Isospin character of low-lying states in 56Fe.

Low-lying states in {sup 56}Fe, up to an excitation energy of about 4 MeV, have been investigated by means of inelastic proton and deuteron scattering experiments at {ital E}{sub {ital p}}=65 and 400 MeV and at {ital E}{sub {ital d}}=56 MeV, respectively. Measured cross sections and analyzing powers have been compared with coupled-channels calculations using collective form factors; calculations in both the Schr{umlt o}dinger and Dirac formalisms have been carried out for the proton data. For each probe, the matrix elements have been deduced for transitions from the ground state and from the 2{sub 1}{sup +} state to six quadrupole (2{sup +}) states to one octupole (3{sub 1}{sup {minus}}) and two hexadecapole (4{sub 1}{sup +} and 4{sub 2}{sup +}) states. The obtained matrix elements and the previous values from {gamma} decay or electron inelastic scattering have been used to evaluate the isospin character of the transitions. To discuss the quadrupole mixed-symmetry states in {sup 56}Fe, the deduced neutron ({ital M}{sub {ital n}}) and proton ({ital M}{sub {ital p}}) components of the matrix elements, or equivalently the isoscalar ({ital M}{sub {ital s}}) and isovector ({ital M}{sub {ital v}}) parts, have been compared with theoretical calculations based on the neutron-proton interacting bosonmore » model and on the shell model evaluated in a full {ital f}-{ital p} configuration space. {copyright} {ital 1996 The American Physical Society.}« les

Therapeutic effect of autologous compact bone-derived mesenchymal stem cell transplantation on prion disease

Prion diseases are fatal neurodegenerative disorders of humans and animals and no effective treatments are currently available. Allogenic transplantation of immortalized human mesenchymal stem cells (MSCs) can prolong the survival of mice infected with prions. However, autologous transplantation is an appropriate model for evaluating the effects of MSCs on prion diseases. Therefore, we isolated and purified MSCs from the femur and tibia of mice as compact bone-derived MSCs (CB-MSCs). Flow cytometric analysis showed that CB-MSCs were negative for myeloid stem cell-derived cell markers CD11b and CD45, but positive for molecules such as Sca-1, CD105 and CD90.2, which are reported to be expressed on MSCs. The ability of CB-MSCs to migrate to brain extracts from prion-infected mice was confirmed by an in vitro migration assay. Intrahippocampus transplantation of CB-MSCs at 120 days post-inoculation marginally but significantly prolonged the survival of mice infected with the Chandler prion strain. The transplantation of CB-MSCs did not influence the accumulation of diseasespecific prion protein. However, the CB-MSC transplantation enhanced microglial activation, which appeared to be polarized to the M2-type activation state. These results suggest that autologous MSC transplantation is a possible treatment for prion diseases, while the modification of microglial activation may be a therapeutic target for neurodegenerative diseases

Investigation of Tumor Heterogeneity Using Integrated Single-Cell RNA Sequence Analysis to Focus on Genes Related to Breast Cancer-, EMT-, CSC-, and Metastasis-Related Markers in Patients with HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) protein, which is characterized by the amplification of ERBB2, is a molecular target for HER2-overexpressing breast cancer. Many targeted HER2 strategies have been well developed thus far. Furthermore, intratumoral heterogeneity in HER2 cases has been observed with immunohistochemical staining and has been considered one of the reasons for drug resistance. Therefore, we conducted an integrated analysis of the breast cancer single-cell gene expression data for HER2-positive breast cancer cases from both scRNA-seq data from public datasets and data from our cohort and compared them with those for luminal breast cancer datasets. In our results, heterogeneous distribution of the expression of breast cancer-related genes (ESR1, PGR, ERBB2, and MKI67) was observed. Various gene expression levels differed at the single-cell level between the ERBB2-high group and ERBB2-low group. Moreover, molecular functions and ERBB2 expression levels differed between estrogen receptor (ER)-positive and ER-negative HER2 cases. Additionally, the gene expression levels of typical breast cancer-, CSC-, EMT-, and metastasis-related markers were also different across each patient. These results suggest that diversity in gene expression could occur not only in the presence of ERBB2 expression and ER status but also in the molecular characteristics of each patient

