318 research outputs found
Free-Vibration Analysis of Rotating Beams by a Variable-Order Finite-Element Method
The free vibration of rotating beams is analyzed by means of a finite-element method of variable order. This method entails displacement functions that are a complete power series of a variable number of terms. The terms are arranged so that the generalized coordinates are composed of displacements and slopes at the element extremities and, additionally, displacements at certain points within the element. The displacement is assumed to be analytic within an element and thus can be approximated to any degree of accuracy desired by a complete power series. Numerical results are presented for uniform beams with zero and nonzero hub radii, tapered beams, and a nonuniform beam with discontinuities. Since the present method reduces to a conventional beam finite-element method for a cubic displacement function, the results are compared and found to be superior to the conventional results in terms of accuracy for a given number of degrees of freedom. Indeed, essentially exact eigenvalues and eigenvectors are obtained with this technique, which is far more rapidly convergent than other approaches in the literature
Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9
RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissue-specific Rbpjk mutant (Prx1Cre;Rbpjk(f/f)), Rbpjk mutant/Sox9 haploinsufficient (Prx1Cre;Rbpjk(f/f);Sox9(f/+)), and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors
Immunological considerations of modern animal models of malignant primary brain tumors
Recent advances in animal models of glioma have facilitated a better understanding of biological mechanisms underlying gliomagenesis and glioma progression. The limitations of existing therapy, including surgery, chemotherapy, and radiotherapy, have prompted numerous investigators to search for new therapeutic approaches to improve quantity and quality of survival from these aggressive lesions. One of these approaches involves triggering a tumor specific immune response. However, a difficulty in this approach is the the scarcity of animal models of primary CNS neoplasms which faithfully recapitulate these tumors and their interaction with the host's immune system. In this article, we review the existing methods utilized to date for modeling gliomas in rodents, with a focus on the known as well as potential immunological aspects of these models. As this review demonstrates, many of these models have inherent immune system limitations, and the impact of these limitations on studies on the influence of pre-clinical therapeutics testing warrants further attention
Satb1 overexpression drives tumor-promoting activities in cancer-associated dendritic cells
Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.Fil: Tesone, Amelia J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Rutkowski, Melanie R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Brencicova, Eva. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Svoronos, Nikolaos. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Perales Puchal, Alfredo. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Stephen, Tom L.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Allegrezza, Michael J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Payne, Kyle K.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Nguyen, Jenny M.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados UnidosFil: Wickramasinghe, Jayamanna. The Wistar Institute. Center for Systems and Computational Biology; Estados UnidosFil: Tchou, Julia. University of Pennsylvania; Estados UnidosFil: Borowsky, Mark E.. Christiana Care Health System. Helen F. Graham Cancer Center; Estados UnidosFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kossenkov, Andrew V.. The Wistar Institute. Center for Systems and Computational Biology; Estados UnidosFil: Conejo Garcia, José R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unido
NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum homeostasis
Many metabolic diseases disrupt endoplasmic reticulum (ER) homeostasis, but little is known about how metabolic activity is communicated to the ER. Here, we show in hepatocytes and other metabolically active cells that decreasing the availability of substrate for the tricarboxylic acid (TCA) cycle diminished NADPH production, elevated glutathione oxidation, led to altered oxidative maturation of ER client proteins, and attenuated ER stress. This attenuation was prevented when glutathione oxidation was disfavored. ER stress was also alleviated by inhibiting either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity increased NADPH production, glutathione reduction, and ER stress. Validating these findings, deletion of the Mitochondrial Pyruvate Carrier-which is known to decrease TCA cycle activity and protect the liver from steatohepatitis-also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. Together, our results demonstrate a novel pathway by which mitochondrial metabolic activity is communicated to the ER through the relay of redox metabolites
Lyman Continuum Escape Fraction of Star-forming Dwarf Galaxies at z ~ 1
