Neural Fourier Transform: A General Approach to Equivariant Representation Learning

Symmetry learning has proven to be an effective approach for extracting the hidden structure of data, with the concept of equivariance relation playing the central role. However, most of the current studies are built on architectural theory and corresponding assumptions on the form of data. We propose Neural Fourier Transform (NFT), a general framework of learning the latent linear action of the group without assuming explicit knowledge of how the group acts on data. We present the theoretical foundations of NFT and show that the existence of a linear equivariant feature, which has been assumed ubiquitously in equivariance learning, is equivalent to the existence of a group invariant kernel on the dataspace. We also provide experimental results to demonstrate the application of NFT in typical scenarios with varying levels of knowledge about the acting group

Helicobacter pylori Exploits Host Membrane Phosphatidylserine for Delivery, Localization, and Pathophysiological Action of the CagA Oncoprotein

SummaryWhen delivered into gastric epithelial cells via type IV secretion, Helicobacter pylori CagA perturbs host cell signaling and thereby promotes gastric carcinogenesis. However, the mechanisms of CagA delivery, localization, and action remain poorly understood. We show that direct contact of H. pylori with epithelial cells induces externalization of the inner leaflet enriched host phospholipid, phosphatidylserine, to the outer leaflet of the host plasma membrane. CagA, which is exposed on the bacterial surface via type IV secretion, interacts with the externalized phosphatidylserine to initiate its entry into cells. CagA delivery also requires energy-dependent host cell processes distinct from known endocytic pathways. Within polarized epithelial cells, CagA is tethered to the inner leaflet of the plasma membrane through interaction with phosphatidylserine and binds the polarity-regulating host kinase PAR1/MARK to induce junctional and polarity defects. Thus, host membrane phosphatidylserine plays a key role in the delivery, localization, and pathophysiological action of CagA

A Heterothermic Kinetic Model of Hydrogen Absorption in Metals with Subsurface Transport

A versatile numerical model for hydrogen absorption into metals was developed. Our model addresses the kinetics of surface adsorption, subsurface transport (which plays an important role for metals with active surfaces), and bulk diffusion processes. This model can allow researchers to perform simulations for various conditions, such as different material species, dimensions, structures, and operating conditions. Furthermore, our calculation scheme reflects the relationship between the temperature changes in metals caused by the heat of adsorption and absorption and the temperature-dependent kinetic parameters for simulation precision purposes. We demonstrated the numerical fitting of the experimental data for various Pd temperatures and sizes, with a single set of kinetic parameters, to determine the unknown kinetic constants. Using the developed model and determined kinetic constants, the transitions of the rate-determining steps on the conditions of metal-hydrogen systems are systematically analyzed. Conventionally, the temperature change of metals during hydrogen adsorption and absorption has not been a favorable phenomenon because it can cause errors when numerically estimating the hydrogen absorption rates. However, by our calculation scheme, the experimental data obtained under temperature changing conditions can be positively used for parameter fitting to efficiently and accurately determine the kinetic constants of the absorption process, even from a small number of experimental runs. In addition, we defined an effectiveness factor as the ratio between the actual absorption rate and the virtually calculated non-bulk-diffusion-controlled rate, to evaluate the quantitative influence of each individual transport process on the overall absorption process. Our model and calculation scheme may be a useful tool for designing high-performance hydrogen storage systems

Genetic screening of KCNJ8 in Japanese patients with J-wave syndromes or idiopathic ventricular fibrillation

AbstractBackgroundJ-point elevation has been demonstrated to be associated with ventricular fibrillation (VF) and has been proposed as a cause of the J-wave syndrome (JWS). A mutation of KCNJ8, S422L, was reported as a culprit gene. This study aimed to determine the prevalence of KCNJ8 mutations in a Japanese population with JWS or idiopathic VF (IVF).MethodsA total of 230 probands with JWS and IVF underwent genetic screening of KCNJ8. To analyze and compare clinical and electrocardiographic characteristics, the probands were divided into 4 groups: Brugada (Br) pattern only, early repolarization (ER) pattern only, Br and ER patterns, and true IVF.ResultsThe results of the genetic analysis revealed no S422L or other KCNJ8 mutations and indicated no significant difference between the groups.ConclusionThe KCNJ8 mutation showed no association with JWS or IVF among our Japanese patients

Atrial arrhythmogenicity in aged Scn5a+/∆KPQ mice modeling long QT type 3 syndrome and its relationship to Na+ channel expression and cardiac conduction

Recent studies have reported that human mutations in Nav1.5 predispose to early age onset atrial arrhythmia. The present experiments accordingly assess atrial arrhythmogenicity in aging Scn5a+/∆KPQ mice modeling long QT3 syndrome in relationship to cardiac Na+ channel, Nav1.5, expression. Atrial electrophysiological properties in isolated Langendorff-perfused hearts from 3- and 12-month-old wild type (WT), and Scn5a+/∆KPQ mice were assessed using programmed electrical stimulation and their Nav1.5 expression assessed by Western blot. Cardiac conduction properties were assessed electrocardiographically in intact anesthetized animals. Monophasic action potential recordings demonstrated increased atrial arrhythmogenicity specifically in aged Scn5a+/ΔKPQ hearts. These showed greater action potential duration/refractory period ratios but lower atrial Nav1.5 expression levels than aged WT mice. Atrial Nav1.5 levels were higher in young Scn5a+/ΔKPQ than young WT. These levels increased with age in WT but not Scn5a+/ΔKPQ. Both young and aged Scn5a+/ΔKPQ mice showed lower heart rates and longer PR intervals than their WT counterparts. Young Scn5a+/ΔKPQ mice showed longer QT and QTc intervals than young WT. Aged Scn5a+/ΔKPQ showed longer QRS durations than aged WT. PR intervals were prolonged and QT intervals were shortened in young relative to aged WT. In contrast, ECG parameters were similar between young and aged Scn5a+/ΔKPQ. Aged murine Scn5a+/ΔKPQ hearts thus exhibit an increased atrial arrhythmogenicity. The differing Nav1.5 expression and electrocardiographic indicators of slowed cardiac conduction between Scn5a+/ΔKPQ and WT, which show further variations associated with aging, may contribute toward atrial arrhythmia in aged Scn5a+/ΔKPQ hearts

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