Answer Refinement Modification: Refinement Type System for Algebraic Effects and Handlers

Algebraic effects and handlers are a mechanism to structure programs with computational effects in a modular way. They are recently gaining popularity and being adopted in practical languages, such as OCaml. Meanwhile, there has been substantial progress in program verification via refinement type systems. However, thus far, there has not been a satisfactory refinement type system for algebraic effects and handlers. In this paper, we fill the void by proposing a novel refinement type system for algebraic effects and handlers. The expressivity and usefulness of algebraic effects and handlers come from their ability to manipulate delimited continuations, but delimited continuations also complicate programs' control flow and make their verification harder. To address the complexity, we introduce a novel concept that we call answer refinement modification (ARM for short), which allows the refinement type system to precisely track what effects occur and in what order when a program is executed, and reflect the information as modifications to the refinements in the types of delimited continuations. We formalize our type system that supports ARM (as well as answer type modification) and prove its soundness. Additionally, as a proof of concept, we have implemented a corresponding type checking and inference algorithm for a subset of OCaml 5, and evaluated it on a number of benchmark programs. The evaluation demonstrates that ARM is conceptually simple and practically useful. Finally, a natural alternative to directly reasoning about a program with delimited continuations is to apply a continuation passing style (CPS) transformation that transforms the program to a pure program. We investigate this alternative, and show that the approach is indeed possible by proposing a novel CPS transformation for algebraic effects and handlers that enjoys bidirectional (refinement-)type-preservation.Comment: 66 page

Enhanced Merge Sort- A New Approach to the Merging Process

AbstractOne of the major fundamental issues of Computer Science is arrangement of elements in the database. The efficiency of the sorting algorithms is to optimize the importance of other sorting algorithms11. The optimality of these sorting algorithms is judged while calculating their time and space complexities12. The idea behind this paper is to modify the conventional Merge Sort Algorithm and to present a new method with reduced execution time. The newly proposed algorithm is faster than the conventional Merge Sort algorithm having a time complexity of O(n log2 n). The proposed algorithm has been tested, implemented, compared and the experimental results are promising

Prevention of Reg I-induced β-cell apoptosis by IL-6/dexamethasone through activation of HGF gene regulation

AbstractReg (regenerating gene) product, Reg protein, is induced in pancreatic β-cells and acts as autocrine/paracrine growth factor for regeneration via the cell surface Reg receptor. However, high concentrations of Reg I protein induced β-cell apoptosis. In the present study, we found that hepatocyte growth factor (HGF) attenuated the β-cell apoptosis induced by the high concentrations of Reg I protein and that the combined stimulation of interleukin-6 (IL-6) and dexamethasone (Dx) induced the accumulation of HGF mRNA as well as Reg I mRNA in β-cells. The accumulation of the HGF mRNA was caused by the activation of the HGF promoter. Deletion analysis revealed that the region of −96 to −92 of the HGF gene was responsible for the promoter activation by IL-6+Dx. The promoters contain a consensus transcription factor binding sequence for signal transducer and activator of transcription (STAT). Site-directed mutations of STAT-binding motif in the region markedly attenuated the HGF promoter activity. Chromatin immunoprecipitation assay showed that STAT3 is located at the active HGF promoter in response to IL-6+Dx stimulation. These results strongly suggest that the combined stimulation of IL-6 and glucocorticoids induces the activation of both Reg and HGF genes and that the anti-apoptotic effects of HGF against the Reg I-induced apoptosis may help β-cell regeneration by Reg I protein

Activation of TRPV1 and TRPM8 Channels in the Larynx and Associated Laryngopharyngeal Regions Facilitates the Swallowing Reflex

