT in the SECRET randomized trial and TOP-SECRET parallel registry. Adults diagnosed with symptomatic CVT within <14 days were included. We examined time to diagnosis and number of health care encounters prior to diagnosis and associations with demographics, clinical and radiologic features and functional and patient-reported outcomes (PROMS) at days 180&365. Results: Of 103 participants, 68.9% were female; median age was 45 (IQR 31.0-61.0). Median time from symptom onset to diagnosis was 4 (1-8) days. Diagnosis on first presentation to medical attention was made in 60.2%. The difference in time to diagnosis for single versus multiple presentations was on the order of days (3[1-7] vs. 5[2-11.75], p=0.16). Women were likelier to have multiple presentations (OR 2.53; 95% CI1.00-6.39; p=0.05) and longer median times to diagnosis (5[2-8]days vs. 2[1-4.5] days; p=0.005). However, this was not associated with absolute or change in functional, or any patient reported, outcome measures (PROMs) at days 180&365. Conclusions: Diagnosis of CVT was commonly delayed; women were likelier to have multiple presentations. We found no association between delayed diagnosis and outcomes.

Background: Efgartigimod is a human IgG1 antibody Fc fragment recently approved by Health Canada for patients with acetylcholine receptor antibody positive (AChR-Ab+) generalized myasthenia gravis (gMG). We assessed cost-effectiveness of efgartigimod vs chronic IVIg for adult patients with AChR-Ab+ gMG. Methods: A Markov model estimated costs (treatment and administration, disease monitoring, complications from chronic corticosteroid use, exacerbation and crisis management, adverse events, end-of-life care) and benefits (quality-adjusted life-years [QALYs]). The analysis was conducted from the Canadian healthcare system perspective. Health state transition probabilities were estimated using data from ADAPT, ADAPT+, and a network meta-analysis comparing efgartigimod with chronic IVIg. Utility values were obtained from MyRealWorld MG. Patients with MG-ADL ≥5 who did not die/discontinue were assumed to receive treatment every 4 weeks or every 3 weeks over the lifetime horizon. Results: Over the lifetime horizon, efgartigimod and chronic IVIg were predicted to have total discounted QALYs of 16.80 and 13.35, and total discounted costs of $1,913,294 and $2,170,315, respectively. Efgartigimod dominated chronic IVIg with incremental QALYs of 3.45 and cost savings of $257,020 over the lifetime horizon. Conclusions: Efgartigimod may provide greater benefit at lower costs than chronic IVIg for Canadian patients with AChR-Ab+ gMG, with substantial healthcare system savings over the lifetime horizon.

Sulfur mustard (SM) is a threat to both civilian and military populations. Human skin is highly sensitive to SM, causing delayed erythema, edema, and inflammatory cell infiltration, followed by the appearance of large fluid-filled blisters. Skin wound repair is prolonged following blistering, which can result in impaired barrier function. Key to understanding the action of SM in the skin is the development of animal models that have a pathophysiology comparable to humans such that quantitative assessments of therapeutic drugs efficacy can be assessed. Two animal models, hairless guinea pigs and swine, are preferred to evaluate dermal products because their skin is morphologically similar to human skin. In these animal models, SM induces degradation of epidermal and dermal tissues but does not induce overt blistering, only microblistering. Mechanisms of wound healing are distinct in these animal models. Whereas a guinea pig heals by contraction, swine skin, like humans, heals by re-epithelialization. Mice, rats, and rabbits are also used for SM mechanistic studies. However, healing is also mediated by contraction; moreover, only microblistering is observed. Improvements in animal models are essential for the development of therapeutics to mitigate toxicity resulting from dermal exposure to SM.

For a group G and $m\ge 1$, let $G^m$ denote the subgroup generated by the elements $g^m$, where g runs through G. The subgroups not of the form $G^m$ are the nonpower subgroups of G. We classify the groups with at most nine nonpower subgroups.

Baseline data on local status of threatened species are often limited, and alternative information sources such as local ecological knowledge (LEK) have potential to provide conservation insights but require critical evaluation. We assess the usefulness of LEK to generate conservation evidence for the Hainan Peacock-pheasant Polyplectron katsumatae, a poorly known threatened island galliform. Interview surveys in rural communities across eight forested landscapes on Hainan provided a new dataset of sightings of Peacock-pheasants and other galliforms. Fewer respondents had seen Peacock-pheasants compared to other species across most landscapes, although Peacock-pheasant sightings showed significant across-landscape variation, with substantially more total and recent sightings from Yinggeling National Nature Reserve. However, validation of interview data with camera trapping data from Houmiling Provincial Nature Reserve, a landscape with few reported sightings, suggests a more optimistic possible status for Peacock-pheasants, which were detected as frequently as Red Junglefowl Gallus gallus and Silver Pheasant Lophura nycthemera during systematic camera trap placement. Hainan Peacock-pheasant sighting rates might be influenced by various factors (e.g. restricted local access to forests), with absolute abundance possibly greater than expected from limited sightings. Conversely, relative across-landscape abundance patterns from LEK are likely to be valid, as similar detection biases exist across surveyed landscapes.

