The NEDD8 system is essential for cell cycle progression and morphogenetic pathway in mice

NEDD8/Rub1 is a ubiquitin (Ub)-like molecule that covalently ligates to target proteins through an enzymatic cascade analogous to ubiquitylation. This modifier is known to target all cullin (Cul) family proteins. The latter are essential components of Skp1/Cul-1/F-box protein (SCF)–like Ub ligase complexes, which play critical roles in Ub-mediated proteolysis. To determine the role of the NEDD8 system in mammals, we generated mice deficient in Uba3 gene that encodes a catalytic subunit of NEDD8-activating enzyme. Uba3−/− mice died in utero at the periimplantation stage. Mutant embryos showed selective apoptosis of the inner cell mass but not of trophoblastic cells. However, the mutant trophoblastic cells could not enter the S phase of the endoreduplication cycle. This cell cycle arrest was accompanied with aberrant expression of cyclin E and p57Kip2. These results suggested that the NEDD8 system is essential for both mitotic and the endoreduplicative cell cycle progression. β-Catenin, a mediator of the Wnt/wingless signaling pathway, which degrades continuously in the cytoplasm through SCF Ub ligase, was also accumulated in the Uba3−/− cytoplasm and nucleus. Thus, the NEDD8 system is essential for the regulation of protein degradation pathways involved in cell cycle progression and morphogenesis, possibly through the function of the Cul family proteins

Statistical distribution of binary ligands within rhodium-organic octahedra tunes microporosity in their assemblies

Structure-porosity relationships for metal-organic polyhedra (MOPs) are hardly investigated because they tend to be amorphized after activation, which inhibits crystallographic characterization. Here, we show a mixed-ligand strategy to statistically distribute two distinct carbazole-type ligands within rhodium-based octahedral MOPs, leading to systematic tuning of the microporosity in the resulting amorphous solids

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

Multiple Pathways in the Self-Assembly Process of a Pd₄L₈ Coordination Tetrahedron

The self-assembly of a Pd₄<b>1</b>₈ coordination tetrahedron (<b>Tet</b>) from a ditopic ligand, <b>1</b>, and palladium­(II) ions, [PdPy*₄]²⁺ (Py* = 3-chloropyridine), was investigated by a ¹H NMR-based quantitative approach (quantitative analysis of self-assembly process, QASAP), which allows one to monitor the average composition of the intermediates not observed by NMR spectroscopy. The self-assembly of <b>Tet</b> takes place mainly through three pathways and about half of the <b>Tet</b> structures were produced through the reaction of a kinetically produced Pd₃L₆ double-walled triangle (<b>DWT</b>) and 200-nm-sized large intermediates (<b>Int</b>^<b>L</b>). In two of the three pathways, the leaving ligand (Py*), which is not a component of <b>Tet</b>, catalytically assisted the self-assembly. Such a multiplicity of the self-assembly process of <b>Tet</b> suggests that molecular self-assembly takes place on an energy landscape like a protein-folding funnel

Coordination/Metal–Organic Cages Inside Out

Cage-like molecules, assembled by the coordination of multiple metal ions and organic links, are pushing new frontiers in science due to their design flexibility and the resulting diverse and unique chemical properties. This field has been advanced by two close but distinct chemistry communities. Consequently, the family of molecules referred to as coordination cages (CCs) constituted of metal-pyridine coordination bonds or metal–organic cages (MOCs) based on dinuclear tetracarboxylates paddlewheel complexes in each community had not been reviewed cross-sectionally, even though they are conceptually similar. This review article extracted and compared experimental information on a total of 197 CCs and 78 MOCs from 182 reports to identify their synthetic and structural signatures. We did not merely enumerate the reports we collected; we meta-analyzed the data extracted from the reports and highlighted both the similarities and dissimilarities between CCs and MOCs. As a result, we clarified the key parameters governing the synthetic conditions. Furthermore, we identified a new research direction by visualizing unexplored features and properties of CCs and MOCs. This review article provides a good tutorial both for researchers attempting to cross the boundary between CCs and MOCs and those who are new to the field