DAPK2 is a novel modulator of trail-induced apoptosis and it regulates oxidative stress in cancer cells by preserving mitochondrial function

Targeting molecules involved in Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) -mediated signalling has been hailed by many as a potential magic bullet to efficiently kill cancer cells, with little side effects on normal cells. Indeed, initial clinical trials showed that antibodies against TRAIL receptors, death receptor (DR) 4 and DR5 are well tolerated by cancer patients. Despite the initial efficacy issues in the clinical setting, novel approaches to trigger TRAIL-mediated apoptosis are being developed and its clinical potential is being reappraised. Unfortunately, many patients develop resistance to TRAIL-induced apoptosis and there is thus impetuous for identifying additional resistance mechanisms that may be targetable and usable in combination therapies. Here, we show that the death associated protein kinase (DAPK) 2 is a modulator of TRAIL signalling. DAPK2 is a serine/threonine kinase that belongs to the DAPK family. Like DAPK1, it has been implicated in programmed cell death, the regulation of autophagy and developmental processes. Ablation of DAPK2 using RNAi causes phosphorylation of NF-κB and its transcriptional activity in several cancer cell lines. This then leads to the induction of a variety of NF-κB target genes, which includes DR4 and DR5. DR4 and DR5 protein expression is correspondingly increased on the cell surface and this leads to the sensitisation of resistant cells to TRAIL-induced killing. As DAPK2 is a kinase, it is imminently druggable and our data thus offer a novel avenue to overcome TRAIL-resistance in the clinic. We have additionally identified a new role for DAPK2 in the regulation of mitochondrial integrity. RNAi-mediated depletion of DAPK2 leads to a number of metabolic changes, including a significantly decreased rate of oxidative phosphorylation in combination with an overall destabilised mitochondrial membrane potential. This phenotype is further corroborated by an increase in the production of mitochondrial superoxide anions and general oxidative stress. This role of DAPK2 is completely novel and could impact significantly on the understanding of DAPK2’s function in physiology and disease.Open Acces

A Risk Analysis of Converting CRP Acres to a Wheat-Sorghum-Fallow Rotation

This study examines the economic potential of producing a wheat (Triticum aesitivum) and grain sorghum (Sorghum bicolor (L.) Moench) rotation with three different tillage strategies compared to the Conservation Reserve Program (CRP) in a semi-arid region. This research uses stochastic efficiency with respect to a function (SERF) to determine the preferred management strategies under various risk preferences and utility-weighted certainty equivalent risk premiums. Yields, input rates, and field operations from an experimental field in western Kansas are used to calculate net returns for each tillage strategy. Although current net returns to crop production using reduced tillage and no-tillage strategies are higher than CRP, risk analysis indicates CRP would be the preferred strategy for some risk-averse managers.Conservation Reserve Program, conservation tillage, simulation, sorghum, wheat, risk, Agricultural and Food Policy, Crop Production/Industries, Farm Management, Land Economics/Use, Risk and Uncertainty,

Off target effects of sulforaphane include the de-repression of long-terminal repeats through histone acetylation events

Sulforaphane is a naturally occurring isothiocyanate in cruciferous vegetables. Sulforaphane inhibits histone deacetylases, leading to the transcriptional activation of genes including tumor suppressor genes. The compound has attracted considerable attention in the chemoprevention of prostate cancer. Here we tested the hypothesis that sulforaphane is not specific for tumor suppressor genes but also activates loci such as long terminal repeats (LTRs), which might impair genome stability. Studies were conducted using chemically pure sulforaphane in primary human IMR-90 fibroblasts and in broccoli sprout feeding studies in healthy adults. Sulforaphane (2.0 μM) caused an increase in LTR transcriptional activity in cultured cells. Consumption of broccoli sprouts (34, 68, or 102g) by human volunteers caused a dose dependent elevation in LTR mRNA in circulating leukocytes, peaking at more than a 10-fold increase. This increase in transcript levels was associated with an increase in histone H3 K9 acetylation marks in LTR 15 in peripheral blood mononuclear cells from subjects consuming sprouts. Collectively, this study suggests that sulforaphane has off-target effects that warrant further investigation when recommending high levels of sulforaphane intake, despite its promising activities in chemoprevention

Escape Worthiness of Vehicles with Passive Belt Restraint Systems

There are a variety of conditions that can exist in the post-crash environment which make rapid escape necessary for survival or to avoid further injury. These include a post-crash fire, the vehicle going into the water, or avoiding being struck in a secondary collision. The National Highway Traffic Safety Administration (NHTSA) has defined this parameter vehicle escapeworthiness. It has been estimated in past research performed by the author for NHTSA that escapeworthiness becomes important in up to 7% of all vehicle crashes. Since escapeworthiness research was performed in the early 1970's, the advent of passive shoulder belt systems has made it necessary to again review the impact of this development on escapeworthiness. In particular, the inability of the occupants to release the passive restraint because the door cannot be opened after the crash, coupled with the inability to release the passive restraint due to its design or a lack of experience, or knowledge of how to release the passive restraint while the door is closed, creates a serious problem. Thus, the present study was performed to investigate the impact of passive restraint systems on the time required to escape from the vehicle under various conditions of available escape routes, and physical condition of the occupants. The experimental design included the variables of age, gender, escape route, level of incapacitation and type of passive restraint system. The times to effect an escape as well as the method of escaping were determined through videographic analysis of all escape trials. The findings demonstrated that the use of passive restraint systems increased the time to escape significantly, ranging from 37 to 65 percent for the respective conditions. This difference may determine whether a person survives or not after some post-crash conditions. The results have significance for the design of passive restraint systems for easy release, while at the same time not creating an incentive for some users to routinely leave the passive restraint unfastened.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Chandra X-ray Observatory Arcsecond Imaging of the Young, Oxygen-rich Supernova Remnant 1E0102.2-7219

