Mitochondria of Malaria Parasites as a Drug Target

Mitochondria are organelle, which is found in most eukaryotic cells, and play an important roll in production of many biosynthetic intermediates as well as energy transduction. Recently, it has been reported that mitochondria contribute to cellular stress responses such as apoptosis and autophagy. These functions of mitochondria are known to be essential for survival and maintenance of homeostasis. The mitochondria of malaria parasites are quite different from those of their vertebrate hosts. Because these differences markedly contribute to drug selectivity, we have focused on the Plasmodium mitochondrion to develop antimalarial drugs. Here we summarize recent advances in our knowledge of the mitochondria of malaria parasites and discuss future prospective antimalarial drugs targeting the parasite mitochondrion

Chiral Soliton Lattice Formation in Monoaxial Helimagnet Yb(Ni1−x_{1-x}Cux_x)3_3Al9_9

Helical magnetic structures and its responses to external magnetic fields in Yb(Ni$_x$Cu$_{1-x}$)$_3$Al$_9$, with a chiral crystal structure of the space group $R32$, have been investigated by resonant X-ray diffraction. It is shown that the crystal chirality is reflected to the helicity of the magnetic structure by a one to one relationship, indicating that there exists an antisymmetric exchange interaction mediated via the conduction electrons. When a magnetic field is applied perpendicular to the helical axis ($c$ axis), the second harmonic peak of $(0, 0, 2q)$ develops with increasing the field. The third harmonic peak of $(0, 0, 3q)$ has also been observed for the $x$=0.06 sample. This result provides a strong evidence for the formation of a chiral magnetic soliton lattice state, a periodic array of the chiral twist of spins, which has been suggested by the characteristic magnetization curve. The helical ordering of magnetic octupole moments, accompanying with the magnetic dipole order, has also been detected.Comment: 13 pages, 18 figures, accepted for publication in J. Phys. Soc. Jp

Augmin-dependent microtubule nucleation at microtubule walls in the spindle

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Cell Biology 202 (2013): 25-33, doi:10.1083/jcb.201304031.The formation of a functional spindle requires microtubule (MT) nucleation from within the spindle, which depends on augmin. How augmin contributes to MT formation and organization is not known because augmin-dependent MTs have never been specifically visualized. In this paper, we identify augmin-dependent MTs and their connections to other MTs by electron tomography and 3D modeling. In metaphase spindles of human cells, the minus ends of MTs were located both around the centriole and in the body of the spindle. When augmin was knocked down, the latter population of MTs was significantly reduced. In control cells, we identified connections between the wall of one MT and the minus end of a neighboring MT. Interestingly, the connected MTs were nearly parallel, unlike other examples of end–wall connections between cytoskeletal polymers. Our observations support the concept of augmin-dependent MT nucleation at the walls of existing spindle MTs. Furthermore, they suggest a mechanism for maintaining polarized MT organization, even when noncentrosomal MT initiation is widespread.This work was supported by the Next Generation grant (Japan Society for the Promotion of Science), Human Frontier Science Program, James A. and Faith Miller Memorial Fund (to G. Goshima), the Hori Sciences and Arts Foundation, the Sasakawa Scientific Research Grant, the Kazato Research foundation (to T. Kamasaki), and the National Institutes of Health (8P41GM103431-42 to A. Hoenger). T. Kamasaki was a recipient of the Japan Society for the Promotion of Science postdoctoral fellowship.2014-01-0

Functional importance of Crenarchaea-specific extra-loop revealed by an X-ray structure of a heterotetrameric crenarchaeal splicing endonuclease

Archaeal splicing endonucleases (EndAs) are currently classified into three groups. Two groups require a single subunit protein to form a homodimer or homotetramer. The third group requires two nonidentical protein components for the activity. To elucidate the molecular architecture of the two-subunit EndA system, we studied a crenarchaeal splicing endonuclease from Pyrobaculum aerophilum. In the present study, we solved a crystal structure of the enzyme at 1.7-Å resolution. The enzyme adopts a heterotetrameric form composed of two catalytic and two structural subunits. By connecting the structural and the catalytic subunits of the heterotetrameric EndA, we could convert the enzyme to a homodimer that maintains the broad substrate specificity that is one of the characteristics of heterotetrameric EndA. Meanwhile, a deletion of six amino acids in a Crenarchaea-specific loop abolished the endonuclease activity even on a substrate with canonical BHB motif. These results indicate that the subunit architecture is not a major factor responsible for the difference of substrate specificity between single- and two-subunit EndA systems. Rather, the structural basis for the broad substrate specificity is built into the crenarchaeal splicing endonuclease itself

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