Diagnostic performance of serum interferon gamma, matrix metalloproteinases, and periostin measurements for pulmonary tuberculosis in Japanese patients with pneumonia

Serum markers that differentiate between tuberculous and non-tuberculous pneumonia would be clinically useful. However, few serum markers have been investigated for their association with either disease. In this study, serum levels of interferon gamma (IFN-γ), matrix metalloproteinases 1 and 9 (MMP-1 and MMP-9, respectively), and periostin were compared between 40 pulmonary tuberculosis (PTB) and 28 non-tuberculous pneumonia (non-PTB) patients. Diagnostic performance was assessed by analysis of receiver-operating characteristic (ROC) curves and classification trees. Serum IFN-γ and MMP-1 levels were significantly higher and serum MMP-9 levels significantly lower in PTB than in non- PTB patients (p < 0.001, p = 0.002, p < 0.001, respectively). No significant difference was observed in serum periostin levels between groups. ROC curve analysis could not determine the appropriate cut-off value with high sensitivity and specificity; therefore, a classification tree method was applied. This method identified patients with limited infiltration into three groups with statistical significance (p = 0.01), and those with MMP-1 levels < 0.01 ng/ mL and periostin levels ≥ 118.8 ng/mL included only non-PTB patients (95% confidence interval 0.0–41.0). Patients with extensive infiltration were also divided into three groups with statistical significance (p < 0.001), and those with MMP-9 levels < 3.009 ng/mL included only PTB patients (95% confidence interval 76.8–100.0). In conclusion, the novel classification tree developed using MMP-1, MMP-9, and periostin data distinguished PTB from non- PTB patients. Further studies are needed to validate our cut-off values and the overall clinical usefulness of these markers

Gene regulatory network analysis defines transcriptome landscape with alternative splicing of human umbilical vein endothelial cells during replicative senescence

Background Endothelial cell senescence is the state of permanent cell cycle arrest and plays a critical role in the pathogenesis of age-related diseases. However, a comprehensive understanding of the gene regulatory network, including genome-wide alternative splicing machinery, involved in endothelial cell senescence is lacking. Results We thoroughly described the transcriptome landscape of replicative senescent human umbilical vein endothelial cells. Genes with high connectivity showing a monotonic expression increase or decrease with the culture period were defined as hub genes in the co-expression network. Computational network analysis of these genes led to the identification of canonical and non-canonical senescence pathways, such as E2F and SIRT2 signaling, which were down-regulated in lipid metabolism, and chromosome organization processes pathways. Additionally, we showed that endothelial cell senescence involves alternative splicing. Importantly, the first and last exon types of splicing, as observed in FLT1 and ACACA, were preferentially altered among the alternatively spliced genes during endothelial senescence. We further identified novel microexons in PRUNE2 and PSAP, each containing 9 nt, which were altered within the specific domain during endothelial senescence. Conclusions These findings unveil the comprehensive transcriptome pathway and novel signaling regulated by RNA processing, including gene expression and splicing, in replicative endothelial senescence.Medicine, Faculty ofNon UBCPathology and Laboratory Medicine, Department ofReviewedFacultyResearcherOthe

Total Synthesis of a TNBC-Selective Cytotoxic Bromo Nor-eremophilane, PC-A, and Its Preliminary Structure–Activity Relationships

PC-A (1), a bromo nor-eremophilane, showed selective antiproliferative activity against a triple-negative breast cancer (TNBC) cell line. This unique activity prompted us to establish a total synthesis to facilitate a structure–activity relationship (SAR) study and selectivity optimization. An enantioselective first total synthesis of 1 was achieved starting from (R)-carvone through a side chain extension with a Mukaiyama aldol reaction and decalin construction. The synthesized decalin derivatives and debromo PC-A (2) were evaluated for antiproliferative activity against five human tumor cell lines, including TNBC, to assess preliminary SAR correlations

