Space-Efficient Gradual Typing in Coercion-Passing Style

Herman et al. pointed out that the insertion of run-time checks into a gradually typed program could hamper tail-call optimization and, as a result, worsen the space complexity of the program. To address the problem, they proposed a space-efficient coercion calculus, which was subsequently improved by Siek et al. The semantics of these calculi involves eager composition of run-time checks expressed by coercions to prevent the size of a term from growing. However, it relies also on a nonstandard reduction rule, which does not seem easy to implement. In fact, no compiler implementation of gradually typed languages fully supports the space-efficient semantics faithfully. In this paper, we study coercion-passing style, which Herman et al. have already mentioned, as a technique for straightforward space-efficient implementation of gradually typed languages. A program in coercion-passing style passes "the rest of the run-time checks" around - just like continuation-passing style (CPS), in which "the rest of the computation" is passed around - and (unlike CPS) composes coercions eagerly. We give a formal coercion-passing translation from ?S by Siek et al. to ?S?, which is a new calculus of first-class coercions tailored for coercion-passing style, and prove correctness of the translation. We also implement our coercion-passing style transformation for the Grift compiler developed by Kuhlenschmidt et al. An experimental result shows stack overflow can be prevented properly at the cost of up to 3 times slower execution for most partially typed practical programs

Gradual session types

Session types are a rich type discipline, based on linear types, that lifts the sort of safety claims that come with type systems to communications. However, web-based applications and microservices are often written in a mix of languages, with type disciplines in a spectrum between static and dynamic typing. Gradual session types address this mixed setting by providing a framework which grants seamless transition between statically typed handling of sessions and any required degree of dynamic typing. We propose Gradual GV as a gradually typed extension of the functional session type system GV. Following a standard framework of gradual typing, Gradual GV consists of an external language, which relaxes the type system of GV using dynamic types, and an internal language with casts, for which operational semantics is given, and a cast-insertion translation from the former to the latter. We demonstrate type and communication safety as well as blame safety, thus extending previous results to functional languages with session-based communication. The interplay of linearity and dynamic types requires a novel approach to specifying the dynamics of the language.Comment: Preprint of an article to appear in Journal of Functional Programmin

Autosomal dominant pseudohypoaldosteronism type 1 with a novel splice site mutation in MR gene

<p>Abstract</p> <p>Background</p> <p>Autosomal dominant pseudohypoaldosteronism type 1 (PHA1) is a rare inherited condition that is characterized by renal resistance to aldosterone as well as salt wasting, hyperkalemia, and metabolic acidosis. Renal PHA1 is caused by mutations of the human mineralcorticoid receptor gene (<it>MR</it>), but it is a matter of debate whether <it>MR </it>mutations cause mineralcorticoid resistance via haploinsufficiency or dominant negative mechanism. It was previously reported that in a case with nonsense mutation the mutant mRNA was absent in lymphocytes because of nonsense mediated mRNA decay (NMD) and therefore postulated that haploinsufficiency alone can give rise to the PHA1 phenotype in patients with truncated mutations.</p> <p>Methods and Results</p> <p>We conducted genomic DNA analysis and mRNA analysis for familial PHA1 patients extracted from lymphocytes and urinary sediments and could detect one novel splice site mutation which leads to exon skipping and frame shift result in premature termination at the transcript level. The mRNA analysis showed evidence of wild type and exon-skipped RT-PCR products.</p> <p>Conclusion</p> <p>mRNA analysis have been rarely conducted for PHA1 because kidney tissues are unavailable for this disease. However, we conducted RT-PCR analysis using mRNA extracted from urinary sediments. We could demonstrate that NMD does not fully function in kidney cells and that haploinsufficiency due to NMD with premature termination is not sufficient to give rise to the PHA1 phenotype at least in this mutation of our patient. Additional studies including mRNA analysis will be needed to identify the exact mechanism of the phenotype of PHA.</p

Effectiveness of Messenger RNA Coronavirus Disease 2019 Vaccines Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections During the Delta Variant Epidemic in Japan: Vaccine Effectiveness Real-time Surveillance for SARS-CoV-2 (VERSUS)

Background. Although high vaccine effectiveness of messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines has been reported in studies in several countries, data are limited from Asian countries, especially against the Delta (B.1.617.2) variant.Methods. We conducted a multicenter test-negative case-control study in patients aged ≥16 years visiting hospitals or clinics with signs or symptoms consistent with COVID-19 from 1 July to 30 September 2021, when the Delta variant was dominant (≥90% of SARS-CoV-2 infections) nationwide in Japan. Vaccine effectiveness of BNT162b2 or mRNA-1273 against symptomatic SARS-CoV-2 infections was evaluated. Waning immunity among patients aged 16–64 years was also assessed.Results. We enrolled 1936 patients, including 396 test-positive cases and 1540 test-negative controls for SARS-CoV-2. The median age was 49 years, 53.4% were male, and 34.0% had underlying medical conditions. Full vaccination (receiving 2 doses ≥14 days before symptom onset) was received by 6.6% of cases and 38.8% of controls. Vaccine effectiveness of full vaccination against symptomatic SARS-CoV-2 infections was 88.7% (95% confidence interval [CI], 78.8%–93.9%) among patients aged 16–64 years and 90.3% (95% CI, 73.6%–96.4%) among patients aged ≥65 years. Among patients aged 16–64 years, vaccine effectiveness was 91.8% (95% CI, 80.3%–96.6%) within 1–3 months after full vaccination, and 86.4% (95% CI, 56.9%–95.7%) within 4–6 months.Conclusions. mRNA COVID-19 vaccines had high effectiveness against symptomatic SARS-CoV-2 infections in Japan during July–September 2021, when the Delta variant was dominant nationwide