The larynx and associated laryngopharyngeal regions are innervated by the superior laryngeal nerve (SLN) and are highly reflexogenic. Transient receptor potential (TRP) channels have recently been detected in SLN innervated regions; however, their involvement in the swallowing reflex has not been fully elucidated. Here, we explore the contribution of two TRP channels, TRPV1 and TRPM8, located in SLN-innervated regions to the swallowing reflex. Immunohistochemistry identified TRPV1 and TRPM8 on cell bodies of SLN afferents located in the nodose-petrosal-jugular ganglionic complex. The majority of TRPV1 and TRPM8 immunoreactivity was located on unmyelinated neurons. Topical application of different concentrations of TRPV1 and TRPM8 agonists modulated SLN activity. Application of the agonists evoked a significantly greater number of swallowing reflexes compared with the number evoked by distilled water. The intervalbetween the reflexes evoked by the agonists was shorter than that produced by distilled water. Prior topical application of respective TRPV1 or TRPM8 antagonists significantly reduced the number of agonist-evoked reflexes. The findings suggest that the activation of TRPV1 and TRPM8 channels present in the swallowing-related regions can facilitate the evoking of swallowing reflex. Targeting the TRP channels could be a potential therapeutic strategy for the management of dysphagia

The Role of Transient Receptor Potential (TRP) Channels in the Transduction of Dental Pain

Dental pain is a common health problem that negatively impacts the activities of daily living. Dentine hypersensitivity and pulpitis-associated pain are among the most common types of dental pain. Patients with these conditions feel pain upon exposure of the affected tooth to various external stimuli. However, the molecular mechanisms underlying dental pain, especially the transduction of external stimuli to electrical signals in the nerve, remain unclear. Numerous ion channels and receptors localized in the dental primary afferent neurons (DPAs) and odontoblasts have been implicated in the transduction of dental pain, and functional expression of various polymodal transient receptor potential (TRP) channels has been detected in DPAs and odontoblasts. External stimuli-induced dentinal tubular fluid movement can activate TRP channels on DPAs and odontoblasts. The odontoblasts can in turn activate the DPAs by paracrine signaling through ATP and glutamate release. In pulpitis, inflammatory mediators may sensitize the DPAs. They could also induce post-translational modifications of TRP channels, increase trafficking of these channels to nerve terminals, and increase the sensitivity of these channels to stimuli. Additionally, in caries-induced pulpitis, bacterial products can directly activate TRP channels on DPAs. In this review, we provide an overview of the TRP channels expressed in the various tooth structures, and we discuss their involvement in the development of dental pain

Inhibitory effects of local anesthetics on the proteasome and their biological actions

Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indicated that these LAs were bound to the β5 subunit of the 20S proteasome, and not to the other active subunits, β1 and β2. Consistently, pilsicainide inhibited only chymotrypsin-like activity, whereas it did not inhibit the caspase-like and trypsin-like activities. In addition, we confirmed that the aromatic ring of these LAs was critical for inhibiting the proteasome. These LAs stabilized p53 and suppressed proliferation of p53-positive but not of p53-negative cancer cells

Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP. View Full-Tex

Phylogenetic groups and cephalosporin resistance genes of Escherichia coli from diseased food-producing animals in Japan

A total of 318 Escherichia coli isolates obtained from different food-producing animals affected with colibacillosis between 2001 and 2006 were subjected to phylogenetic analysis: 72 bovine isolates, 89 poultry isolates and 157 porcine isolates. Overall, the phylogenetic group A was predominant in isolates from cattle (36/72, 50%) and pigs (101/157, 64.3%) whereas groups A (44/89, 49.4%) and D (40/89, 44.9%) were predominant in isolates from poultry. In addition, group B2 was not found among diseased food-producing animals except for a poultry isolate. Thus, the phylogenetic group distribution of E. coli from diseased animals was different by animal species. Among the 318 isolates, cefazolin resistance (minimum inhibitory concentrations: ≥32 μg/ml) was found in six bovine isolates, 29 poultry isolates and three porcine isolates. Of them, 11 isolates (nine from poultry and two from cattle) produced extended spectrum β-lactamase (ESBL). The two bovine isolates produced blaCTX-M-2, while the nine poultry isolates produced blaCTX-M-25 (4), blaSHV-2 (3), blaCTX-M-15 (1) and blaCTX-M-2 (1). Thus, our results showed that several types of ESBL were identified and three types of β-lactamase (SHV-2, CTX-M-25 and CTX-M-15) were observed for the first time in E. coli from diseased animals in Japan