Total Synthesis of a TNBC-Selective Cytotoxic Bromo Nor-eremophilane, PC-A, and Its Preliminary Structure–Activity Relationships

PC-A (1), a bromo nor-eremophilane, showed selective antiproliferative activity against a triple-negative breast cancer (TNBC) cell line. This unique activity prompted us to establish a total synthesis to facilitate a structure–activity relationship (SAR) study and selectivity optimization. An enantioselective first total synthesis of 1 was achieved starting from (R)-carvone through a side chain extension with a Mukaiyama aldol reaction and decalin construction. The synthesized decalin derivatives and debromo PC-A (2) were evaluated for antiproliferative activity against five human tumor cell lines, including TNBC, to assess preliminary SAR correlations

Development of the Rabbit NASH Model Resembling Human NASH and Atherosclerosis

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease which may progress into liver fibrosis and cancer. Since NASH patients have a high prevalence of atherosclerosis and ensuing cardiovascular diseases, simultaneous management of NASH and atherosclerosis is required. Currently, rodents are the most common animal models for NASH and accompanying liver fibrosis, but there are great differences in lipoprotein profiles between rodents and humans, which makes it difficult to reproduce the pathology of NASH patients with atherosclerosis. Rabbits can be a promising candidate for assessing NASH and atherosclerosis because lipoprotein metabolism is more similar to humans compared with rodents. To develop the NASH model using rabbits, we treated the Japanese White rabbit with a newly developed high-fat high-cholesterol diet (HFHCD) containing palm oil 7.5%, cholesterol 0.5%, and ferrous citrate 0.5% for 16 weeks. HFHCD-fed rabbits exhibited NASH at 8 weeks after commencing the treatment and developed advanced fibrosis by the 14th week of treatment. In addition to hypercholesterolemia, atherosclerotic lesion developed in the aorta after 8 weeks. Therefore, this rabbit NASH model might contribute to exploring the concurrent treatment options for human NASH and atherosclerosis

A novel vaccine strategy using quick and easy conversion of bacterial pathogens to unnatural amino acid-auxotrophic suicide derivatives

ABSTRACTWe propose a novel strategy for quick and easy preparation of suicide live vaccine candidates against bacterial pathogens. This method requires only the transformation of one or more plasmids carrying genes encoding for two types of biological devices, an unnatural amino acid (uAA) incorporation system and toxin-antitoxin systems in which translation of the antitoxins requires the uAA incorporation. Escherichia coli BL21-AI laboratory strains carrying the plasmids were viable in the presence of the uAA, whereas the free toxins killed these strains after the removal of the uAA. The survival time after uAA removal could be controlled by the choice of the uAA incorporation system and toxin-antitoxin systems. Multilayered toxin-antitoxin systems suppressed escape frequency to less than 1 escape per 109 generations in the best case. This conditional suicide system also worked in Salmonella enterica and E. coli clinical isolates. The S. enterica vaccine strains were attenuated with a >105 fold lethal dose. Serum IgG response and protection against the parental pathogenic strain were confirmed. In addition, the live E. coli vaccine strain was significantly more immunogenic and provided greater protection than a formalin-inactivated vaccine. The live E. coli vaccine was not detected after inoculation, presumably because the uAA is not present in the host animals or the natural environment. These results suggest that this strategy provides a novel way to rapidly produce safe and highly immunogenic live bacterial vaccine candidates.IMPORTANCELive vaccines are the oldest vaccines with a history of more than 200 years. Due to their strong immunogenicity, live vaccines are still an important category of vaccines today. However, the development of live vaccines has been challenging due to the difficulties in achieving a balance between safety and immunogenicity. In recent decades, the frequent emergence of various new and old pathogens at risk of causing pandemics has highlighted the need for rapid vaccine development processes. We have pioneered the use of uAAs to control gene expression and to conditionally kill host bacteria as a biological containment system. This report proposes a quick and easy conversion of bacterial pathogens into live vaccine candidates using this containment system. The balance between safety and immunogenicity can be modulated by the selection of the genetic devices used. Moreover, the uAA-auxotrophy can prevent the vaccine from infecting other individuals or establishing the environment