Loss of mTOR signaling affects cone function, cone structure and expression of cone specific proteins without affecting cone survival

Cones are the primary photoreceptor (PR) cells responsible for vision in humans. They are metabolically highly active requiring phosphoinositide 3-kinase (PI3K) activity for long-term survival. One of the downstream targets of PI3K is the kinase mammalian target of rapamycin (mTOR), which is a key regulator of cell metabolism and growth, integrating nutrient availability and growth factor signals. Both PI3K and mTOR are part of the insulin/mTOR signaling pathway, however if mTOR is required for long-term PR survival remains unknown. This is of particular interest since deregulation of this pathway in diabetes results in reduced PR function before the onset of any clinical signs of diabetic retinopathy. mTOR is found in two distinct complexes (mTORC1 and mTORC2) that are characterized by their unique accessory proteins RAPTOR and RICTOR respectively. mTORC1 regulates mainly cell metabolism in response to nutrient availability and growth factor signals, while mTORC2 regulates pro-survival mechanisms in response to growth factors. Here we analyze the effect on cones of loss of mTORC1, mTORC2 and simultaneous loss of mTORC1 and mTORC2. Interestingly, neither loss of mTORC1 nor mTORC2 affects cone function or survival at one year of age. However, outer and inner segment morphology is affected upon loss of either complex. In contrast, concurrent loss of mTORC1 and mTORC2 leads to a reduction in cone function without affecting cone viability. The data indicates that PI3K mediated pro-survival signals diverge upstream of both mTOR complexes in cones, suggesting that they are independent of mTOR activity. Furthermore, the data may help explain why PR function is reduced in diabetes, which can lead to deregulation of both mTOR complexes simultaneously. Finally, although mTOR is a key regulator of cell metabolism, and PRs are metabolically highly active, the data suggests that the role of mTOR in regulating the metabolic transcriptome in healthy cones is minimal

Mid-Upper Arm Circumference based Nutrition Programming: evidence for a new approach in regions with high burden of Acute Malnutrition

In therapeutic feeding programs (TFP), mid-upper arm circumference (MUAC) shows advantages over weight-for-height Z score (WHZ) and is recommended by the World Health Organization (WHO) as an independent criterion for screening children 6-59 months old. Here we report outcomes and treatment response from a TFP using MUAC ≤118 mm or oedema as sole admission criteria for severe acute malnutrition (SAM)

Quest for COSMOS Submillimeter Galaxy Counterparts using CARMA and VLA: Identifying Three High-redshift Starburst Galaxies

We report on interferometric observations at 1.3 mm at 2"-3" resolution using the Combined Array for Research in Millimeter-wave Astronomy. We identify multi-wavelength counterparts of three submillimeter galaxies (SMGs; F_(1mm) > 5.5 mJy) in the COSMOS field, initially detected with MAMBO and AzTEC bolometers at low, ~10"-30", resolution. All three sources—AzTEC/C1, Cosbo-3, and Cosbo-8—are identified to coincide with positions of 20 cm radio sources. Cosbo-3, however, is not associated with the most likely radio counterpart, closest to the MAMBO source position, but with that farther away from it. This illustrates the need for intermediate-resolution (~2") mm-observations to identify the correct counterparts of single-dish-detected SMGs. All of our three sources become prominent only at NIR wavelengths, and their mm-to-radio flux based redshifts suggest that they lie at redshifts z ≳ 2. As a proof of concept, we show that photometric redshifts can be well determined for SMGs, and we find photometric redshifts of 5.6 ± 1.2, 1.9^(+0.9)_(–0.5), and ~4 for AzTEC/C1, Cosbo-3, and Cosbo-8, respectively. Using these we infer that these galaxies have radio-based star formation rates of ≳ 1000 M_☉ yr^(–1) and IR luminosities of ~10^(13) L_☉ consistent with properties of high-redshift SMGs. In summary, our sources reflect a variety of SMG properties in terms of redshift and clustering, consistent with the framework that SMGs are progenitors of z ~ 2 and today's passive galaxies

Decomposing Star Formation and Active Galactic Nucleus with Spitzer Mid-Infrared Spectra: Luminosity Functions and Co-Evolution

We present Spitzer 7-38um spectra for a 24um flux limited sample of galaxies at z~0.7 in the COSMOS field. The detailed high-quality spectra allow us to cleanly separate star formation (SF) and active galactic nucleus (AGN) in individual galaxies. We first decompose mid-infrared Luminosity Functions (LFs). We find that the SF 8um and 15um LFs are well described by Schechter functions. AGNs dominate the space density at high luminosities, which leads to the shallow bright-end slope of the overall mid-infrared LFs. The total infrared (8-1000um) LF from 70um selected galaxies shows a shallower bright-end slope than the bolometrically corrected SF 15um LF, owing to the intrinsic dispersion in the mid-to-far-infrared spectral energy distributions. We then study the contemporary growth of galaxies and their supermassive black holes (BHs). Seven of the 31 Luminous Infrared Galaxies with Spitzer spectra host luminous AGNs, implying an AGN duty cycle of 23+/-9%. The time-averaged ratio of BH accretion rate and SF rate matches the local M_BH-M_bulge relation and the M_BH-M_host relation at z ~ 1. These results favor co-evolution scenarios in which BH growth and intense SF happen in the same event but the former spans a shorter lifetime than the latter. Finally, we compare our mid-infrared spectroscopic selection with other AGN identification methods and discuss candidate Compton-thick AGNs in the sample. While only half of the mid-infrared spectroscopically selected AGNs are detected in X-ray, ~90% of them can be identified with their near-infrared spectral indices.Comment: ApJ Accepted. emulateapj style. 16 pages, 9 figures, 4 table

