| 1. |
|
|
| 2. |
- Namkoong, H, et al.
(författare)
-
DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
-
Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. 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.
|
|
| 3. |
- Wang, QBS, et al.
(författare)
-
The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 4. |
|
|
| 5. |
- Sakatani, N., et al.
(författare)
-
Anomalously porous boulders on (162173) Ryugu as primordial materials from its parent body
- 2021
-
Ingår i: Nature Astronomy. - : Springer Nature. - 2397-3366. ; 5:8, s. 766-774
-
Tidskriftsartikel (refereegranskat)abstract
- Planetesimals—the initial stage of the planetary formation process—are considered to be initially very porous aggregates of dusts1,2, and subsequent thermal and compaction processes reduce their porosity3. The Hayabusa2 spacecraft found that boulders on the surface of asteroid (162173) Ryugu have an average porosity of 30–50% (refs. 4,5,6), higher than meteorites but lower than cometary nuclei7, which are considered to be remnants of the original planetesimals8. Here, using high-resolution thermal and optical imaging of Ryugu’s surface, we discovered, on the floor of fresh small craters (<20 m in diameter), boulders with reflectance (~0.015) lower than the Ryugu average6 and porosity >70%, which is as high as in cometary bodies. The artificial crater formed by Hayabusa2’s impact experiment9 is similar to these craters in size but does not have such high-porosity boulders. Thus, we argue that the observed high porosity is intrinsic and not created by subsequent impact comminution and/or cracking. We propose that these boulders are the least processed material on Ryugu and represent remnants of porous planetesimals that did not undergo a high degree of heating and compaction3. Our multi-instrumental analysis suggests that fragments of the highly porous boulders are mixed within the surface regolith globally, implying that they might be captured within collected samples by touch-down operations10,11.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Sekiguchi, M, et al.
(författare)
-
Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
- 2020
-
Ingår i: NPJ precision oncology. - : Springer Science and Business Media LLC. - 2397-768X. ; 4:1, s. 20-
-
Tidskriftsartikel (refereegranskat)abstract
- Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of NQO1 and ODC1. Inhibition of NQO1 and ODC1 in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.
|
|
| 9. |
- Isobe, T, et al.
(författare)
-
Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
- 2022
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4501-
-
Tidskriftsartikel (refereegranskat)abstract
- KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
- Kubota, Y, et al.
(författare)
-
Comprehensive genetic analysis of pediatric germ cell tumors identifies potential drug targets
- 2020
-
Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1, s. 544-
-
Tidskriftsartikel (refereegranskat)abstract
- To elucidate the molecular pathogenesis of pediatric germ cell tumors (GCTs), we performed DNA methylation array analysis, whole transcriptome sequencing, targeted capture sequencing, and single-nucleotide polymorphism array analysis using 51 GCT samples (25 female, 26 male), including 6 germinomas, 2 embryonal carcinomas, 4 immature teratomas, 3 mature teratomas, 30 yolk sac tumors, and 6 mixed germ cell tumors. Among the 51 samples, 11 were from infants, 23 were from young children, and 17 were from those aged ≥10 years. Sixteen of the 51 samples developed in the extragonadal regions. Germinomas showed upregulation of pluripotent genes and global hypomethylation. Pluripotent genes were also highly expressed in embryonal carcinomas. These genes may play essential roles in embryonal carcinomas given that their binding sites are hypomethylated. Yolk sac tumors exhibited overexpression of endodermal genes, such as GATA6 and FOXA2, the binding sites of which were hypomethylated. Interestingly, infant yolk sac tumors had different DNA methylation patterns from those observed in older children. Teratomas had higher expression of ectodermal genes, suggesting a tridermal nature. Based on our results, we suggest that KIT, TNFRSF8, and ERBB4 may be suitable targets for the treatment of germinoma, embryonal carcinomas, and yolk sac tumors, respectively.
|
|
| 14. |
- Kimura, S, et al.
