Conical Singular Solutions in (2+1)-Dimensional Gravity Employing the ADM Canonical Formalism

Topological solutions in the (2+1)-dimensional Einstein theory of gravity are studied within the ADM canonical formalism. It is found that a conical singularity appears in the closed de Sitter universe solution as a topological defect in the case of the Einstein theory with a cosmological constant. Quantum effects on the conical singularity are studied using the de Broglie-Bohm interpretation. Finite quantum tunneling effects are obtained for the closed de Sitter universe, while no quantum effects are obtained for an open universe.Comment: 15 pages, 3 figure

Comparative Efficacy and Safety of Linezolid and Quinupristin-Dalfopristin in the Treatment of Vancomycin-Resistant Enterococcus Infections: A Meta-Analysis

Introduction: Vancomycin-resistant Enterococcus (VRE) is one of the most important causative organisms of nosocomial infections. Once VRE outbreaks occur in hospitals, enormous efforts must be made to control them, especially in wards housing neutropenic or transplant patients. The purpose of this meta-analysis was to investigate the efficacy and adverse event profile of linezolid versus that of Quinupristin-Dalfopristin for the treatment of VRE infections.Methodology: Literature searches of PubMed, MEDLINE, and EMBASE databases were performed on April 5, 2017 using combined text words with the following MeSH/EMTREE terms: “linezolid” and “Quinupristin-Dalfopristin” and “Enterococcus” and “human.” The odds ratios (ORs) with 95% confidence intervals (CIs) for individual studies were calculated and pooled separately. The pooled estimates were combined using the inverse variance weighting scheme and random effect method.Results: A systematic search identified 674 articles, and five involving 333 patients were included in the final analysis. One study was a prospective randomized controlled trial, and four were retrospective studies. The mortality rate in the groups of patients treated with linezolid was significantly lower than that in patients treated with Quinupristin-Dalfopristin (OR: 0.47; 95% CI: 0.23 to 0.97; heterogeneity P=0.13, Z=2.05, P=0.04; I2=44%; Begg’s test: P=0.33; Egger’s test: P=0.78). The clinical and microbiological responses indicated no significant differences between the linezolid and Quinupristin-Dalfopristin groups (58% and 43%, respectively, P=0.6; OR: 1.51; 95% CI: 0.75 to 3.04; heterogeneity P=0.32; Z=1.15, P=0.25; I2=0%). The adverse event proiles differed between the Linezolid and quinupristin-dalfopristin groups.Conclusion: Our results suggest a significantly lower mortality rate in patients treated with linezolid than in those treated with Quinupristin-Dalfopristin for VRE infections; however, this was limited by a variety of factors (mostly retrospective)

Dynamical mass generation of a two-component fermion in Maxwell-Chern-Simons QED_3: The lowest ladder approximation

Dynamical mass generation of a two-component fermion in $QED_3$ with a Chern-Simons term is investigated by solving the Schwinger-Dyson equation formulated in the lowest ladder approximation. Dependence of the dynamical fermion mass on a gauge-fixing parameter, a gauge coupling constant, and a topological mass is examined by approximated analytical and also numerical methods. The inclusion of the Chern-Simons term makes impossible to choose a peculiar gauge in which a wave function renormalization is absent. The numerical evaluation shows that the wave function renormalization is fairly close to 1 in the Landau gauge. It means that this gauge is still a specific gauge where the Ward-Takahashi identity is satisfied approximately. We also find that the dynamical mass is almost constant if the topological mass is larger than the coupling constant, while it decreases when the topological mass is comparable to or smaller than the coupling constant and tends to the value in $QED_3$ without the Chern-Simons term.Comment: 22 pages, 9 figures, Version to appear in Phys. Rev.

