423 research outputs found
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Drosophila nuclear lamin precursor Dm0 is translated from either of two developmentally regulated mRNA species apparently encoded by a single gene.
A cDNA clone encoding a portion of Drosophila nuclear lamins Dm1 and Dm2 has been identified by screening a lambda-gt11 cDNA expression library using Drosophila lamin-specific monoclonal antibodies. Two different developmentally regulated mRNA species were identified by Northern blot analysis using the initial cDNA as a probe, and full-length cDNA clones, apparently corresponding to each message, have been isolated. In vitro transcription of both full-length cDNA clones in a pT7 transcription vector followed by in vitro translation in wheat germ lysate suggests that both clones encode lamin Dm0, the polypeptide precursor of lamins Dm1 and Dm2. Nucleotide sequence analyses confirm the impression that both cDNA clones code for the identical polypeptide, which is highly homologous with human lamins A and C as well as with mammalian intermediate filament proteins. The two clones differ in their 3'-untranslated regions. In situ hybridization of lamin cDNA clones to Drosophila polytene chromosomes shows only a single locus of hybridization at or near position 25F on the left arm of chromosome 2. Southern blot analyses of genomic DNA are consistent with the notion that a single or only a few highly similar genes encoding Drosophila nuclear lamin Dm0 exist in the genome
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XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies.
Treatment options for high grade urothelial cancers are limited and have remained largely unchanged for several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as a single agent treatment for numerous different malignancies, but its efficacy in limiting bladder malignancies has not been tested. In this study we assessed selinexor-dependent cytotoxicity in several bladder tumor cells and report that selinexor effectively reduced XPO1 expression and limited cell viability in a dose dependent manner. The decrease in cell viability was due to an induction of apoptosis and cell cycle arrest. These results were recapitulated in in vivo studies where selinexor decreased tumor growth. Tumors treated with selinexor expressed lower levels of XPO1, cyclin A, cyclin B, and CDK2 and increased levels of RB and CDK inhibitor p27, a result that is consistent with growth arrest. Cells expressing wildtype RB, a potent tumor suppressor that promotes growth arrest and apoptosis, were most susceptible to selinexor. Cell fractionation and immunofluorescence studies showed that selinexor treatment increased nuclear RB levels and mechanistic studies revealed that RB ablation curtailed the response to the drug. Conversely, limiting CDK4/6 dependent RB phosphorylation by palbociclib was additive with selinexor in reducing bladder tumor cell viability, confirming that RB activity has a role in the response to XPO1 inhibition. These results provide a rationale for XPO1 inhibition as a novel strategy for the treatment of bladder malignancies
A tight-binding potential for atomistic simulations of carbon interacting with transition metals: Application to the Ni-C system
We present a tight-binding potential for transition metals, carbon, and
transition metal carbides, which has been optimized through a systematic
fitting procedure. A minimal basis, including the s, p electrons of carbon and
the d electrons of the transition metal, is used to obtain a transferable
tight-binding model of the carbon-carbon, metal-metal and metal-carbon
interactions applicable to binary systems. The Ni-C system is more specifically
discussed. The successful validation of the potential for different atomic
configurations indicates a good transferability of the model and makes it a
good choice for atomistic simulations sampling a large configuration space.