Steinernema populi n. sp. was recovered by baiting from beneath poplar trees in China. Morphological and molecular features provided evidence for placing the new species into the Kushidai clade. The new species is characterized by the following morphological features: third-stage infective juveniles (IJ) with a body length of 1095 (973–1172) μm, a distance from the anterior end to excretory pore of 77 (70–86) μm and a tail length of 64 (55–72) μm. The Body length/Tail length (c) ratio and Anterior end to Excretory pore/ Tail length × 100 (E%) of S. populi n. sp. are substantially greater than those of all other ‘Feltiae–Kushidai–Monticolum’ group members. The first-generation males can be recognized by a spicule length of 66 (57–77) μm and a gubernaculum length of 46 (38–60) μm. The new species is further characterized by sequences of the internal transcribed spacer and partial 28S regions of the ribosomal DNA. Phylogenetic analyses show that Steinernema akhursti and Steinernema kushidai are the closest relatives to S. populi n. sp.

Acritarch biostratigraphic and δ13C chemostratigraphic data from the Krol A Formation in the Solan area (Lesser Himalaya, northern India) are integrated to aid inter-basinal correlation of early–middle Ediacaran strata. We identified a prominent negative δ13C excursion (likely equivalent to EN2 in the lower Doushantuo Formation in the Yangtze Gorges area of South China), over a dozen species of acanthomorphs (including two new species—Cavaspina tiwariae Xiao n. sp., Dictyotidium grazhdankinii Xiao n. sp.), and numerous other microfossils from an interval in the Krol A Formation. Most microfossil taxa from the Krol A and the underlying Infra-Krol formations are also present in the Doushantuo Formation. Infra-Krol acanthomorphs support a correlation with the earliest Doushantuo biozone: the Appendisphaera grandis-Weissiella grandistella-Tianzhushania spinosa Assemblage Zone. Krol A microfossils indicate a correlation with the second or (more likely, when δ13C data are considered) the third biozone in the lower Doushantuo Formation (i.e., the Tanarium tuberosum-Schizofusa zangwenlongii or Tanarium conoideum-Cavaspina basiconica Assemblage Zone). The association of acanthomorphs with EN2 in the Krol Formation fills a critical gap in South China where chert nodules, and thus acanthomorphs, are rare in the EN2 interval. Like many other Ediacaran acanthomorphs assemblages, Krol A and Doushantuo acanthomorphs are distributed in low paleolatitudes, and they may represent a distinct paleobiogeographic province in east Gondwana. The Indian data affirm the stratigraphic significance of acanthomorphs and δ13C, clarify key issues of lower Ediacaran bio- and chemostratigraphic correlation, and strengthen the basis for the study of Ediacaran eukaryote evolution and paleobiogeography.

UUID: http://zoobank.org/5289fdb2-0e49-4b3b-880f-f5b21acab371.

The Fanshi Basin is one of the NE–SW-striking depocentres formed along the northern segment of the fault-bounded Shanxi rift. In order to understand the crustal driving stresses that led to the basin formation and development, a palaeostress analysis of a large quantity of fault-slip data collected mainly at the boundaries of the basin was accomplished. The stress inversion of these data revealed three stress regimes. The oldest SR1 was a Neogene stress regime giving rise to a strike-slip deformation with NE–SW contraction and NW–SE extension. SR1 activated the large faults trending NNE–NE, i.e. (sub)parallel to the main strike of the Shanxi rift, as right-lateral strike-slip faults. It was subjected to the Shanxi rift before the activation of the Fanshi Basin boundary fault, i.e. the Fanshi (or Wutai) fault, as a normal fault. The next is a short-lived NE–SW extensional stress regime SR2 in early Pleistocene time, which shows the inception of the basin’s extension. A strong NW–SE to NNW–SSE extensional stress regime SR3 has governed the northern segment of the Shanxi rift since late Pleistocene time and is the present-day extension. It gave rise to the current half-graben geometry of the Fanshi Basin by activating the Fanshi (or Wutai) fault as a normal fault in the southern part of the graben. Because of the dominance of the NW–SE to NNW–SSE extension, which is perpendicular to the NE–SW extension, mutual permutations between σ3 and σ2 due to inherited fault patterns might have occurred while the crustal stresses in the Fanshi Basin changed from the SR1 to SR3 stress regimes.

