Superresolution Full-polarimetric Imaging for Radio Interferometry with Sparse Modeling

We propose a new technique for radio interferometry to obtain superresolution full-polarization images in all four Stokes parameters using sparse modeling. The proposed technique reconstructs the image in each Stokes parameter from the corresponding full-complex Stokes visibilities by utilizing two regularization functions: the ℓ 1 norm and the total variation (TV) of the brightness distribution. As an application of this technique, we present simulated linear polarization observations of two physically motivated models of M87 with the Event Horizon Telescope. We confirm that ℓ 1+TV regularization can achieve an optimal resolution of ~25%–30% of the diffraction limit λ/D[subscript max], which is the nominal spatial resolution of a radio interferometer for both the total intensity (i.e., Stokes I) and linear polarizations (i.e., Stokes Q and U). This optimal resolution is better than that obtained from the widely used Cotton–Schwab CLEAN algorithm or from using ℓ 1 or TV regularizations alone. Furthermore, we find that ℓ 1+TV regularization can achieve much better image fidelity in linear polarization than other techniques over a wide range of spatial scales, not only in the superresolution regime, but also on scales larger than the diffraction limit. Our results clearly demonstrate that sparse reconstruction is a useful choice for high-fidelity full-polarimetric interferometric imaging

Imaging the Schwarzschild-radius-scale Structure of M87 with the Event Horizon Telescope Using Sparse Modeling

We propose a new imaging technique for radio and optical/infrared interferometry. The proposed technique reconstructs the image from the visibility amplitude and closure phase, which are standard data products of short-millimeter very long baseline interferometers such as the Event Horizon Telescope (EHT) and optical/infrared interferometers, by utilizing two regularization functions: the ℓ_1-norm and total variation (TV) of the brightness distribution. In the proposed method, optimal regularization parameters, which represent the sparseness and effective spatial resolution of the image, are derived from data themselves using cross-validation (CV). As an application of this technique, we present simulated observations of M87 with the EHT based on four physically motivated models. We confirm that ℓ_1 + TV regularization can achieve an optimal resolution of ~20%–30% of the diffraction limit λ/D_(max), which is the nominal spatial resolution of a radio interferometer. With the proposed technique, the EHT can robustly and reasonably achieve super-resolution sufficient to clearly resolve the black hole shadow. These results make it promising for the EHT to provide an unprecedented view of the event-horizon-scale structure in the vicinity of the supermassive black hole in M87 and also the Galactic center Sgr A*

TDRD5 is required for retrotransposon silencing, chromatoid body assembly, and spermiogenesis in mice

Tdrd5-deficient mice develop a functional haploid genome despite spermiogenesis arrest at the round spermatid stage

Cyclosporin A Associated Helicase-Like Protein Facilitates the Association of Hepatitis C Virus RNA Polymerase with Its Cellular Cyclophilin B

BACKGROUND: Cyclosporin A (CsA) is well known as an immunosuppressive drug useful for allogeneic transplantation. It has been reported that CsA inhibits hepatitis C virus (HCV) genome replication, which indicates that cellular targets of CsA regulate the viral replication. However, the regulation mechanisms of HCV replication governed by CsA target proteins have not been fully understood. PRINCIPAL FINDINGS: Here we show a chemical biology approach that elucidates a novel mechanism of HCV replication. We developed a phage display screening to investigate compound-peptide interaction and identified a novel cellular target molecule of CsA. This protein, named CsA associated helicase-like protein (CAHL), possessed RNA-dependent ATPase activity that was negated by treatment with CsA. The downregulation of CAHL in the cells resulted in a decrease of HCV genome replication. CAHL formed a complex with HCV-derived RNA polymerase NS5B and host-derived cyclophilin B (CyPB), known as a cellular cofactor for HCV replication, to regulate NS5B-CyPB interaction. CONCLUSIONS: We found a cellular factor, CAHL, as CsA associated helicase-like protein, which would form trimer complex with CyPB and NS5B of HCV. The strategy using a chemical compound and identifying its target molecule by our phage display analysis is useful to reveal a novel mechanism underlying cellular and viral physiology

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

Unraveling the Structural and Property Differences Between Highly Similar Chiral and Racemic Crystals Composed of Analogous Molecules

The structural differences between chiral and racemic crystals of enantiomers have piqued interest, as exemplified by the classical Wallach\u27s rule. However, the mechanical and thermal disparities between these materials have not been thoroughly investigated. This study reports the structural and mechanical differences between chiral and racemic crystals of two analogous molecules. The similarity of molecular and crystal structures between the two analogs was validated through comparison with known chiral-racemic crystal pairs. The Young\u27s moduli of the four crystals revealed larger values for racemic crystals than their chiral counterparts, consistent with the intermolecular interaction energies projected along the loading direction. The thermal response of crystals plays a significant role in their elastic behavior, and the temperature dependence of interaction energies along [001] direction was found to agree with the temperature dependence of lattice dynamics for all four crystals

Efficient production of bispecific antibody by FAST-IgTM and its application to NXT007 for the treatment of hemophilia A

ABSTRACTEfficient production of bispecific antibodies (BsAbs) in single mammalian cells is essential for basic research and industrial manufacturing. However, preventing unwanted pairing of heavy chains (HCs) and light chains (LCs) is a challenging task. To address this, we created an engineering technology for preferential cognate HC/LC and HC/HC paring called FAST-Ig (Four-chain Assembly by electrostatic Steering Technology – Immunoglobulin), and applied it to NXT007, a BsAb for the treatment of hemophilia A. We introduced charged amino-acid substitutions at the HC/LC interface to facilitate the proper assembly for manufacturing a standard IgG-type BsAb. We generated CH1/CL interface-engineered antibody variants that achieved > 95% correct HC/LC pairing efficiency with favorable pharmacological properties and developability. Among these, we selected a design (C3) that allowed us to separate the mis-paired species with an unintended pharmacological profile using ion-exchange chromatography. Crystal structure analysis demonstrated that the C3 design did not affect the overall structure of both Fabs. To determine the final design for HCs-heterodimerization, we compared the stability of charge-based and knobs into hole-based Fc formats in acidic conditions and selected the more stable charge-based format. FAST-Ig was also applicable to stable CHO cell lines for industrial production and demonstrated robust chain pairing with different subclasses of parent BsAbs. Thus, it can be applied to a wide variety of BsAbs both preclinically and clinically