This approach appears to be very efficient to describe interactions in systems
containing carbon and transition metal elements
Phase and transport velocities in particle and electromagnetic beams
In a coherent monoenergetic beam of non-interacting particles, the phase
velocity and the particle transport velocity are functions of position, with
the strongest variation being in the focal region. These velocities are
everywhere parallel to each other, and their product is constant in space. For
a coherent monochromatic electromagnetic beam, the energy transport velocity is
never greater than the speed of light, and can even be zero. The phase
velocities (one each for the non-zero components of the electric and magnetic
fields, in general) can be different from each other and from the energy
transport velocity, both in direction and in magnitude. The phase velocities at
a given point are independent of time, for both particle and electromagnetic
beams. The energy velocity is independent of time for the particle beam, but in
general oscillates (with angular frequency 2w) in magnitude and direction about
its mean value at a given point in the electromagnetic beam. However, there
exist electromagnetic steady beams, within which the energy flux, energy
density and energy velocity are all independent of time.Comment: 9 pages, 12 figure
Occurrence and overlap of natural disasters, complex emergencies and epidemics during the past decade (1995–2004)
BACKGROUND: The fields of expertise of natural disasters and complex emergencies (CEs) are quite distinct, with different tools for mitigation and response as well as different types of competent organizations and qualified professionals who respond. However, natural disasters and CEs can occur concurrently in the same geographic location, and epidemics can occur during or following either event. The occurrence and overlap of these three types of events have not been well studied. METHODS: All natural disasters, CEs and epidemics occurring within the past decade (1995–2004) that met the inclusion criteria were included. The largest 30 events in each category were based on the total number of deaths recorded. The main databases used were the Emergency Events Database for natural disasters, the Uppsala Conflict Database Program for CEs and the World Health Organization outbreaks archive for epidemics. ANALYSIS: During the past decade, 63% of the largest CEs had ≥1 epidemic compared with 23% of the largest natural disasters. Twenty-seven percent of the largest natural disasters occurred in areas with ≥1 ongoing CE while 87% of the largest CEs had ≥1 natural disaster. CONCLUSION: Epidemics commonly occur during CEs. The data presented in this article do not support the often-repeated assertion that epidemics, especially large-scale epidemics, commonly occur following large-scale natural disasters. This observation has important policy and programmatic implications when preparing and responding to epidemics. There is an important and previously unrecognized overlap between natural disasters and CEs. Training and tools are needed to help bridge the gap between the different type of organizations and professionals who respond to natural disasters and CEs to ensure an integrated and coordinated response
Activation of PyMT in β Cells Induces Irreversible Hyperplasia, but Oncogene-Dependent Acinar Cell Carcinomas When Activated in Pancreatic Progenitors
It is unclear whether the cellular origin of various forms of pancreatic cancer involves transformation or transdifferentiation of different target cells or whether tumors arise from common precursors, with tumor types determined by the specific genetic alterations. Previous studies suggested that pancreatic ductal carcinomas might be induced by polyoma middle T antigen (PyMT) expressed in non-ductal cells. To ask whether PyMT transforms and transdifferentiates endocrine cells toward exocrine tumor phenotypes, we generated transgenic mice that carry tetracycline-inducible PyMT and a linked luciferase reporter. Induction of PyMT in β cells causes β-cell hyperplastic lesions that do not progress to malignant neoplasms. When PyMT is de-induced, β cell proliferation and growth cease; however, regression does not occur, suggesting that continued production of PyMT is not required to maintain the viable expanded β cell population. In contrast, induction of PyMT in early pancreatic progenitor cells under the control of Pdx1 produces acinar cell carcinomas and β-cell hyperplasia. The survival of acinar tumor cells is dependent on continued expression of PyMT. Our findings indicate that PyMT can induce exocrine tumors from pancreatic progenitor cells, but cells in the β cell lineage are not transdifferentiated toward exocrine cell types by PyMT; instead, they undergo oncogene-dependent hyperplastic growth, but do not require PyMT for survival
IL-6 Stabilizes Twist and Enhances Tumor Cell Motility in Head and Neck Cancer Cells through Activation of Casein Kinase 2
BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer worldwide. Unfortunately, the survival of patients with SCCHN has not improved in the last 40 years, and thus new targets for therapy are needed. Recently, elevations in serum level of interleukin 6 (IL-6) and expression of Twist in tumor samples were found to be associated with poor clinical outcomes in multiple types of cancer, including SCCHN. Although Twist has been proposed as a master regulator of epithelial-mesenchymal transition and metastasis in cancers, the mechanisms by which Twist levels are regulated post-translationally are not completely understood. Tumor progression is characterized by the involvement of cytokines and growth factors and Twist induction has been connected with a number of these signaling pathways including IL-6. Since many of the effects of IL-6 are mediated through activation of protein phosphorylation cascades, this implies that Twist expression must be under a tight control at the post-translational level in order to respond in a timely manner to external stimuli. METHODOLOGY/PRINCIPAL FINDINGS: Our data show that IL-6 increases Twist expression via a transcription-independent mechanism in many SCCHN cell lines. Further investigation revealed that IL-6 stabilizes Twist in SCCHN cell lines through casein kinase 2 (CK2) phosphorylation of Twist residues S18 and S20, and that this phosphorylation inhibits degradation of Twist. Twist phosphorylation not only increases its stability but also enhances cell motility. Thus, post-translational modulation of Twist contributes to its tumor-promoting properties. CONCLUSIONS/SIGNIFICANCE: Our study shows Twist expression can be regulated at the post-translational level through phosphorylation by CK2, which increases Twist stability in response to IL-6 stimulation. Our findings not only provide novel mechanistic insights into post-translational regulation of Twist but also suggest that CK2 may be a viable therapeutic target in SCCHN
Preclinical evaluation of cyclin dependent kinase 11 and casein kinase 2 survival kinases as RNA interference targets for triple negative breast cancer therapy
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