The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of ...CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9(+) acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.
Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell ...self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design.
Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) ...sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.
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•KDOAM-25 is a selective inhibitor of KDM5A-D, the H3K4me3 lysine demethylases•KDOAM-25 inhibits the demethylation of H3K4me3 in an immunofluorescence assay•Increased KDM5B expression correlates with shorter survival in multiple myeloma•KDOAM-25-treated cells show an increase in H3K4me3 at transcription start sites
Tumber et al. report the discovery and characterization of KDOAM-25, a potent and selective inhibitor of the KDM5 H3K4me3 lysine demethylases. KDOAM-25 inhibits the cellular demethylation of H3K4me3 at transcription start sites and the proliferation of MM1S multiple myeloma cells.
BACKGROUND: Feed cost constitutes about 70% of the cost of raising broilers, but the efficiency of feed utilization has not kept up the growth potential of today's broilers. Improvement in feed ...efficiency would reduce the amount of feed required for growth, the production cost and the amount of nitrogenous waste. We studied residual feed intake (RFI) and feed conversion ratio (FCR) over two age periods to delineate their genetic inter-relationships. METHODS: We used an animal model combined with Gibb sampling to estimate genetic parameters in a pedigreed random mating broiler control population. RESULTS: Heritability of RFI and FCR was 0.42-0.45. Thus selection on RFI was expected to improve feed efficiency and subsequently reduce feed intake (FI). Whereas the genetic correlation between RFI and body weight gain (BWG) at days 28-35 was moderately positive, it was negligible at days 35-42. Therefore, the timing of selection for RFI will influence the expected response. Selection for improved RFI at days 28-35 will reduce FI, but also increase growth rate. However, selection for improved RFI at days 35-42 will reduce FI without any significant change in growth rate. The nature of the pleiotropic relationship between RFI and FCR may be dependent on age, and consequently the molecular factors that govern RFI and FCR may also depend on stage of development, or on the nature of resource allocation of FI above maintenance directed towards protein accretion and fat deposition. The insignificant genetic correlation between RFI and BWG at days 35-42 demonstrates the independence of RFI on the level of production, thereby making it possible to study the molecular, physiological and nutrient digestibility mechanisms underlying RFI without the confounding effects of growth. The heritability estimate of FCR was 0.49 and 0.41 for days 28-35 and days 35-42, respectively. CONCLUSION: Selection for FCR will improve efficiency of feed utilization but because of the genetic dependence of FCR and its components, selection based on FCR will reduce FI and increase growth rate. However, the correlated responses in both FI and BWG cannot be predicted accurately because of the inherent problem of FCR being a ratio trait.
We have extended our previous survey of the association of mitochondrial prevalence in particular tissues with ascites susceptibility in broilers. We previously reported that in breast muscle of 22 ...week old susceptible line male birds had significantly higher mtDNA copy number relative to nuclear copy number (mtDNA/nucDNA), compared to resistant line male birds. The higher copy number correlated with higher expression of PPARGC1A mRNA gene. Ascites is a significant metabolic disease associated with fast-growing meat-type chickens (broilers) and is a terminal result of pulmonary hypertension syndrome. We now report the mtDNA/nucDNA ratio in lung, liver, heart, thigh, and breast of both genders at 3, and 20 weeks old. At 3 weeks the mtDNA/nucDNA ratio is significantly higher in lung, breast, and thigh for susceptible line males compared to the resistant line males. Conversely, we see the opposite for lung and breast in females. At 20 weeks of age the differences between males from the two lines is lost for lung, and thigh. Although there is a significant reduction in the mtDNA/nucDNA ratio of breast from 3 weeks to 20 weeks in the susceptible line males, the susceptible males remain higher than resistant line males for this specific tissue. We assessed relative expression of five genes known to regulate mitochondrial biogenesis for lung, thigh and breast muscle from males and females of both lines with no consistent pattern to explain the marked gender and line differences for these tissues. Our results indicate clear sex differences in mitochondrial biogenesis establishing a strong association between the mtDNA quantity in a tissue-specific manner and correlated with ascites-phenotype. We propose that mtDNA/nucDNA levels could serve as a potential predictive marker in breeding programs to reduce ascites.
Abstract
We present optical and near-infrared (NIR) (
ugriYJH
) photometry of host galaxies of Type Ia supernovae (SN Ia) observed by the
Carnegie Supernova Project-I
. We determine host galaxy ...stellar masses and, for the first time, study their correlation with SN Ia standardized luminosity across optical and NIR (
uBgVriYJH
) bands. In the individual bands, we find that SNe Ia are more luminous in more massive hosts with luminosity offsets ranging between −0.07 ± 0.03 and −0.15 ± 0.04 mag after light-curve standardization. The slope of the SN Ia Hubble residual-host mass relation is negative across all
uBgVriYJH
bands with values ranging between −0.029 ± 0.029 and −0.093 ± 0.031 mag dex
−1
—implying that SNe Ia in more massive galaxies are brighter than expected. The near-constant observed correlations across optical and NIR bands indicate that dust may not play a significant role in the observed luminosity offset–host mass correlation. We measure projected separations between SNe Ia and their host centers, and find that SNe Ia that explode beyond a projected 10 kpc have a 50%– 60% reduction of the dispersion in Hubble residuals across all bands—making them a more uniform subset of SNe Ia. Dust in host galaxies, peculiar velocities of nearby SN Ia, or a combination of both may drive this result as the color excesses of SNe Ia beyond 10 kpc are found to be generally lower than those interior, but there is also a diminishing trend of the dispersion as we exclude nearby events. We do not find that SN Ia average luminosity varies significantly when they are grouped in various host morphological types. Host galaxy data from this work will be useful, in conjunction with future high-redshift samples, in constraining cosmological parameters.
