Cooperative Binding of Ferrocenylnaphthalene Diimide Carrying β-Cyclodextrin Converts Double-Stranded DNA to a Rod-Like Structure

Ferrocenylnaphthalene diimide carrying β-cyclodextrin (β-CD), 1, intercalated into double-stranded DNA with a binding affinity of K = (6.6 ± 0.8) × 104 M–1 and a binding site size of n = 4, with a high positive cooperative parameter of ω = 14. β-CD and ferrocene moieties of the compound contributed to the formation of the intermolecular inclusion complex on DNA. Binding of 1 resulted in conversion of the DNA duplex to a rod-like form, which was cleaved upon adamantylamine addition

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

Effect of Polymers and Storage Relative Humidity on Amorphous Rebamipide and Its Solid Dispersion Transformation: Multiple Spectra Chemometrics of Powder X-Ray Diffraction and Near-Infrared Spectroscopy

This study aimed to investigate the effect of polymers and storage relative humidity on amorphous rebamipide (RB) and its solid dispersion phase transformation using chemometrics based on multiple datasets. The amorphous RB was prepared using particle mixture and grinding methods with hydroxypropyl cellulose, polyvinylpyrrolidone, and sodium dodecyl sulfate. Prepared amorphous RB and solid dispersion samples were stored under a relative humidity of 30% and 75% for four weeks. Infrared spectra of the dispersion samples suggested that the hydrogen bond network was constructed among quinolinone, carbonyl acid, and amide of RB and other polymers. The dataset combining near-infrared (NIR) spectra and powder X-ray diffractograms were applied to principal component analysis (PCA). The relationship between diffractograms and NIR spectra was evaluated using loadings and the PCA score. The multiple spectra analysis is useful for evaluating model amorphous active pharmaceutical ingredients without a standard sample

Formation of nitrogen-vacancy centers in 4H-SiC and their near infrared photoluminescence properties

NCVSi− centers in SiC [nitrogen-vacancy (NV) centers], which produce near-infrared (NIR) photoluminescence (PL) at room temperature, is expected to have applications as quantum sensors for in vivo imaging and sensing. To realize quantum sensing using NV centers, clarification of the formation mechanism as well as control of the high-density formation is necessary. This paper reports a comprehensive investigation on the NIR-PL properties originating from NV centers in high purity semi-insulating and nitrogen (N) contained 4H-SiC substrates formed by ion beam irradiation and subsequent thermal annealing. It is shown that NV centers are exclusively formed by the contained N as impurities rather than the implanted N, and also the heavier ion irradiations induce the NV center formation effectively than the lighter ion irradiations. The study on thermal annealing at different temperatures reveals that the optimal temperature is 1000 °C. From the results of temperature dependence on the PL intensity, it is shown that little thermal quenching of the PL intensity appears at room temperature and the PL signal is collected even at 783 K. The formation mechanism of NV centers is also discussed based on the obtained results

Electrical detection of TV2a-type silicon vacancy spin defect in 4H-SiC MOSFETs

Color centers in silicon carbide (4H-SiC) are potentially usable as spin defects for quantum sensing and quantum information technology. In particular, neutral divacancies (the P6/P7centers, VSiVC 0) and a certain type of silicon vacancies (the TV2a center, VSi - at the k site) are promising for addressing and manipulating single spins. Although the TV2a spin is readable at room temperature, the readout techniques have been limited to luminescence-based ones (e.g., optically detected magnetic resonance). In this study, we demonstrated electrical detection of TV2a-type silicon vacancies at room temperature by using electrically detected magnetic resonance on 4H-SiC metal–oxide–semiconductor field effect transistors (MOSFETs). TV2a spin defects were embedded in the channel region of well-defined 4H-SiC MOSFETs via controlled proton irradiation. The number of detected TV2a spins was estimated to be 10^5. We also found that the charge state of the TV2aspin defect can be controlled by varying the gate voltage applied to the MOSFET

Creation of nitrogen-vacancy centers in SiC by ion irradiation

Color centers which act as stable single photon emitters (SPEs) in wide bandgap semiconductors are key elements for quantum technologies. Silicon carbide (SiC) is regarded as a promising host material for qubit/quantum sensor. It was reported that negatively charged nitrogen-vacancy (NcVsi-) center in SiC (S=1) act as SPS with its zero phonon line (ZPL) around 1170 ~1250 nm. However, detailed characteristics of NcVsi- center in SiC have not yet been clarified since the creation methods for NcVsi- have not yet been established.In this study, various energetic charged particles such as protons, nitrogen (N), silicon (Si) and iodine (I) ions were irradiated into n-type and high purity semi-insulation (HPSI) hexagonal (4H) SiC and subsequently annealed up to 1100C. The creation of NcVsi in SiC are evaluated on the basis of photoluminescence (PL) characteristics.30th International Conference on Defects in Smiconductors (ICDS-30

Sip1, a conserved AP-1 accessory protein, is important for Golgi/endosome trafficking in fission yeast.

We had previously identified the mutant allele of apm1(+) that encodes a homolog of the mammalian μ 1A subunit of the clathrin-associated adaptor protein-1 (AP-1) complex and demonstrated that the AP-1 complex plays a role in Golgi/endosome trafficking, secretion, and vacuole fusion in fission yeast. Here, we isolated a mutant allele of its4(+)/sip1(+), which encodes a conserved AP-1 accessory protein. The its4-1/sip1-i4 mutants and apm1-deletion cells exhibited similar phenotypes, including sensitivity to the calcineurin inhibitor FK506, Cl(-) and valproic acid as well as various defects in Golgi/endosomal trafficking and cytokinesis. Electron micrographs of sip1-i4 mutants revealed vacuole fragmentation and accumulation of abnormal Golgi-like structures and secretory vesicles. Overexpression of Apm1 suppressed defective membrane trafficking in sip1-i4 mutants. The Sip1-green fluorescent protein (GFP) co-localized with Apm1-mCherry at Golgi/endosomes, and Sip1 physically interacted with each subunit of the AP-1 complex. We found that Sip1 was a Golgi/endosomal protein and the sip1-i4 mutation affected AP-1 localization at Golgi/endosomes, thus indicating that Sip1 recruited the AP-1 complex to endosomal membranes by physically interacting with each subunit of this complex. Furthermore, Sip1 is required for the correct localization of Bgs1/Cps1, 1,3-β-D-glucan synthase to polarized growth sites. Consistently, the sip1-i4 mutants displayed a severe sensitivity to micafungin, a potent inhibitor of 1,3-β-D-glucan synthase. Taken together, our findings reveal a role for Sip1 in the regulation of Golgi/endosome trafficking in coordination with the AP-1 complex, and identified Bgs1, required for cell wall synthesis, as the new cargo of AP-1-dependent trafficking