To date, no direct detection of Lyman continuum emission has been measured for intermediate-redshift (z ~ 1) star-forming galaxies. We combine Hubble Space Telescope grism spectroscopy with GALEX UV and ground-based optical imaging to extend the search for escaping Lyman continuum to a large (~600) sample of z ~ 1 low-mass log(M)≃ 9.3 M_☉), moderately star-forming (ψ ≾ 10M_☉ yr^(−1)) galaxies selected initially on Hα emission. The characteristic escape fraction of LyC from star-forming galaxies (SFGs) that populate this parameter space remains weakly constrained by previous surveys, but these faint (sub-Lsstarf) SFGs are assumed to play a significant role in the reionization of neutral hydrogen in the intergalactic medium (IGM) at high redshift z > 6. We do not make an unambiguous detection of escaping LyC radiation from this z ~ 1 sample, individual non-detections to constrain the absolute Lyman continuum escape fraction, f_(esc) 200Å), which are thought to be close analogs of high redshift sources of reionization. For reference, we also present an emissivity-weighted escape fraction that is useful for measuring the general contribution SFGs to the ionizing UV background. In the discussion, we consider the implications of these intermediate redshift constraints for the reionization of hydrogen in the IGM at high (z > 6) redshift. If we assume our z ~ 1 SFGs, for which we measure this emissivity-weighted f_(esc), are analogs to the high redshift sources of reionization, we find it is difficult to reconcile reionization by faint (M}_(UV) ≾-13) SFGs with a low escape fraction (f_(esc) < 3%), with constraints from independent high redshift observations. If f_(esc) evolves with redshift, reionization by SFGs may be consistent with observations from Planck
HST Grism-derived Forecasts for Future Galaxy Redshift Surveys
The mutually complementary Euclid and Roman galaxy redshift surveys will use Hα- and [O III]-selected emission-line galaxies (ELGs) as tracers of the large-scale structure at 0.9 ≾ z ≾ 1.9 (Hα) and 1.5 ≾ z ≾ 2.7 ([O III]). It is essential to have a reliable and sufficiently precise knowledge of the expected numbers of Hα-emitting galaxies in the survey volume in order to optimize these redshift surveys for the study of dark energy. Additionally, these future samples of ELGs will, like all slitless spectroscopy surveys, be affected by a complex selection function that depends on galaxy size and luminosity, line equivalent width (EW), and redshift errors arising from the misidentification of single ELGs. Focusing on the specifics of the Euclid survey, we combine two slitless spectroscopic WFC3-IR data sets—3D-HST+AGHAST and the WFC3 Infrared Spectroscopic Parallel survey—to construct a Euclid-like sample that covers an area of 0.56 deg² and includes 1277 ELGs. We detect 1091 (~3270 deg⁻²) Hα+[N II]-emitting galaxies in the range 0.9 ≤ z ≤ 1.6 and 162 (~440 deg⁻²) [O III] λ5007 emitters over 1.5 ≤ z ≤ 2.3 with line fluxes ≥2 × 10⁻¹⁶ erg s⁻¹ cm⁻². The median of the Hα+[N II] EW distribution is ~250 Å, and the effective radii of the continuum and Hα+[N II] emission are correlated with a median of ~0.”38 and significant scatter (σ ~ 0.”2–0.”35). Finally, we explore the prevalence of redshift misidentification in future Euclid samples, finding potential contamination rates of ~14%–20% and ~6% down to 2 × 10⁻¹⁶ erg s⁻¹ cm−2 and 6 × 10⁻¹⁷ erg s⁻¹ cm⁻², respectively, although with increased wavelength coverage these percentages drop to nearly zero
The Hubble Space Telescope Wide Field Camera 3 Early Release Science data: Panchromatic Faint Object Counts for 0.2-2 microns wavelength
We describe the Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) Early
Release Science (ERS) observations in the Great Observatories Origins Deep
Survey (GOODS) South field. The new WFC3 ERS data provide calibrated, drizzled
mosaics in the UV filters F225W, F275W, and F336W, as well as in the near-IR
filters F098M (Ys), F125W (J), and F160W (H) with 1-2 HST orbits per filter.
Together with the existing HST Advanced Camera for Surveys (ACS) GOODS-South
mosaics in the BViz filters, these panchromatic 10-band ERS data cover 40-50
square arcmin at 0.2-1.7 {\mu}m in wavelength at 0.07-0.15" FWHM resolution and
0.090" Multidrizzled pixels to depths of AB\simeq 26.0-27.0 mag (5-{\sigma})
for point sources, and AB\simeq 25.5-26.5 mag for compact galaxies.
In this paper, we describe: a) the scientific rationale, and the data taking
plus reduction procedures of the panchromatic 10-band ERS mosaics; b) the
procedure of generating object catalogs across the 10 different ERS filters,
and the specific star-galaxy separation techniques used; and c) the reliability
and completeness of the object catalogs from the WFC3 ERS mosaics. The
excellent 0.07-0.15" FWHM resolution of HST/WFC3 and ACS makes star- galaxy
separation straightforward over a factor of 10 in wavelength to AB\simeq 25-26
mag from the UV to the near-IR, respectively.Comment: 51 pages, 71 figures Accepted to ApJS 2011.01.2
Current status and unanswered questions on the use of Denosumab in giant cell tumor of bone
Denosumab is a monoclonal antibody to RANK ligand approved for use in giant cell tumour (GCT) of bone. Due to its efficacy, Denosumab is recommended as the first option in inoperable or metastatic GCT. Denosumab has also been used pre-operatively to downstage tumours with large soft tissue extension to allow for less morbid surgery. The role of Denosumab for conventional limb GCT of bone is yet to be defined. Further studies are required to determine whether local recurrence rates will be decreased with the adjuvant use of Denosumab along with surgery. The long term use and toxicity of this agent is unknown as is the proportion of patients with primary or secondary resistance. It is advised that complicated cases of GCT requiring Denosumab treatment should be referred and followed up at expert centres. Collaborative studies involving further clinical trials and rigorous data collection are strongly recommended to identify the optimum use of this drug
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