A Novel Enzymatic System against Oxidative Stress in the Thermophilic Hydrogen-Oxidizing Bacterium Hydrogenobacter thermophilus

Rubrerythrin (Rbr) is a non-heme iron protein composed of two distinctive domains and functions as a peroxidase in anaerobic organisms. A novel Rbr-like protein, ferriperoxin (Fpx), was identified in Hydrogenobacter thermophilus and was found not to possess the rubredoxin-like domain that is present in typical Rbrs. Although this protein is widely distributed among aerobic organisms, its function remains unknown. In this study, Fpx exhibited ferredoxin:NADPH oxidoreductase (FNR)-dependent peroxidase activity and reduced both hydrogen peroxide (H2O2) and organic hydroperoxide in the presence of NADPH and FNR as electron donors. The calculated Km and Vmax values of Fpx for organic hydroperoxides were comparable to that for H2O2, demonstrating a multiple reactivity of Fpx towards hydroperoxides. An fpx gene disruptant was unable to grow under aerobic conditions, whereas its growth profiles were comparable to those of the wild-type strain under anaerobic and microaerobic conditions, clearly indicating the indispensability of Fpx as an antioxidant of H. thermophilus in aerobic environments. Structural analysis suggested that domain-swapping occurs in Fpx, and this domain-swapped structure is well conserved among thermophiles, implying the importance of structural stability of domain-swapped conformation for thermal environments. In addition, Fpx was located on a deep branch of the phylogenetic tree of Rbr and Rbr-like proteins. This finding, taken together with the wide distribution of Fpx among Bacteria and Archaea, suggests that Fpx is an ancestral type of Rbr homolog that functions as an essential antioxidant and may be part of an ancestral peroxide-detoxification system

Effectiveness of mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infections during the SARS-CoV-2 Omicron BA.1 and BA.2 epidemic in Japan: vaccine effectiveness real-time surveillance for SARS-CoV-2 (VERSUS)

Background: Evaluating COVID-19 vaccine effectiveness (VE) domestically is crucial for assessing and determining national vaccination policy. This study aimed to evaluate VE of mRNA COVID-19 vaccines in Japan. Methods: We conducted a multicenter test-negative case-control study. The study comprised indivi-duals aged ≥16 visiting medical facilities with COVID-19-related signs or symptoms from 1 January to 26 June 2022, when Omicron BA.1 and BA.2 were dominant nationwide. We evaluated VE of primary and booster vaccination against symptomatic SARS-CoV-2 infections and relative VE of booster compared with primary.Results: We enrolled 7,931 episodes, including 3,055 test positive. The median age was 39, 48.0% were male, and 20.5% had underlying medical conditions. In individuals aged 16 to 64, VE of primary vaccination within 90 days was 35.6% (95% CI, 19.0–48.8%). After booster, VE increased to 68.7% (60.6–75.1%). In individuals aged ≥65, VE of primary and booster was 31.2% (−44.0–67.1%) and 76.5% (46.7–89.7%), respectively. Relative VE of booster compared with primary vaccination was 52.9% (41.0– 62.5%) in individuals aged 16 to 64 and 65.9% (35.7–81.9%) in individuals aged ≥65.Conclusions: During BA.1 and BA.2 epidemic in Japan, mRNA COVID-19 primary vaccination provided modest protection. Booster vaccination was necessary to protect against symptomatic infections

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Biosynthetic Studies of Phomopsins Unveil Posttranslational Installation of Dehydroamino Acids by UstYa Family Proteins

UstYa family proteins (DUF3328) are widely and specifically distributed in fungi. They are known to be involved in the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs) and nonribosomal peptides, and possibly catalyze various reactions, including oxidative cyclization and chlorination. In this study, we focused on phomopsin A, a fungal RiPP consisting of unique nonproteinogenic amino acids. Gene knockout experiments demonstrated that three UstYa homologues, phomYc, phomYd, and phomYe, are essential for the desaturation of amino acid moieties, showing unprecedented function among UstYa family proteins. Sequence similarity network analysis indicated that their amino acid sequences are highly diverged and that most remain uncharacterized, paving the way for genome mining of fungal metabolites with unique modifications

Strength development and hydration progress of a cement-based solidifying agent used in cementtreated soil containing volcanic mineral components

This study investigates the relationship between the strength development and hydration progress of cement-based solidifying agents (CBSAs) in cement-treated soil with volcanic mineral components. A CBSA is a cement-based material used as a soil stabilizer. It is known that the strength development of cement-based materials is inhibited by volcanic mineral components, e.g., allophane, and CBSAs are specially controlled against hydration inhibitions. Previous studies showed that allophane might be the governing factor for the inhibition of cement hydration, and its response to the hydration properties should be investigated. In this study, cement-paste and cement-treated–soil specimens are made with three types of binder (ordinary Portland cement, blast-furnace slag cement, and a CBSA) to investigate the hydration progress and strength development. Uniaxial compression tests were conducted, and the strength development was measured with the different binder types. It was found that the strengths of the cement-paste specimens at day 28 were almost the same with the three binders, while they differed in the mortar specimens that contained allophane. X-ray diffraction/Rietveld analyses were conducted to measure the hydration properties. From the results, it was supposed that, owing to the lack of Ca(OH)2, the pozzolanic reaction was stagnant. Considering the ion concentration of the pore water in the solidified materials, quantitative estimations of the strength development affected by allophane should be possible in the future