Semantic Foundations of Higher-Order Probabilistic Programs in Isabelle/HOL

Higher-order probabilistic programs are used to describe statistical models and machine-learning mechanisms. The programming languages for them are equipped with three features: higher-order functions, sampling, and conditioning. In this paper, we propose an Isabelle/HOL library for probabilistic programs supporting all of those three features. We extend our previous quasi-Borel theory library in Isabelle/HOL. As a basis of the theory, we formalize s-finite kernels, which is considered as a theoretical foundation of first-order probabilistic programs and a key to support conditioning of probabilistic programs. We also formalize the Borel isomorphism theorem which plays an important role in the quasi-Borel theory. Using them, we develop the s-finite measure monad on quasi-Borel spaces. Our extension enables us to describe higher-order probabilistic programs with conditioning directly as an Isabelle/HOL term whose type is that of morphisms between quasi-Borel spaces. We also implement the qbs prover for checking well-typedness of an Isabelle/HOL term as a morphism between quasi-Borel spaces. We demonstrate several verification examples of higher-order probabilistic programs with conditioning

Discovery of a lectin domain that regulates enzyme activity in mouse N-acetylglucosaminyltransferase-IVa (MGAT4A)

N-Glycosylation is a common post-translational modification, and the number of GlcNAc branches in N-glycans impacts glycoprotein functions. N-Acetylglucosaminyltransferase-IVa (GnT-IVa, also designated as MGAT4A) forms a β1-4 GlcNAc branch on the α1-3 mannose arm in N-glycans. Downregulation or loss of GnT-IVa causes diabetic phenotypes by dysregulating glucose transporter-2 in pancreatic β-cells. Despite the physiological importance of GnT-IVa, its structure and catalytic mechanism are poorly understood. Here, we identify the lectin domain in mouse GnT-IVa’s C-terminal region. The crystal structure of the lectin domain shows structural similarity to a bacterial GlcNAc-binding lectin. Comprehensive glycan binding assay using 157 glycans and solution NMR reveal that the GnT-IVa lectin domain selectively interacts with the product N-glycans having a β1-4 GlcNAc branch. Point mutation of the residue critical to sugar recognition impairs the enzymatic activity, suggesting that the lectin domain is a regulatory subunit for efficient catalytic reaction. Our findings provide insights into how branching structures of N-glycans are biosynthesized

Activation of XBP1 but not ATF6α rescues heart failure induced by persistent ER stress in medaka fish

The unfolded protein response is triggered in vertebrates by ubiquitously expressed IRE1α/β (although IRE1β is gut-specific in mice), PERK, and ATF6α/β, transmembrane-type sensor proteins in the ER, to cope with ER stress, the accumulation of unfolded and misfolded proteins in the ER. Here, we burdened medaka fish, a vertebrate model organism, with ER stress persistently from fertilization by knocking out the AXER gene encoding an ATP/ADP exchanger in the ER membrane, leading to decreased ATP concentration–mediated impairment of the activity of Hsp70- and Hsp90-type molecular chaperones in the ER lumen. ER stress and apoptosis were evoked from 4 and 6 dpf, respectively, leading to the death of all AXER-KO medaka by 12 dpf because of heart failure (medaka hatch at 7 dpf). Importantly, constitutive activation of IRE1α signaling --but not ATF6α signaling-- rescued this heart failure and allowed AXER-KO medaka to survive 3 d longer, likely because of XBP1-mediated transcriptional induction of ER-associated degradation components. Thus, activation of a specific pathway of the unfolded protein response can cure defects in a particular organ

Electrophysiologic Characteristics of Electrically Induced Nonsustained Ventricular Tachycardia in the Late Stage of Canine Myocardial Infarction

To examine electrophysiologic characteristics of electrically induced nonsustained ventricular tachycardia (NSVT), open chest electrophysiologic study was performed on 21 dogs with 25-day-old anteroapical myocardial infarction. Six of the 21 dogs had reproducibly inducible NSVT and five had reproducibly inducible sustained ventricular tachycardia (SuVT) in response to programmed ventricular stimulation. Remaining 10 dogs had no reproducibly inducible ventricular tachycardia or ventricular fibrillation (VF) in response to programmed ventricular stimulation. Twelve NSVTs in the 6 dogs were characterized by beat-to-beat variations of cycle length and QRS morphology of surface lead and also by wide disparity of local activation of the left ventricle, whereas 10 SuVTs in the five dogs did not show these electrophysiologic characteristics except during the first three to four beats. Three of the 12 NSVTs transformed into VF. Cycle lengths of these three NSVTs showed progressive shortening before transformation into VF. None of the 10 SuVTs transformed into VF. Continuous disorganized electrical activity was recorded on endocardial electrograms of the left ventricle in four of the 12 NSVTs, but not in the 10 SuVTs. It is concluded that in the late stage of canine myocardial infarction nonsustained ventricular tachycardia is an unstable ventricular tachyarrhythmia with some differences in electrophysiologic manifestation from sustained ventricular tachycardia