(författare)
-
Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism
- 2021
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 16:1, s. e0245526-
-
Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma, the most common extracranial solid malignancy among children, originates from undifferentiated neural crest cells (NCC). Despite recent intensified treatment, high-risk patients still have a high mortality rate. To explore a new therapeutic strategy, we performed an integrated genomic and transcriptomic analysis of 30 high-risk neuroblastoma cases. Based on the expression profiling of RNA sequencing, neuroblastoma was classified into Mesenchymal (MES; n = 5) and Noradrenergic (ADRN; n = 25) clusters, as previously reported in the super-enhancer landscape. The expression patterns in MES-cluster cases were similar to normal adrenal glands, with enrichment in secretion-related pathways, suggesting chromaffin cell-like features built from NCC-derived Schwann cell precursors (SCPs). In contrast, neuron-related pathways were enriched in the ADRN-cluster, indicating sympathoblast features reported to originate from NCC but not via SCPs. Thus, MES- and ADRN-clusters were assumed to be corresponding to differentiation pathways through SCP and sympathoblast, respectively. ADRN-cluster cases were further classified into MYCN- and ATRX-clusters, characterized by genetic alterations, MYCN amplifications and ATRX alterations, respectively. MYCN-cluster cases showed high expression of ALDH18A1, encoding P5CS related to proline production. As reported in other cancers, this might cause reprogramming of proline metabolism leading to tumor specific proline vulnerability candidate for a target therapy of metabolic pathway. In ATRX-cluster, SLC18A2 (VMAT2), an enzyme known to prevent cell toxicity due to the oxidation of dopamine, was highly expressed and VMAT2 inhibitor (GZ-793A) represented significant attenuation of cell growth in NB-69 cell line (high SLC18A2 expression, no MYCN amplification) but not in IMR-32 cell line (MYCN amplification). In addition, the correlation of VMAT2 expression with metaiodobenzylguanidine (MIBG) avidity suggested a combination of VMAT2 inhibitor and MIBG radiation for a novel potential therapeutic strategy in ATRX-cluster cases. Thus, targeting the characteristics of unique neuroblastomas may prospectively improve prognosis.
|
|
| 15. |
|
|
| 16. |
- De La Fuente, Eduardo, et al.
(författare)
-
Detection of a new molecular cloud in the LHAASO J2108+5157 region supporting a hadronic PeVatron scenario
- 2023
-
Ingår i: Publication of the Astronomical Society of Japan. - 2053-051X .- 0004-6264. ; 75:3, s. 546-566
-
Tidskriftsartikel (refereegranskat)abstract
- PeVatrons are the most powerful naturally occurring particle accelerators in the Universe. The identification of counterparts associated to astrophysical objects such as dying massive stars, molecular gas, star-forming regions, and star clusters is essential to clarify the underlying nature of the PeV emission, i.e., hadronic or leptonic. We present 12,13CO (J = 2→1) observations made with the 1.85 m radio-Telescope of the Osaka Prefecture University toward the Cygnus OB7 molecular cloud, which contains the PeVatron candidate LHAASO J2108+5157. We investigate the nature of the sub-PeV (gamma-ray) emission by studying the nucleon density determined from the content of H i and H2, derived from the CO observations. In addition to MML[2017]4607, detected via the observations of the optically thick 12CO (J = 1→0) emission, we infer the presence of an optically thin molecular cloud, named [FKT-MC]2022, whose angular size is 1-1 ± 0.}^\circ}}2. We propose this cloud as a new candidate to produce the sub-PeV emission observed in LHAASO J2108+5157. Considering a distance of 1.7 kpc, we estimate a nucleon (H i + H2) density of 37 ± 14 cm-3, and a total nucleon mass(H i + H2) of 1.5 ± 0.6 × 104 M·. On the other hand, we confirm that Kronberger 82 is a molecular clump with an angular size of 0°1, a nucleon density ∼103 cm-3, and a mass ∼103 M·. Although Kronberger 82 hosts the physical conditions to produce the observed emission of LHAASO J2108+5157, [FKT-MC]2022 is located closer to it, suggesting that the latter could be the one associated to the sub-PeV emission. Under this scenario, our results favour a hadronic origin for the emission.
|
|
| 17. |
- De La Fuente, Eduardo, et al.
