Adsorption and Desorption of Bioactive Proteins on Hydroxyapatite for Protein Delivery Systems

Hydroxyapatite (HA) is a precursor of bone and has been studied as a biomaterial. We attempted HA to apply to protein delivery systems. In this study, the association and dissociation properties of two types of bioactive proteins, cytochrom c and insulin, to HA were investigated. Cytochrom c was less associated with HA than insulin, which was easily released from it. However, the release of insulin from HA was slow. Insulin was released from HA at pH 7.4 more rapidly than at pH 3. The association and dissociation properties might be influenced by the size, solubility and net charge of protein. HA is a potential protein carrier with controlled release

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

Solubilization of Paclitaxel by Self-Assembled Amphiphilic Phospholipid-Mimetic Polymers with Varied Hydrophobicity

2-Methacryloyloxyethyl phosphorylcholine (MPC) polymers have been used as a coating agent on medical devices and as a carrier in drug delivery systems (DDSs). Paclitaxel (PTX) is a water-insoluble anticancer drug whose solubilizer is necessary for administration. Block and random copolymers composed of hydrophilic MPC and butyl methacrylate, named PMB, show different properties, depending on the polymer sequence and MPC content. In the present study, we used amphiphilic MPC polymers comprising hydrophobic dodecyl methacrylate (DMA). The self-assembling properties and PTX solubilization of random and block poly(MPC-co-DMA)s (rPMDs and bPMDs) with different compositions were examined and compared. rPMDs with high DMA content formed large and relatively loose self-assembled structures, which solubilized PTX. However, bPMDs formed small and compact self-assembled structures with poor PTX solubilization. PTX solubilized by PMB with small and loose self-assembled structures showed efficient drug action, similar to free PTX; however, rPMDs fell short of demonstrating PTX efficiency. Our results suggest that the self-assembling properties and the hydrophobicity of amphiphilic MPC polymers largely affect PTX solubilization as well as drug action, which is required to be controlled by the polymer sequence, as well as the structure and composition of the hydrophobic monomer for efficient DDS

Synthesis of a Dual-Color Fluorescent Dendrimer for Diagnosis of Cancer Metastasis in Lymph Nodes

Detection of cancer metastasis spread in lymph nodes is important in cancer diagnosis. In this study, a fluorescence imaging probe was designed for the detection of both lymph node and tumor cells using always-ON and activatable fluorescence probes with different colors. Rhodamine B (Rho), a matrix metalloproteinase−2 (MMP−2)-responsive green fluorescence probe, and a tumor-homing peptide were conjugated to a carboxy-terminal dendrimer that readily accumulates in lymph nodes. The activatable green fluorescence signal increased in the presence of MMP−2, which is secreted by tumor cells. Both the always-ON Rho signal and the activatable green fluorescence signal were observed from tumor cells, but only the weak always-ON Rho signal was from immune cells. Thus, this type of dendrimer may be useful for non-invasive imaging to diagnose cancer metastasis in lymph nodes

Control of Stimuli Sensitivity in pH-Switchable LCST/UCST-Type Thermosensitive Dendrimers by Changing the Dendrimer Structure

Stimuli-sensitive materials, such as pH- and temperature-responsive polymers, are useful as smart materials. Phenylalanine (Phe)-modified polyamidoamine (PAMAM) dendrimers with succinic acid termini, PAMAM-Phe-Suc, have been reported as unique pH-switchable lower critical solution temperature (LCST)-/upper critical solution temperature (UCST)-type thermosensitive polymers. Regulating the phase transition behavior of dendrimers is important for their applications. This study investigated the relationship between the dendrimer structure and stimuli sensitivity. Phe-modified PAMAM dendrimers with cyclohexanedicarboxylate termini (PAMAM-Phe-CHex) and sulfonate termini (PAMAM-Phe-SO3Na) were synthesized. The temperature-dependent transmittance of these aqueous dendrimer solutions was examined at various pH values. PAMAM-Phe-CHex with Phe at all termini (PAMAM-Phe64-CHex) demonstrated a broad UCST-like phase transition at pH 7.0 but lacked an LCST-type phase transition. PAMAM-Phe-CHex with ≤ 27 Phe residues showed both LCST- and UCST-like phase transitions at different pH values, but the phase transition was broad. PAMAM-Phe-SO3Na showed both LCST- and UCST-type phase transitions at different pH values, and the transition temperature increased as the bound Phe number decreased. Thus, the phase transition behavior of PAMAM-Phe-SO3Na dendrimers can be regulated by varying the Phe/PAMAM ratios

Piracy at Sea

X, 310 p. 32 illus., 30 illus. in color.online re

Comparing Niko Niko Room's educational support effects of university students, elementary students, and guardians (5) : Questionnaires from 2011

In this study, the effects of Niko Niko Room's educational support program perceived by university students, elementary students, and guardians were compared. 21 university students, 21 elementary students, and 21 guardians who took part in the educational support program held in 2011 answered questionnaires measuring ability of university students, degrees of satisfactions, and degrees of interests. Comparisons between university students and elementary students, between university students and guardians, between elementary students and guardians, and among university students, elementary students, and guardians were made. University students tended to underestimate their educational ability, compared to elementary students. Overall, university students, elementary students, and guardians positively evaluated the effects of the educational support program