Abstract
We present a method of extrapolating the spectroscopic behavior of Type Ia supernovae (SNe Ia) in the near-infrared (NIR) wavelength regime up to 2.30
μ
m using optical spectroscopy. Such a ...process is useful for accurately estimating K-corrections and other photometric quantities of SNe Ia in the NIR. A principal component analysis is performed on data consisting of Carnegie Supernova Project I & II optical and NIR FIRE spectra to produce models capable of making these extrapolations. This method differs from previous spectral template methods by not parameterizing models strictly by photometric light-curve properties of SNe Ia, allowing for more flexibility of the resulting extrapolated NIR flux. A difference of around −3.1% to −2.7% in the total integrated NIR flux between these extrapolations and the observations is seen here for most test cases including Branch core-normal and shallow-silicon subtypes. However, larger deviations from the observation are found for other tests, likely due to the limited high-velocity and broad-line SNe Ia in the training sample. Maximum-light principal components are shown to allow for spectroscopic predictions of the color-stretch light-curve parameter,
s
BV
, within approximately ±0.1 units of the value measured with photometry. We also show these results compare well with NIR templates, although in most cases the templates are marginally more fitting to observations, illustrating a need for more concurrent optical+NIR spectroscopic observations to truly understand the diversity of SNe Ia in the NIR.
Concomitant invasive ovarian mucinous adenocarcinoma, unilateral renal agenesis and bicornuate uterus is a rare combination. Unilateral renal agenesis has been associated with genital anomalies, such ...as unicornuate and bicornuate uterus. Furthermore, a wealth of studies has reported the association between unicornuate uterus and ovarian anomalies, such as the absence of an ovary or ectopic ovaries, but rarely has there been a combination of the three to the best of our knowledge. The present case report is the first case presentation with a combination of the three syndromes: ovarian mucinous tumor, unilateral renal agenesis, and bicornuate uterus.
We report the case of a 17-year-old who presented with abdominal distension. On examination, a CT scan revealed a large multicystic abdominal mass on the right side, with an absence of the right kidney while the left kidney was normal in size, appearance, and position. Intraoperatively, massive blood-stained ascitic fluid was evacuated. Additionally, a large whitish polycystic intra-abdominal mass with mucus-like materials and solid areas was attached to the midpoint of the colon and the right ovary, with visible metastasis to the omentum. The uterus was bicornuate. The mass and omentum were taken for histopathology and a diagnosis of invasive ovarian mucinous cystadenocarcinoma with metastasis to the colon and omentum was made after a pathological report.
The presence of these conditions in the same individual could potentially complicate medical management and fertility considerations. Thus, a need for a multidisciplinary medical team, including gynecologists, urologists, and oncologists, to address their unique needs and provide appropriate treatment and guidance. Further research and case studies are needed to better understand the possible association and implications of these rare co-occurring conditions.
Ascites syndrome is the most severe manifestation of pulmonary hypertension in fast-growing broilers. The disease can be attributed to increased body weights of birds, where the higher metabolic load ...is not matched by sufficient oxygen supply to the cells and tissues. Although there are environmental components, the disease exhibits moderate to high heritability. The current study uses high throughput whole genome resequencing (WGR) to identify genes and chromosomal regions associated with ascites.
The WGR data identified the CPQ gene on chromosome 2. The association was confirmed by genotyping a large collection of DNAs from phenotyped birds from three distinct broiler lines using SNPs in intron 6 and exon 8 of the CPQ gene. By combining the genotype data for these two SNP loci, we identified three different alleles segregating in the three broiler lines. Particular genotypes could be associated with resistance to ascites. We further determined that particular genotypes most associated with resistance overexpress CPQ mRNA in three tissues which might explain the role of these alleles in contributing to resistance.
Our findings indicate CPQ is an important determinant of pulmonary hypertension syndrome leading to ascites in broilers. We identified particular SNPs that can be used for marker-assisted selection of broilers for resistance to the disease. Our findings validate WGR as a highly efficient approach to map determinants contributing to complex phenotypic or disease-related traits. The CPQ gene has been associated with pulmonary hypertension in genome-wide association studies in humans. Therefore, ascites investigations in broilers are likely to provide insights into some forms of hypertension in humans.
1991T-like Supernovae Phillips, M. M.; Ashall, C.; Brown, Peter J. ...
The Astrophysical journal. Supplement series,
07/2024, Letnik:
273, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract Understanding the nature of the luminous 1991T-like supernovae (SNe) is of great importance to SN cosmology as they are likely to have been more common in the early Universe. In this paper, ...we explore the observational properties of 1991T-like SNe to study their relationship to other luminous, slow-declining Type Ia supernovae (SNe Ia). From the spectroscopic and photometric criteria defined in Phillips et al., we identify 17 1991T-like SNe from the literature. Combining these objects with 10 1991T-like SNe from the Carnegie Supernova Project-II, the spectra, light curves, and colors of these events, along with their host galaxy properties, are examined in detail. We conclude that 1991T-like SNe are closely related in essentially all of their UV, optical, and near-infrared properties—as well as their host galaxy parameters—to the slow-declining subset of Branch core-normal SNe and to the intermediate 1999aa-like events, forming a continuum of luminous SNe Ia. The overriding difference between these three subgroups appears to be the extent to which 56 Ni mixes into the ejecta, producing the premaximum spectra dominated by Fe iii absorption, the broader UV light curves, and the higher luminosities that characterize the 1991T-like events. Nevertheless, the association of 1991T-like SNe with the rare Type Ia circumstellar material SNe would seem to run counter to this hypothesis, in which case 1991T-like events may form a separate subclass of SNe Ia, possibly arising from single-degenerate progenitor systems.
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