BRCA1/2 Mutation Frequency is HIGH in Japanese Triple-Negative Breast Cancer Patients

Germline mutations of BRCA1/2 genes cause hereditary breast and/or ovarian cancer. However, whether guidelines like those of the National Comprehensive Cancer Network (NCCN) can suitably predict the likelihood of BRCA1/2 mutations in the Japanese population is unclear. Methods BRCA1/2 gene mutation frequencies were investigated in relation to parameters such as age, family history (FH), and breast cancer subtype using data collected from 922 Japanese breast cancer patients who underwent surgery between September 2010 and June 2013. BRCA1/2 mutations were present in 15 of 57 (26.3%) tested patients. The frequency of the mutations was not significantly related to age. Among the 180 patients who reported an FH of breast cancer, 11 of the 37 who were tested (29.7%) were positive for BRCA1/2 mutations. Of those with an FH of ovarian cancer (n = 34), seven of 12 patients tested (58.3%) were carriers of BRCA1/2 (P = 0.013). Six of these seven carriers were triple-negative breast cancer (TNBC) patients. In all, there were 97 TNBC patients, and the presence of the BRCA1/2 mutation in this subgroup was significantly greater than in non-TNBC patients, with 12 of 17 TNBC patients (70.5%) testing positive (P = 0.03). There were 59 TNBC patients < 60 years of age, and of the 16 (27.1%) who underwent BRCA1/2 genetic testing, 11 (68.8%) were found to have mutations in BRCA1/2. Among the TNBC patients, 29 also reported an FH of breast or ovarian cancer; of these, nine of the 13 tested (69.2%) were positive for a BRCA1/2 mutation. The data demonstrate that BRCA1/2 mutations are observed more frequently in TNBC patients, especially those < 60 years of age or in combination with an FH of breast and/or ovarian cancer, suggesting that some of the NCCN guidelines can adequately predict BRCA1/2 carriers in the Japanese population

FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters

乳がんの再発を起こす原因細胞を解明. 京都大学プレスリリース. 2023-11-16.The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na⁺/K⁺ pump. Accordingly, FXYD3⁺ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3⁺ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3⁺ CSCs were sensitive to senolytic Na⁺/K⁺ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3⁺ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na⁺/K⁺ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis

Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

<p>Abstract</p> <p>Background</p> <p>Human hemangiosarcoma (HSA) tends to have a poor prognosis; its tumorigenesis has not been elucidated, as there is a dearth of HSA clinical specimens and no experimental model for HSA. However, the incidence of spontaneous HSA is relatively high in canines; therefore, canine HSA has been useful in the study of human HSA. Recently, the production of angiogenic growth factors and their receptors in human and canine HSA has been reported. Moreover, the growth-factor environment of HSA is very similar to that of pathophysiological angiogenesis, which some homeobox genes regulate in the transcription of angiogenic molecules. In the present study, we established 6 xenograft canine HSA tumors and detected the expression of growth factors, their receptors, and angiogenic homeobox genes.</p> <p>Methods</p> <p>Six primary canine HSAs were xenografted to nude mice subcutaneously and serially transplanted. Subsequently, the expressions of vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factors (bFGF), flt-1 and flk-1 (receptors of VEGF-A), FGFR-1, and angiogenic homeobox genes HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 were investigated in original and xenograft tumors by histopathology, immunostaining, and reverse transcription polymerase chain reaction (RT-PCR), using canine-specific primer sets.</p> <p>Results</p> <p>Histopathologically, xenograft tumors comprised a proliferation of neoplastic cells that were varied in shape, from spindle-shaped and polygonal to ovoid; some vascular-like structures and vascular clefts of channels were observed, similar to those in the original tumors. The expression of endothelial markers (CD31 and vWF) was detected in xenograft tumors by immunohistochemistry and RT-PCR. Moreover, the expression of VEGF-A, bFGF, flt-1, flk-1, FGFR-1, HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 was detected in xenograft tumors. Interestingly, expressions of bFGF tended to be higher in 3 of the xenograft HSA tumors than in the other tumors.</p> <p>Conclusion</p> <p>We established 6 xenograft canine HSA tumors in nude mice and found that the expressions of angiogenic growth factors and their receptors in xenograft HSAs were similar to those in spontaneous HSA. Furthermore, we detected the expression of angiogenic homeobox genes; therefore, xenograft models may be useful in analyzing malignant growth in HSA.</p

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