We present observations of the young, Oxygen-rich supernova remnant 1E0102.2-7219 taken by the Chandra X-ray Observatory during Chandra's Orbital Activation and Checkout phase. The boundary of the blast wave shock is clearly seen for the first time, allowing the diameter of the remnant and the mean blast wave velocity to be determined accurately. The prominent X-ray bright ring of material may be the result of the reverse shock encountering ejecta; the radial variation of O VII vs. O VIII emission indicates an ionizing shock propagating inwards, possibly through a strong density gradient in the ejecta. We compare the X-ray emission to Australia Telescope Compact Array 6 cm radio observations (Amy and Ball) and to archival Hubble Space Telescope [O III] observations. The ring of radio emission is predominantly inward of the outer blast wave, consistent with an interpretation as synchrotron radiation originating behind the blast wave, but outward of the bright X-ray ring of emission. Many (but not all) of the prominent optical filaments are seen to correspond to X-ray bright regions. We obtain an upper limit of ~9e33 erg/s (3 sigma) on any potential pulsar X-ray emission from the central region.Comment: Accepted for pulication in Ap. J. Letters. 4 pages, 6 figures (one color figure). Formatted with emulateapj5. Revised to incorporate copyediting changes. High-resolution postscript (3.02MB) and tiff versions of the color figure are available from http://chandra.harvard.edu/photo/cycle1/0015multi/index.htm

The DESI Experiment, a whitepaper for Snowmass 2013

The Dark Energy Spectroscopic Instrument (DESI) is a massively multiplexed fiber-fed spectrograph that will make the next major advance in dark energy in the timeframe 2018-2022. On the Mayall telescope, DESI will obtain spectra and redshifts for at least 18 million emission-line galaxies, 4 million luminous red galaxies and 3 million quasi-stellar objects, in order to: probe the effects of dark energy on the expansion history using baryon acoustic oscillations (BAO), measure the gravitational growth history through redshift-space distortions, measure the sum of neutrino masses, and investigate the signatures of primordial inflation. The resulting 3-D galaxy maps at z<2 and Lyman-alpha forest at z>2 will make 1%-level measurements of the distance scale in 35 redshift bins, thus providing unprecedented constraints on cosmological models.Comment: 14 pages, 4 figures, a White Paper for Snowmass 201

Histone acetylation increases in response to ferulic, gallic, and sinapic acids acting synergistically in vitro to inhibit \u3ci\u3eCandida albicans\u3c/i\u3e yeast‐to‐hyphae transition

Novel treatments are needed to prevent candidiasis/candidemia infection due to the emergence of Candida species resistant to current antifungals. Considering the yeast-to‐hyphae switch is a critical factor to Candida albicans virulence, phenols common in plant sources have been reported to demonstrating their ability to prevent dimorphism. Therefore, phenols present in many agricultural waste stress (ferulic (FA) and gallic (GA) acid) were initially screened in isolation for their yeast‐to‐hyphae inhibitory properties at times 3, 6, and 24 hr. Both FA and GA inhibited 50% of hyphae formation inhibitory concentration (IC50) but at a concentration of 8.0 ± 0.09 and 90.6 ± 1.05 mM, respectively, at 24 hr. However, the inhibitory effect of FA increased by 1.9–2.6 fold when combined with different GA concentrations. GA and FA values decreased even lower when sinapic acid (SA) was added as a third component. As evidenced by concave isobolograms and combination indexes less than 1, both GA:F A and GA:FA:SA combinations acted synergistically to inhibit 50% hyphae formation at 24 hr. Lastly, acetylation of histone H3 lysine 56 acetylation (H3K56) was higher in response to the triple phenolic cocktail (using the IC50 24 hr inhibitory concentration level) comparable with the nontreated samples, indicating that the phenols inhibited hyphal growth in part by targeting H3K56 acetylation

A Map of the Universe

We have produced a new conformal map of the universe illustrating recent discoveries, ranging from Kuiper belt objects in the Solar system, to the galaxies and quasars from the Sloan Digital Sky Survey. This map projection, based on the logarithm map of the complex plane, preserves shapes locally, and yet is able to display the entire range of astronomical scales from the Earth's neighborhood to the cosmic microwave background. The conformal nature of the projection, preserving shapes locally, may be of particular use for analyzing large scale structure. Prominent in the map is a Sloan Great Wall of galaxies 1.37 billion light years long, 80% longer than the Great Wall discovered by Geller and Huchra and therefore the largest observed structure in the universe.Comment: Figure 8, and additional material accessible on the web at: http://www.astro.princeton.edu/~mjuric/universe

Eleven years of radio monitoring of the Type IIn supernova SN 1995N

We present radio observations of the optically bright Type IIn supernova SN 1995N. We observed the SN at radio wavelengths with the Very Large Array (VLA) for 11 years. We also observed it at low radio frequencies with the Giant Metrewave Radio Telescope (GMRT) at various epochs within $6.5-10$ years since explosion. Although there are indications of an early optically thick phase, most of the data are in the optically thin regime so it is difficult to distinguish between synchrotron self absorption (SSA) and free-free absorption (FFA) mechanisms. However, the information from other wavelengths indicates that the FFA is the dominant absorption process. Model fits of radio emission with the FFA give reasonable physical parameters. Making use of X-ray and optical observations, we derive the physical conditions of the shocked ejecta and the shocked CSM.Comment: 22 pages, 2 tables, 13 figures, Accepted for publication in Astrophysical Journa

Characterization of Rat Meibomian Gland Ion and Fluid Transport

We establish novel primary rat meibomian gland (MG) cell culture systems and explore the ion transport activities of the rat MG