In vivo efficacy of KRP-109, a novel elastase inhibitor, in a murine model of severe pneumococcal pneumonia.

KRP-109 is a novel specific inhibitor of neutrophil elastase (NE). Various studies suggest that NE inhibitors reduce lung injury associated with systemic inflammatory response syndrome (SIRS). In this study, the efficacy of KRP-109 was examined using a murine model of severe pneumonia induced by Streptococcus pneumoniae (S. pneumoniae). Female mice (CBA/J, aged 5 weeks) were inoculated intranasally with penicillin-susceptible S. pneumoniae (ATCC49619 strain, 2.5 × 10(8) CFU/mouse). KRP-109 (30 or 50 mg/kg) or physiological saline as a control was administered intraperitoneally every 8 h beginning at 8 h after inoculation, and survival rate was evaluated over 7 days. Histopathological and bacteriological analyses of the lung, and bronchoalveolar lavage were performed at 48 h post-infection. The mice treated with KRP-109 (KRP-109 mice) tended to have higher survival rate than those given saline. The lung tissues of the KRP-109 mice had few neutrophils in the alveolar walls and less inflammation. Furthermore, KRP-109 decreased significantly total cell and neutrophil counts, and cytokine levels (interleukin 1β and macrophage inflammatory protein 2) in bronchoalveolar lavage fluid. Viable bacterial numbers in lung were not influenced by treatment of KRP-109. The present results indicate that KRP-109 reduces lung inflammation in a murine model, and that KRP-109 may be useful for the treatment of patients with severe pneumonia

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

ゲノム解析から急性赤白血病の変異プロファイルと治療標的を解明 --特定の遺伝子変異群の組み合わせと、特徴となる遺伝子の増幅が鍵--. 京都大学プレスリリース. 2022-08-05.Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL

High-resolution seismic reflection survey across the Western Boundary Fault Zone of the Nagano Basin, Central Japan: Data acquisition and processing

The Western Boundary Fault Zone of the Nagano Basin borders the eastern margin of Northern Fossa Magna, which has undergone strong horizontal shortening since Pliocene. The Western Boundary Fault Zone of the Nagano Basin is considered to be a back thrust that developed on the hanging wall side of the Itoigawa-Shizuoka Tectonic Line. To reveal the subsurface structure of the Western Boundary Fault Zone of the Nagano Basin, we carried out a high-resolution seismic reflection survey along the Saigawa River, southern Nagano City. The source used in this survey was a mini-vibrator (T-15000). Source and receiver spacing was 10 m. 180 channels of geophone arrays were used to record each shot. The seismic section obtained after careful data processing shows fairly flat Quaternary basin fillings in the eastern part of the seismic line. The Quaternary basin fillings are interpreted to be in west-dipping fault contact with west-dipping Neogene strata underlying the Saigawa Hills

High-resolution seismic reflection profiling across the Shiraiwa fault, eastern margin of the Yokote basin fault zone, northeast Japan : data acquisition and processing

The eastern margin of the Yokote basin fault zone extends about 56km at the western foot of the Ou Backbone Range, northeast Japan. The Rikuu earthquake (M=7.2) occurred in the Ou Backbone Range (Mahiru Range) on 31st August, 1896. Associated with this earthquake, four thrust faults-Obonai, Shiraiwa, Ota, and Senya fault3 appeared on the surface of the western foot of the Mahiru Range. These faults were highly sinuous with numerous gaps and en echelon steps. We conducted a high-resolution seismic reflection profiling survey across the Shiraiwa fault. The obtained seismic reflection data were processed by conventional common mid-point methods, post-stack migration, and depth conversion. The subsurface structure across the Shraiwa fault is characterized by branched low-angle reverse faults and conjugate back-thrust. The emergent thrust associated with the 1896 earthquake is regarded to be a subsidiary reverse fault

DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Krüppel-like factor 15 gene expression

Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (GR) in adipogenesis have not been well characterized yet. Here, we show that inhibition of GR activity using the GR antagonist RU486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (MEF) differentiation into adipocytes. Moreover, in MEFs isolated from GR knockout (GRnull) and GRdim mice deficient in GR DNA-binding activity, adipogenesis was blocked. We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation. Moreover, transfection of MEFs with siRNA for KLF15 significantly attenuated the expressions of adipogenic-marker genes and the lipid accumulation. Our results provide a new mechanism for understanding glucocorticoids-dependent adipogenesis and that GR promotes adipogenesis via KLF15 gene expression as a transcriptional direct target