Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation

Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1-3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis. The data suggest a key role of BRPF in regulating gene expression during osteoclastogenesis, and the excellent druggability of these bromodomains may lead to new treatment strategies for patients suffering from bone loss or osteolytic malignant bone lesions

Nanoscale structuring of tungsten tip yields most coherent electron point-source

This report demonstrates the most spatially-coherent electron source ever reported. A coherence angle of 14.3 +/- 0.5 degrees was measured, indicating a virtual source size of 1.7 +/-0.6 Angstrom using an extraction voltage of 89.5 V. The nanotips under study were crafted using a spatially-confined, field-assisted nitrogen etch which removes material from the periphery of the tip apex resulting in a sharp, tungsten-nitride stabilized, high-aspect ratio source. The coherence properties are deduced from holographic measurements in a low-energy electron point source microscope with a carbon nanotube bundle as sample. Using the virtual source size and emission current the brightness normalized to 100 kV is found to be 7.9x10^8 A/sr cm^2

Hot Carrier Transport and Photocurrent Response in Graphene

Strong electron-electron interactions in graphene are expected to result in multiple-excitation generation by the absorption of a single photon. We show that the impact of carrier multiplication on photocurrent response is enhanced by very inefficient electron cooling, resulting in an abundance of hot carriers. The hot-carrier-mediated energy transport dominates the photoresponse and manifests itself in quantum efficiencies that can exceed unity, as well as in a characteristic dependence of the photocurrent on gate voltages. The pattern of multiple photocurrent sign changes as a function of gate voltage provides a fingerprint of hot-carrier-dominated transport and carrier multiplication.Comment: 4 pgs, 2 fg

Report on the Third Workshop on Sustainable Software for Science: Practice and Experiences (WSSSPE3)

This report records and discusses the Third Workshop on Sustainable Software for Science: Practice and Experiences (WSSSPE3). The report includes a description of the keynote presentation of the workshop, which served as an overview of sustainable scientific software. It also summarizes a set of lightning talks in which speakers highlighted to-the-point lessons and challenges pertaining to sustaining scientific software. The final and main contribution of the report is a summary of the discussions, future steps, and future organization for a set of self-organized working groups on topics including developing pathways to funding scientific software; constructing useful common metrics for crediting software stakeholders; identifying principles for sustainable software engineering design; reaching out to research software organizations around the world; and building communities for software sustainability. For each group, we include a point of contact and a landing page that can be used by those who want to join that group's future activities. The main challenge left by the workshop is to see if the groups will execute these activities that they have scheduled, and how the WSSSPE community can encourage this to happen

Well-differentiated Papillary Mesothelioma With Invasive Foci

Well-differentiated papillary mesotheliomas (WDPMs) are usually encountered as incidental findings in the peritoneal cavity in women. Most WDPMs are benign, and the histologic features that indicate a more aggressive course are controversial. We report 20 cases of WDPM, which contained invasive foci. Thirteen cases arose in the peritoneal cavity, 1 in a hernia sac, 3 in the pleural cavity, and 3 in hydroceles. The female:male ratio was 16:4, and age range was 7 to 74 years. Tumor was multifocal in 15 cases. Some tumors showed back-to-back papillae, a pattern mimicking invasion but discernible on pan-keratin stain as compressive crowding. True invasive patterns ranged from simple bland-appearing glands invading the stalks of the papillae to solid foci of invasive tumor of higher cytologic grade than the original WDPM. All 5 tested cases were negative for p16 deletion by fluorescence in situ hybridization, but 2/3 had abnormal karyotypes. Recurrences were seen in 8 patients, and in 4 multiple recurrences were documented. Of 16 patients with follow-up, 14 are alive from periods of 6 months to 6 years (average 3.5 y), and 2 have known recurrent disease. One patient died of disseminated tumor at 8 years but without histologic confirmation of the nature of the tumor. We conclude that WDPM with invasive foci in the papillae appear to be prone to multifocality and recurrence, but that they rarely give rise to life-threatening disease. We suggest that these lesions be called WDPM with invasive foci to alert clinicians to the possibility of recurrence

