Sequent Calculus in the Topos of Trees

Nakano's "later" modality, inspired by G\"{o}del-L\"{o}b provability logic, has been applied in type systems and program logics to capture guarded recursion. Birkedal et al modelled this modality via the internal logic of the topos of trees. We show that the semantics of the propositional fragment of this logic can be given by linear converse-well-founded intuitionistic Kripke frames, so this logic is a marriage of the intuitionistic modal logic KM and the intermediate logic LC. We therefore call this logic $\mathrm{KM}_{\mathrm{lin}}$. We give a sound and cut-free complete sequent calculus for $\mathrm{KM}_{\mathrm{lin}}$ via a strategy that decomposes implication into its static and irreflexive components. Our calculus provides deterministic and terminating backward proof-search, yields decidability of the logic and the coNP-completeness of its validity problem. Our calculus and decision procedure can be restricted to drop linearity and hence capture KM.Comment: Extended version, with full proof details, of a paper accepted to FoSSaCS 2015 (this version edited to fix some minor typos

SGR 1806-20 distance and dust properties in molecular clouds by analysis of a flare x-ray echoes

The soft gamma repeater SGR 1806-20 is most famous for its giant flare from 2004, which yielded the highest gamma-ray flux ever observed on Earth. The flare emphasized the importance of determining the distance to the SGR, thus revealing the flare's energy output, with implications on SGRs energy budget and giant flare rates. We analyze x-ray scattering echoes observed by Swift/XRT following the 2006 August 6 intermediate burst of SGR 1806-20. Assuming positions and opacities of the molecular clouds along the line-of-sight from previous works, we derive direct constrains on the distance to SGR 1806-20, setting a lower limit of 9.4 kpc and an upper limit of 18.6 kpc (90% confidence), compared with a 6-15 kpc distance range by previous works. This distance range matches an energy output of ~10^46 erg/s for the 2004 giant flare. We further use, for the first time, the x-ray echoes in order to study the dust properties in molecular clouds. Analyzing the temporal evolution of the observed flux using a dust scattering model, which assumes a power-law size distribution of the dust grains, we find a power-law index of -3.3_{-0.7}^{+0.6} (1 sigma) and a lower limit of 0.1 micron (2 sigma) on the dust maximal grain size, both conforming to measured dust properties in the diffused interstellar medium (ISM). We advocate future burst follow-up observations with Swift, Chandra and the planned NuSTAR telescopes, as means of obtaining much superior results from such an analysis.Comment: 12 pages, 7 figures, 3 tables, submitted to MNRA

Towards a Proof Theory of G\"odel Modal Logics

Analytic proof calculi are introduced for box and diamond fragments of basic modal fuzzy logics that combine the Kripke semantics of modal logic K with the many-valued semantics of G\"odel logic. The calculi are used to establish completeness and complexity results for these fragments

Pulmonary Macrophages Attenuate Hypoxic Pulmonary Vasoconstriction via beta(3)AR/iNOS Pathway in Rats Exposed to Chronic Intermittent Hypoxia

Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central beta(1)-adrenergic receptors (AR) (brain) and peripheral beta(2)AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate beta(3)AR. However, the relationship between IH and beta(3)AR in the modification of HPV is unknown. It has been observed that chronic stimulation of beta(3)AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates beta(3)AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O-2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of proinflammatory pulmonary macrophages. In these macrophages, both beta(3)AR and iNOS were upregulated and stimulation of the beta(3)AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of beta(3)AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of beta(3)AR/iNOS signaling in chronic IH

The Myeloid Receptor PILRβ Mediates the Balance of Inflammatory Responses through Regulation of IL-27 Production

Paired immunoglobulin-like receptors beta, PILRβ, and alpha, PILRα, are related to the Siglec family of receptors and are expressed primarily on cells of the myeloid lineage. PILRβ is a DAP12 binding partner expressed on both human and mouse myeloid cells. The potential ligand, CD99, is found on many cell types, such as epithelial cells where it plays a role in migration of immune cells to sites of inflammation. Pilrb deficient mice were challenged with the parasite Toxoplasma gondii in two different models of infection induced inflammation; one involving the establishment of chronic encephalitis and a second mimicking inflammatory bowel disease in order to understand the potential role of this receptor in persistent inflammatory responses. It was found that in the absence of activating signals from PILRβ, antigen-presenting cells (APCs) produced increased amounts of IL-27, p28 and promoted IL-10 production in effector T cells. The sustained production of IL-27 led ultimately to enhanced survival after challenge due to dampened immune pathology in the gut. Similar protection was also observed in the CNS during chronic T. gondii infection after i.p. challenge again providing evidence that PILRβ is important for regulating aberrant inflammatory responses

IL-1β Suppresses Innate IL-25 and IL-33 Production and Maintains Helminth Chronicity.

Approximately 2 billion people currently suffer from intestinal helminth infections, which are typically chronic in nature and result in growth retardation, vitamin A deficiency, anemia and poor cognitive function. Such chronicity results from co-evolution between helminths and their mammalian hosts; however, the molecular mechanisms by which these organisms avert immune rejection are not clear. We have found that the natural murine helminth, Heligmosomoides polygyrus bakeri (Hp) elicits the secretion of IL-1β in vivo and in vitro and that this cytokine is critical for shaping a mucosal environment suited to helminth chronicity. Indeed in mice deficient for IL-1β (IL-1β(-/-)), or treated with the soluble IL-1βR antagonist, Anakinra, helminth infection results in enhanced type 2 immunity and accelerated parasite expulsion. IL-1β acts to decrease production of IL-25 and IL-33 at early time points following infection and parasite rejection was determined to require IL-25. Taken together, these data indicate that Hp promotes the release of host-derived IL-1β that suppresses the release of innate cytokines, resulting in suboptimal type 2 immunity and allowing pathogen chronicity

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

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