Lethal impacts of cigarette smoke in cultured tobacco cells

<p>Abstract</p> <p>Background</p> <p>In order to understand and generalize the toxic mechanism of cigarette smoke in living cells, comparison of the data between animal systems and other biological system such as microbial and plant systems is highly beneficial.</p> <p>Objective</p> <p>By employing the tobacco cells as model materials for cigarette smoke toxicity assay, the impacts of the combustion by-products such as nitrogen oxides could be highlighted as the toxic impacts of the plant-derived endogenous chemicals could be excluded in the plant cells.</p> <p>Methods</p> <p>Cigarette smoke-induced cell death was assessed in tobacco cell suspension cultures in the presence and absence of pharmacological inhibitors.</p> <p>Results</p> <p>Cigarette smoke was effective in induction of cell death. The smoke-induced cell death could be partially prevented by addition of nitric oxide (NO) scavenger, suggesting the role for NO as the cell death mediator. Addition of NO donor to tobacco cells also resulted in development of partial cell death further confirming the role of NO as cell death mediator. Members of reactive oxygen species and calcium ion were shown to be protecting the cells from the toxic action of smoke-derived NO.</p

DAT (deacylating autotransporter toxin) from Bordetella parapertussis demyristoylates Gαi GTPases and contributes to cough

The pathogenic bacteria Bordetella pertussis and Bordetella parapertussis cause pertussis (whooping cough) and pertussis-like disease, respectively, both of which are characterized by paroxysmal coughing. We previously reported that pertussis toxin (PTx), which inactivates heterotrimeric GTPases of the Gi family through ADP-ribosylation of their α subunits, causes coughing in combination with Vag8 and lipid A in B. pertussis infection. In contrast, the mechanism of cough induced by B. parapertussis, which produces Vag8 and lipopolysaccharide (LPS) containing lipid A, but not PTx, remained to be elucidated. Here, we show that a toxin we named deacylating autotransporter toxin (DAT) of B. parapertussis inactivates heterotrimeric Gi GTPases through demyristoylation of their α subunits and contributes to cough production along with Vag8 and LPS. These results indicate that DAT plays a role in B. parapertussis infection in place of PTx.Hiramatsu Y., Nishida T., Ota N., et al. DAT (deacylating autotransporter toxin) from Bordetella parapertussis demyristoylates Gαi GTPases and contributes to cough. Proceedings of the National Academy of Sciences of the United States of America 120, e2308260120 (2023); https://doi.org/10.1073/pnas.2308260120

Bordetella pertussis population dynamics and phylogeny in Japan after adoption of acellular pertussis vaccines

Bordetella pertussis, the causative agent of whooping cough, has experienced a resurgence in the past 15 years, despite the existence of both whole-cell and acellular vaccines. Here, we performed whole genome sequencing analysis of 149 clinical strains, provided by the National Institute of Infectious Diseases (NIID), Japan, isolated in 1982-2014, after Japan became the first country to adopt acellular vaccines against B. pertussis. Additionally, we sequenced 39 strains provided by the Konan Kosei Hospital in Aichi prefecture, Japan, isolated in 2008-2013. The genome sequences afforded insight into B. pertussis genome variability and population dynamics in Japan, and revealed that the B. pertussis population in Japan was characterized by two major clades that divided more than 40 years ago. The pertactin gene was disrupted in about 20 % of the 149 NIID isolates, by either a deletion within the signal sequence (ΔSS) or the insertion of IS element IS481 (prn :: IS481). Phylogeny suggests that the parent clones for these isolates originated in Japan. Divergence dating traced the first generation of the pertactin-deficient mutants in Japan to around 1990, and indicated that strains containing the alternative pertactin allele prn2 may have appeared in Japan around 1974. Molecular clock data suggested that observed fluctuations in B. pertussis population size may have coincided with changes in vaccine usage in the country. The continuing failure to eradicate the disease warrants an exploration of novel vaccine compositions

Spin frustration in antiperovskite systems: (TTF˙+or TSF˙+)3[(Mo6X14)2−Y−]

Two novel antiperovskite charge-transfer (CT) solids composed of a tetraselenafulvalene radical cation (TSF˙+), a dianionic molybdenum cluster unit [Mo6X14]2−, and a halogen anion (Y−) (X, Y = Cl, Br) were prepared by electrocrystallization. Their crystal structures and magnetic properties with regard to spin frustration are discussed together with those of isostructural tetrathiafulvalene (TTF) CT solids previously reported. Both TSF and TTF salts have an apex sharing distorted octahedral spin lattice with a rhombohedral R[3 with combining macron] space group. The calculated overlap integrals based on the crystal structures and insulating nature of the TSF salts indicate that they are Mott insulators. Their spin susceptibilities obeyed the Curie–Weiss law and exhibited an antiferromagnetic ordering at lower temperatures for the TSF salts (Néel temperature, TN = 3.0 K for X = Y = Cl and 5.5 K for X = Y = Br) than the TTF salts. The Curie–Weiss temperatures (|ΘCW| ∼ 1.6–6.3 K) for the TSF salts are lower than those of the TTF salts. For the TSF salts, spin-flop behavior was detected at 3.2 T for X = Y = Cl and 1.5 T for X = Y = Br at 1.9 K. Due to both the distortion of the octahedral geometry of the spin lattice and the anisotropic molecular orientation, the geometrical spin frustrations in TSF and TTF systems are weakened

Molecular epidemiology of Bordetella pertussis in the Philippines in 2012–2014

SummaryObjectivesThe present study was designed to determine the genotypes of circulating Bordetella pertussis in the Philippines by direct molecular typing of clinical specimens.MethodsNasopharyngeal swabs (NPSs) were collected from 50 children hospitalized with pertussis in three hospitals during 2012–2014. Multilocus variable-number tandem repeat analysis (MLVA) was performed on the DNA extracts from NPSs. B. pertussis virulence-associated allelic genes (ptxA, prn, and fim3) and the pertussis toxin promoter, ptxP, were also investigated by DNA sequence-based typing.ResultsTwenty-six DNA extracts yielded a complete MLVA profile, which were sorted into 10 MLVA types. MLVA type 34 (MT34), which is rare in Australia, Europe, Japan, and the USA, was the predominant strain (50%). Seven MTs (MT29, MT32, MT33, and MT283–286, total 42%) were single-locus variants of MT34, while two (MT141 and MT287, total 8%) were double-locus variants of MT34. All MTs had the combination of virulence-associated allelic genes, ptxP1–ptxA1–prn1–fim3A.ConclusionsThe B. pertussis population in the Philippines comprises genetically related strains. These strains are markedly different from those found in patients from other countries where acellular pertussis vaccines are used. The differences in vaccine types between these other countries and the Philippines, where the whole-cell vaccine is still used, may select for distinct populations of B. pertussis

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