(författare)
-
Evidence for a gamma-ray molecular target in the enigmatic PeVatron candidate LHAASO J2108+5157
- 2023
-
Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 675
-
Tidskriftsartikel (refereegranskat)abstract
- Context . Peta-eV (PeV) astronomy emerged in 2021 with the discovery of ultra-high-energy gamma-ray sources associated with powerful natural particle accelerators known as PeVatrons. In order to determine the nature of their emission, namely whether it has a hadronic or leptonic origin, it is essential to characterise the physical parameters of the environment where it originates. Aims . We unambiguously confirm the association of molecular gas with the PeVatron candidate LHAASO J2108+5157 using unprecedented high angular-resolution (17′) 12,13CO(J = 1 → 0) observations carried out with the Nobeyama 45m radio telescope. Methods . We characterised a molecular cloud in the vicinity of the PeVatron candidate LHAASO J2108+5157 by determining its physical parameters from our 12,13CO(J = 1 → 0) line observations. We used an updated estimation of the distance to the cloud, which provided a more reliable result. The molecular emission was compared with excess gamma-ray images obtained with Fermi-LAT at energies above 2 GeV to search for spatial correlations and test a possible hadronic (π0 decay) origin for the gamma-ray emission. Results . We find that the morphology of the spatial distribution of the CO emission is strikingly similar to that of the Fermi-LAT excess gamma ray. By combining our observations with archival 21 cm HI line data, the nucleons (HI + H2) number density of the target molecular cloud is found to be 133.0 ± 45.0 cm-3, for the measured angular size of 0.55 ± 0.02 at a distance of 1.6 ± 0.1 kpc. The resulting total mass of the cloud is M(HI + H2) = 7.5±2.9×103M⊙. Under a hadronic scenario, we obtain a total energy of protons of Wp = 4.3 ± 1.5 × 1046 erg with a cutoff of 700±300 TeV, which reproduces the sub-PeV gamma-ray emission. Conclusions . We identified a molecular cloud in the vicinity of LHAASO J2107+5157 as the main target where cosmic rays from an unknown PeVatron produce the observed gamma-ray emission via π0 decay.
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
- Oksa, L, et al.
(författare)
-
Arginine Methyltransferase PRMT7 Deregulates Expression of RUNX1 Target Genes in T-Cell Acute Lymphoblastic Leukemia
- 2022
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:9
-
Tidskriftsartikel (refereegranskat)abstract
- T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with no well-established prognostic biomarkers. We examined the expression of protein arginine methyltransferases across hematological malignancies and discovered high levels of PRMT7 mRNA in T-ALL, particularly in the mature subtypes of T-ALL. The genetic deletion of PRMT7 by CRISPR-Cas9 reduced the colony formation of T-ALL cells and changed arginine monomethylation patterns in protein complexes associated with the RNA and DNA processing and the T-ALL pathogenesis. Among them was RUNX1, whose target gene expression was consequently deregulated. These results suggest that PRMT7 plays an active role in the pathogenesis of T-ALL.
|
|
| 21. |
- Watanabe, A., et al.
(författare)
-
Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL
- 2020
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 136:20, s. 2319-2333
-
Tidskriftsartikel (refereegranskat)abstract
- Karyotype is an important prognostic factor in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but the underlying pharmacogenomics remain unknown. Asparaginase is an integral component in current chemotherapy for childhood BCP-ALL. Asparaginase therapy depletes serum asparagine. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, but ALL cells are unable to synthesize adequate amounts of asparagine. The ASNS gene has a typical CpG island in its promoter. Thus, methylation of the ASNS CpG island could be one of the epigenetic mechanisms for ASNS gene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNS methylation status with asparaginase sensitivity. The ASNS CpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNS methylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asns and a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1 knockin mice. In 3 childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNS methylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNS gene and protein expression levels. These observations demonstrate that silencing of the ASNS gene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