Investigating the role of the Itoigawa-Shizuoka tectonic line towards the evolution of the Northern Fossa Magna rift basin

AbstractThe Itoigawa-Shizuoka tectonic line (ISTL) fault system is considered to have one of the highest probabilities for a major inland earthquake occurrence in the whole of Japan. It is a complex fault system with the dip directions of the local fault segments changing from north to south between an east-dipping low-angle thrust fault, a strike slip fault and a west-dipping thrust fault. The tectonic relations between the different parts of the fault system and the surrounding geological units are yet to be fully explained. This study aims to reveal the juncture of the northern and central parts of the ISTL and investigate its contribution towards the shaping of the Northern Fossa Magna rift basin. We conducted 3 deployments of 1 or 2 linear arrays of seismic stations across the central and northern ISTL regions and observed local micro-earthquakes for a period of 3 years. Each deployment recorded continuous waveform data for approximately 3 months. Using arrival times of 1193 local earthquakes, we jointly determined earthquake locations and a 3D velocity model, applying the tomography method. We were able to image the regional crustal structures from the surface to a depth of 20km with a spatial resolution of 5km. Subsequently, we used the obtained 3D velocity model to relocate the background local seismicity from 2003 to 2009. The juncture of the northern and central parts of the ISTL was well constrained by our results. The depth extension of the northern parts of the ISTL fault segments follows the bottom of the Miocene Northern Fossa Magna rift basin (NFM) and forms an east-dipping low-angle fault. In contrast, the central parts of the ISTL fault segments are estimated to lie along the eastern boundary of the Matsumoto basin forming an oblique strike slip fault (Fig. 1)

Development of a shutterless continuous rotation method using an X-ray CMOS detector for protein crystallography

A shutterless continuous rotation method using an X-ray complementary metal-oxide semiconductor (CMOS) detector has been developed for high-speed, precise data collection in protein crystallography. The new method and detector were applied to the structure determination of three proteins by multi- and single-wavelength anomalous diffraction phasing and have thereby been proved to be applicable in protein crystallography

Spatial control of translation repression and polarized growth by conserved NDR kinase Orb6 and RNA-binding protein Sts5

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in eLife 5 (2016): e14216, doi:10.7554/eLife.14216.RNA-binding proteins contribute to the formation of ribonucleoprotein (RNP) granules by phase transition, but regulatory mechanisms are not fully understood. Conserved fission yeast NDR (Nuclear Dbf2-Related) kinase Orb6 governs cell morphogenesis in part by spatially controlling Cdc42 GTPase. Here we describe a novel, independent function for Orb6 kinase in negatively regulating the recruitment of RNA-binding protein Sts5 into RNPs to promote polarized cell growth. We find that Orb6 kinase inhibits Sts5 recruitment into granules, its association with processing (P) bodies, and degradation of Sts5-bound mRNAs by promoting Sts5 interaction with 14-3-3 protein Rad24. Many Sts5-bound mRNAs encode essential factors for polarized cell growth, and Orb6 kinase spatially and temporally controls the extent of Sts5 granule formation. Disruption of this control system affects cell morphology and alters the pattern of polarized cell growth, revealing a role for Orb6 kinase in the spatial control of translational repression that enables normal cell morphogenesis.Work in FV’s laboratory is supported by the National Institutes of Health R01 grant number GM095867. Part of this work was also supported by NSF grant 0745129. TT was supported by Japan Society for the Promotion of Science grants 16H02503 and 16K14672 and by Cancer Research UK

Effects of hydrogen ion irradiation on zinc oxide etching

Mechanisms of zinc oxide (ZnO) etching by hydrocarbon plasmas were investigated both experimentally and theoretically with the use of a mass-selected ion beam system and first-principle quantum mechanical (QM) simulation based on the density functional theory. The mass-selected ion beam experiments have shown that the sputtering yield of ZnO increases by a pretreatment of the ZnO film by energetic hydrogen (H) ion injections prior to heavy ion bombardment, suggesting that chemically enhanced etching of ZnO by hydrocarbon plasmas is closely related to hydrogen storage and/or formation of damage in the ZnO layer by energetic hydrogen injections. In this study, the effects of hydrogen storage in ZnO are examined. First-principle QM simulation of ZnO interacting with H atoms has shown that H atoms in ZnO form hydroxyl (OH) groups (or partially convert ZnO to ZnOH), which results in the weakening or breaking of the Zn-O bonds around H atoms and thus makes the ZnO film more prone to physical sputtering. The formation of hydroxyl groups in ZnO is also expected to occur in ZnO etching by hydrocarbon plasmas and increase its sputtering yields over those by inert-gas plasmas generated under similar conditions.H. Li et al., Journal of Vacuum Science & Technology A 35, 05C303 (2017) https://doi.org/10.1116/1.498271