CCAAT/Enhancer Binding Protein β Is Dispensable for Development of Lung Adenocarcinoma

Lung cancer is the leading cause of cancer death worldwide. Although disruption of normal proliferation and differentiation is a vital component of tumorigenesis, the mechanisms of this process in lung cancer are still unclear. A transcription factor, C/EBPβ is a critical regulator of proliferation and/or differentiation in multiple tissues. In lung, C/EBPβ is expressed in alveolar pneumocytes and bronchial epithelial cells; however, its roles on normal lung homeostasis and lung cancer development have not been well described. Here we investigated whether C/EBPβ is required for normal lung development and whether its aberrant expression and/or activity contribute to lung tumorigenesis. We showed that C/EBPβ was expressed in both human normal pneumocytes and lung adenocarcinoma cell lines. We found that overall lung architecture was maintained in Cebpb knockout mice. Neither overexpression of nuclear C/EBPβ nor suppression of CEBPB expression had significant effects on cell proliferation. C/EBPβ expression and activity remained unchanged upon EGF stimulation. Furthermore, deletion of Cebpb had no impact on lung tumor burden in a lung specific, conditional mutant EGFR lung cancer mouse model. Analyses of data from The Cancer Genome Atlas (TCGA) revealed that expression, promoter methylation, or copy number of CEBPB was not significantly altered in human lung adenocarcinoma. Taken together, our data suggest that C/EBPβ is dispensable for development of lung adenocarcinoma

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

COVID-19 vaccine effectiveness against severe COVID-19 requiring oxygen therapy, invasive mechanical ventilation, and death in Japan: A multicenter case-control study (MOTIVATE study).

INTRODUCTION: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation. METHODS: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients. RESULTS: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes. CONCLUSION: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron

Metasurface absorber enhanced thermoelectric conversion

Metasurfaces are artificial thin materials that achieve optical thickness through thin geometrical structure. This feature of metasurfaces results in unprecedented benefits for enhancing the performance of optoelectronic devices. In this study, we report that this metasurface feature is also essential to drive photo-thermoelectric conversion, which requires the accumulation of thermal energy and effective heat conduction. For example, a metasurface-attached thermoelectric device placed in an environment with uniform thermal radiation generates an output voltage by gathering the thermal energies existing in the environment and creating an additional thermal gradient across the thermoelectric element. In contrast, when a 100-μm-thick-carbon-black-coated electrode was used instead of the metasurface, the device showed lower thermoelectric performance than that of the metasurface-attached device although carbon black exhibits higher infrared absorption than the metasurface. These results indicate that metasurface characteristics of optical thickness and thin geometrical structure for achieving the high thermal conductance are essential in enhancing the performance of photo-thermoelectric devices in terms of the effective collection of thermal energies and conduction of local heating

Self-organization of bacterial communities against environmental pH variation: Controlled chemotactic motility arranges cell population structures in biofilms

<div><p>As with many living organisms, bacteria often live on the surface of solids, such as foods, organisms, buildings and soil. Compared with dispersive behavior in liquid, bacteria on surface environment exhibit significantly restricted mobility. They have access to only limited resources and cannot be liberated from the changing environment. Accordingly, appropriate collective strategies are necessarily required for long-term growth and survival. However, in spite of our deepening knowledge of the structure and characteristics of individual cells, strategic self-organizing dynamics of their community is poorly understood and therefore not yet predictable. Here, we report a morphological change in <i>Bacillus subtilis</i> biofilms due to environmental pH variations, and present a mathematical model for the macroscopic spatio-temporal dynamics. We show that an environmental pH shift transforms colony morphology on hard agar media from notched ‘volcano-like’ to round and front-elevated ‘crater-like’. We discover that a pH-dependent dose-response relationship between nutritional resource level and quantitative bacterial motility at the population level plays a central role in the mechanism of the spatio-temporal cell population structure design in biofilms.</p></div

Colony growth simulation designed by resource-response diagram.

<p>(A, B) Bacterial motility is quantitatively assessed with a capillary assay. The vertical axis indicates the number of bacteria that move into ‘capillary’, and the horizontal axis the environmental nutrition level, namely the peptone concentration of the surrounding ‘pond’ solution. Random motility is estimated if the capillary is filled with the same solution as in the pond (A). In most cases, a larger number of bacteria are detected if the capillary solution is more nutritious. The increase represents the chemotactic motility coefficient for a fixed nutritional gradient (B). Solid and dotted lines, random and chemotactic motility response curves fitted by our model. Data represent mean ± s.e.m., <i>n</i> = 4 (A, B). (C) Schematic diagram of the correlation between nutritional resource level and bacterial response. The vertical axis indicates relative values in each component: random motility, chemotactic motility and proliferation rate. (D, F) Three-dimensional views of simulated colonies. (E, G) Simulated nutrition curves (bold black curves). Shown together are the bacterial concentration <i>B</i> and quantitative responses corresponding to the resource-response diagram (color curves) (C). (H, I) Experimental (upper) and simulated (lower) colony growth. Scale bars, 10 mm. (J-M) Vector fields of simulated moving velocity <b><i>u</i></b>, indicated by arrows with heat color scale. Moving velocity in the crater-like colony (K) can be decomposed into its random (L) and chemotactic (M) components. Initial nutrition level, 2.0 g l^-1 peptone (H, I upper); <i>P</i> = 2.0 (H, I lower; D-G, J, K). Chemotactic coefficients, Chem 0 for pH 7.4 (D, E, H, J), Chem + for pH 7.0 (F, G, I, K-M). Incubation time, 3, 5, 7, 9 days post-inoculation (H, I upper); <i>t</i> = T3, T5, T7, T9 (T<i>m</i> = 220*<i>m</i>) (H, I lower); <i>t</i> = T5 in D-G, J-M.</p

Colony growth simulation in different situations.

<p>Experimental (upper) and simulated (lower) patterns. (A, B) Colony growth on inhomogeneous media. Initial nutrition level, 0.5 g l^-1 peptone (upper), <i>P</i> = 0.5 (lower) in left half; 5.0 g l^-1 peptone (upper), <i>P</i> = 5.0 (lower) in right half. (C, D) Mutually interfering two adjacent colonies. Initial nutrition level, 2.0 g l^-1 peptone (upper); <i>P</i> = 2.0 (lower). (E) Another type of colony pattern, dense-branching morphology (DBM)-like, developing in high-moisture and low-nutrient environment (0.5% agar and 0.4 g l^-1 peptone). Chemotactic coefficients, Chem 0 for pH 7.4 (A, C, E), Chem + for pH 7.0 (B, D). Scale bars, 10 mm.</p