Bone is the most common site for advanced breast cancer to metastasise. The proinflammatory cytokine, interleukin-1β (IL-1β) plays a complex and contradictory role in this process. Recent studies have demonstrated that breast cancer patients whose primary tumours express IL-1β are more likely to experience relapse in bone or other organs. Importantly, IL-1β affects different stages of the metastatic process including growth of the primary tumour, epithelial to mesenchymal transition (EMT), dissemination of tumour cells into the blood stream, tumour cell homing to the bone microenvironment and, once in bone, this cytokine participates in the interaction between cancer cells and bone cells, promoting metastatic outgrowth at this site. Interestingly, although inhibition of IL-1β signalling has been shown to have potent anti-metastatic effects, inhibition of the activity of this cytokine has contradictory effects on primary tumours, sometimes reducing but often promoting their growth. In this review, we focus on the complex roles of IL-1β on breast cancer bone metastasis: specifically, we discuss the distinct effects of IL-1β derived from tumour cells and/or microenvironment on inhibition/induction of primary breast tumour growth, induction of the metastatic process through the EMT, promotion of tumour cell dissemination into the bone metastatic niche and formation of overt metastases.

We examined the accuracy of International Classification of Disease 10th iteration (ICD-10) diagnosis codes within Canadian administrative data in identifying cerebral venous thrombosis (CVT). Of 289 confirmed cases of CVT admitted to our comprehensive stroke center between 2008 and 2018, 239/289 were new diagnoses and 204/239 were acute events with only 75/204 representing symptomatic CVTs not provoked by trauma or structural processes. Using ICD-10 codes in any position, sensitivity was 39.1% and positive predictive value was 94.2% for patients with a current or history of CVT and 84.0% and 52.5% for acute and symptomatic CVTs not provoked by trauma or structural processes.

ABSTRACT IMPACT: Our improved understanding of the changes in chromatin accessibility that occur in persistent pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG. OBJECTIVES/GOALS: Efforts to understand genetic variability involved in an individual’s susceptibility to persistent pain support a role for upstream regulation by epigenetic mechanisms. Our objective was to examine the transcriptomic and epigenetic basis of persistent pain following nerve injury. METHODS/STUDY POPULATION: We used a multiomic approach to identify novel molecular pathways associated with nerve injury-induced pain hypersensitivity. Adult Sprague Dawley rats were randomized to Chronic Constriction Injury (CCI) to the sciatic nerve or no treatment (naive). The ipsilateral L4-L6 dorsal root ganglia (DRG)s were removed on Day 14 and used for ChIP-seq for H3K4me1, ATAC-seq, and RNA-seq. We assessed for differential chromatin accessibility, transcription factor motifs, and enrichment for biological processes in chromatin accessible regions associated with cis-regulatory regions identified by ATAC-seq and H3K4me1 enrichment. Luciferase assays determined the functional significance of these sequences. RESULTS/ANTICIPATED RESULTS: We identified 58,446 genomic regions where H3K4me1 enrichment overlapped with chromatin accessibility. Differential analysis identified 2145 of these 58,446 regions that had changes in accessibility after CCI. The majority of these regions were located in introns or intergenic regions. Functional annotation of the differentially accessible regions identified disparate molecular functions enriched following nerve injury which suggests that altered chromatin structure plays a role in the development of mechanical hypersensitivity. Motif analysis identified specific transcription factor families whose binding sequences were enriched in regions of increased or decreased accessibility. Luciferase assays showed significant enhancement or repression of gene transcription. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our data provides a comprehensive map of chromatin accessibility changes in the DRG after CCI and emphasizes the importance of chromatin structure in the development and maintenance of chronic pain.

This paper describes a computational investigation of multimode instability growth and multimaterial mixing induced by multiple shock waves in a high-energy-density (HED) environment, where pressures exceed 1 Mbar. The simulations are based on a series of experiments performed at the National Ignition Facility (NIF) and designed as an HED analogue of non-HED shock-tube studies of the Richtmyer–Meshkov instability and turbulent mixing. A three-dimensional computational modelling framework is presented. It treats many complications absent from canonical non-HED shock-tube flows, including distinct ion and free-electron internal energies, non-ideal equations of state, radiation transport and plasma-state mass diffusivities, viscosities and thermal conductivities. The simulations are tuned to the available NIF data, and traditional statistical quantities of turbulence are analysed. Integrated measures of turbulent kinetic energy and enstrophy both increase by over an order of magnitude due to reshock. Large contributions to enstrophy production during reshock are seen from both the baroclinic source and enstrophy–dilatation terms, highlighting the significance of fluid compressibility in the HED regime. Dimensional analysis reveals that Reynolds numbers and diffusive Péclet numbers in the HED flow are similar to those in a canonical non-HED analogue, but conductive Péclet numbers are much smaller in the HED flow due to efficient thermal conduction by free electrons. It is shown that the mechanism of electron thermal conduction significantly softens local spanwise gradients of both temperature and density, which causes a minor but non-negligible decrease in enstrophy production and small-scale mixing relative to a flow without this mechanism.