The Effect of Galaxy Interactions on Molecular Gas Properties

© 2018. The American Astronomical Society. All rights reserved.Galaxy interactions are often accompanied by an enhanced star formation rate (SFR). Since molecular gas is essential for star formation, it is vital to establish whether and by how much galaxy interactions affect the molecular gas properties. We investigate the effect of interactions on global molecular gas properties by studying a sample of 58 galaxies in pairs and 154 control galaxies. Molecular gas properties are determined from observations with the JCMT, PMO, and CSO telescopes and supplemented with data from the xCOLD GASS and JINGLE surveys at 12CO(1-0) and 12CO(2-1). The SFR, gas mass (), and gas fraction (f gas) are all enhanced in galaxies in pairs by ∼2.5 times compared to the controls matched in redshift, mass, and effective radius, while the enhancement of star formation efficiency (SFE ≡SFR/) is less than a factor of 2. We also find that the enhancements in SFR, and f gas, increase with decreasing pair separation and are larger in systems with smaller stellar mass ratio. Conversely, the SFE is only enhanced in close pairs (separation <20 kpc) and equal-mass systems; therefore, most galaxies in pairs lie in the same parameter space on the SFR- plane as controls. This is the first time that the dependence of molecular gas properties on merger configurations is probed statistically with a relatively large sample and a carefully selected control sample for individual galaxies. We conclude that galaxy interactions do modify the molecular gas properties, although the strength of the effect is dependent on merger configuration.Peer reviewedFinal Accepted Versio

Short‐wave infrared light imaging measures tissue moisture and distinguishes superficial from deep burns

Existing clinical approaches and tools to measure burn tissue destruction are limited resulting in misdiagnosis of injury depth in over 40% of cases. Thus, our objective in this study was to characterize the ability of short‐wave infrared (SWIR) imaging to detect moisture levels as a surrogate for tissue viability with resolution to differentiate between burns of various depths. To accomplish our aim, we constructed an imaging system consisting of a broad‐band Tungsten light source; 1,200‐, 1,650‐, 1,940‐, and 2,250‐nm wavelength filters; and a specialized SWIR camera. We initially used agar slabs to provide a baseline spectrum for SWIR light imaging and demonstrated the differential absorbance at the multiple wavelengths, with 1,940 nm being the highest absorbed wavelength. These spectral bands were then demonstrated to detect levels of moisture in inorganic and in vivo mice models. The multiwavelength SWIR imaging approach was used to diagnose depth of burns using an in vivo porcine burn model. Healthy and injured skin regions were imaged 72 hours after short (20 seconds) and long (60 seconds) burn application, and biopsies were extracted from those regions for histologic analysis. Burn depth analysis based on collagen coagulation histology confirmed the formation of superficial and deep burns. SWIR multispectral reflectance imaging showed enhanced intensity levels in long burned regions, which correlated with histology and distinguished between superficial and deep burns. This SWIR imaging method represents a novel, real‐time method to objectively distinguishing superficial from deep burns.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154351/1/wrr12779_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154351/2/wrr12779.pd

The Innate Immune Database (IIDB)

<p>Abstract</p> <p>Background</p> <p>As part of a National Institute of Allergy and Infectious Diseases funded collaborative project, we have performed over 150 microarray experiments measuring the response of C57/BL6 mouse bone marrow macrophages to toll-like receptor stimuli. These microarray expression profiles are available freely from our project web site <url>http://www.innateImmunity-systemsbiology.org</url>. Here, we report the development of a database of computationally predicted transcription factor binding sites and related genomic features for a set of over 2000 murine immune genes of interest. Our database, which includes microarray co-expression clusters and a host of web-based query, analysis and visualization facilities, is available freely via the internet. It provides a broad resource to the research community, and a stepping stone towards the delineation of the network of transcriptional regulatory interactions underlying the integrated response of macrophages to pathogens.</p> <p>Description</p> <p>We constructed a database indexed on genes and annotations of the immediate surrounding genomic regions. To facilitate both gene-specific and systems biology oriented research, our database provides the means to analyze individual genes or an entire genomic locus. Although our focus to-date has been on mammalian toll-like receptor signaling pathways, our database structure is not limited to this subject, and is intended to be broadly applicable to immunology. By focusing on selected immune-active genes, we were able to perform computationally intensive expression and sequence analyses that would currently be prohibitive if applied to the entire genome. Using six complementary computational algorithms and methodologies, we identified transcription factor binding sites based on the Position Weight Matrices available in TRANSFAC. For one example transcription factor (ATF3) for which experimental data is available, over 50% of our predicted binding sites coincide with genome-wide chromatin immnuopreciptation (ChIP-chip) results. Our database can be interrogated via a web interface. Genomic annotations and binding site predictions can be automatically viewed with a customized version of the Argo genome browser.</p> <p>Conclusion</p> <p>We present the Innate Immune Database (IIDB) as a community resource for immunologists interested in gene regulatory systems underlying innate responses to pathogens. The database website can be freely accessed at <url>http://db.systemsbiology.net/IIDB</url>.</p

NMR Studies of the Hydrogen Storage Compound NaMgH_3

Hydrogen and ^(23)Na NMR were performed to 400 °C on NaMgH3 powder produced by reactive ball-milling of NaH and MgH2. The H resonance shows narrowing already at 100 °C as a narrow line superimposed on the broad, rigid-lattice signal. With increasing temperature, the fraction of spins in the narrow component grows smoothly, approaching 100% near 275 °C. This heterogeneous narrowing suggests a wide distribution of H motion rates. After annealing at 400 °C, the narrow component intensity at temperatures below 200 °C was substantially reduced and both H and ^(23)Na relaxation rates 1/T_1 were decreased. Thus, it appears that the high rates of H motion, particularly on first heating, are due to regions with poorly organized crystal structure. If this disorder could be maintained, this might be an avenue toward improved reaction kinetics of this or other hydrides. In the annealed sample, the activation energy for H diffusion is approximately 95 kJ/mol

Preparation of flexible dielectric nanocomposites using nanocellulose and recycled alum sludge for wearable technology applications

With the rapid development of wearable technology, flexible dielectric materials with environmental-friendly, low-cost and high-energy efficiency characteristics are in increasing demand. In this work, a flexible dielectric nanocomposite was developed by incorporating two components: cellulose nanofibrils (CNF) and recycled alum sludge, as the reinforcement phase and for enhancing the dielectric properties, in a bio-elastomer matrix. CNF and alum sludge were processed from waste materials which would otherwise be disposed to landfills. CNF were derived from water hyacinth, an invasive aquatic weed. Dried water hyacinth was treated using a simple and less energy-intensive process to obtain CNF. The alum sludge raw material was collected from a water treatment plant of Scottish Water and heat treated and refined before being used in preparing the composites. A biodegradable elastomer polydimethylsiloxane was used as the matrix and the nanocomposites were processed by casting the materials in petri dishes. The processed composites were characterised using scanning electron microscopy (SEM), thermogravimetric (TGA/DTG) and X-ray diffraction (XRD) analysis. The SEM micrographs illustrated CNF of approximately 20nm in diameter and alum sludge particles of approximately 200um in size. The TGA/DTG analysis results showed that a total mass of 46% has been removed when the sludge sample was heated up to 900°C. The XRD result showed that both quartz SiO2 and cubic γ-Al2O3 structures can be found in the sample that was heat treated up to 800°C. Other experiments also showed that the composites exhibit comparable mechanical and dielectric performances with other works in the literature. The work depicts that it is a sustainable practice of reusing such wastes in preparing flexible, lightweight and miniature dielectric materials that can be used for wearable technology applications