A Multiwavelength Study of a Sample of 70 micron Selected Galaxies in the COSMOS Field I: Spectral Energy Distributions and Luminosities

We present a large robust sample of 1503 reliable and unconfused 70microm selected sources from the multiwavelength data set of the Cosmic Evolution Survey (COSMOS). Using the Spitzer IRAC and MIPS photometry, we estimate the total infrared luminosity, L_IR (8--1000 microns), by finding the best fit template from several different template libraries. The long wavelength 70 and 160 micron data allow us to obtain a reliable estimate of L_IR, accurate to within 0.2 and 0.05 dex, respectively. The 70 micron data point enables a significant improvement over the luminosity estimates possible with only a 24 micron detection. The full sample spans a wide range in L_IR, L_IR ~ 10^8-10^14 L_sun, with a median luminosity of 10^11.4 L_sun. We identify a total of 687 luminous, 303 ultraluminous, and 31 hyperluminous infrared galaxies (LIRGs, ULIRGs, and HyLIRGs) over the redshift range 0.01<z<3.5 with a median redshift of 0.5. Presented here are the full spectral energy distributions for each of the sources compiled from the extensive multiwavelength data set from the ultraviolet (UV) to the far-infrared (FIR). Using SED fits we find possible evidence for a subset of cooler ultraluminous objects than observed locally. However, until direct observations at longer wavelengths are obtained, the peak of emission and the dust temperature cannot be well constrained. We use these SEDs, along with the deep radio and X-ray coverage of the field, to identify a large sample of candidate active galactic nuclei (AGN). We find that the fraction of AGN increases strongly with L_IR, as it does in the local universe, and that nearly 70% of ULIRGs and all HyLIRGs likely host a powerful AGN.Comment: 31 pages including 31 figures and 6 tables. Accepted for publication in ApJ. The full resolution version is available here: http://www.ifa.hawaii.edu/~jeyhan/paperI/Kartaltepe_70mic_PaperI.pd

Molecular Gas in a Submillimeter Galaxy at z=4.5: Evidence for a Major Merger at 1 Billion Years after the Big Bang

We report the detection of CO molecular line emission in the z=4.5 millimeter-detected galaxy COSMOS_J100054+023436 (hereafter: J100+0234) using the IRAM Plateau de Bure interferometer (PdBI) and NRAO's Very Large Array (VLA). The CO(4-3) line as observed with PdBI has a full line width of ~1000 km/s, an integrated line flux of 0.66 Jy km/s, and a CO luminosity of 3.2e10 L_sun. Comparison to the 3.3sigma detection of the CO(2-1) line emission with the VLA suggests that the molecular gas is likely thermalized to the J=4-3 transition level. The corresponding molecular gas mass is 2.6e10 M_sun assuming an ULIRG-like conversion factor. From the spatial offset of the red- and blue-shifted line peaks and the line width a dynamical mass of 1.1e11 M_sun is estimated assuming a merging scenario. The molecular gas distribution coincides with the rest-frame optical and radio position of the object while being offset by 0.5'' from the previously detected Ly$\alpha$ emission. J1000+0234 exhibits very typical properties for lower redshift (z~2) sub-millimeter galaxies (SMGs) and thus is very likely one of the long sought after high redshift (z>4) objects of this population. The large CO(4-3) line width taken together with its highly disturbed rest-frame UV geometry suggest an ongoing major merger about a billion years after the Big Bang. Given its large star formation rate (SFR) of >1000 M_sun/yr and molecular gas content this object could be the precursor of a 'red-and-dead' elliptical observed at a redshift of z=2.Comment: 12 pages, 3 figures, accepted for publications by ApJ

Millimeter imaging of submillimeter galaxies in the COSMOS field: Redshift distribution

We present new IRAM PdBI 1.3mm continuum observations at ~1.5" resolution of 28 SMGs previously discovered with the 870um bolometer LABOCA at APEX within the central 0.7deg2 of the COSMOS field. 19 out of the 28 LABOCA sources were detected with the PdBI at a >~3sigma level of ~1.4mJy/b. A combined analysis of this new sample with existing interferometrically identified SMGs in the COSMOS field yields the following results: 1) >~15%, and possibly up to ~40% of single-dish detected SMGs consist of multiple sources, 2) statistical identifications of multi-wavelength counterparts to the single-dish SMGs yield that only ~50% of these single-dish SMGs have real radio or IR counterparts, 3) ~18% of interferometric SMGs have only radio or even no multi-wavelength counterpart at all, and 4) ~50-70% of z>~3 SMGs have no radio counterparts down to an rms of 7-12uJy at 1.4GHz. Using the exact interferometric positions to identify proper multi-wavelength counterparts allows us to determine accurate photometric redshifts for these sources. The redshift distributions of the combined and the individual 1.1mm and 870um selected samples have a higher mean and broader width than the redshift distributions derived in previous studies. Our sample supports the previous tentative trend that on average brighter and/or mm-selected SMGs are located at higher redshifts. There is a tentative offset between the mean redshift for the 1.1mm (=3.1+/-0.4) and 870um (=2.6+/-0.4) selected samples, with the 1.1mm sources lying on average at higher redshifts. Based on our nearly complete sample of AzTEC 1.1mm SMGs within a uniform 0.15deg2 area we infer a higher surface density of z>~4 SMGs than predicted by current cosmological models. In summary, our findings imply that (sub-)millimeter interferometric identifications are crucial to build statistically complete and unbiased samples of SMGs.Comment: 35 pages, 18 figures, 10 tables; accepted for publication in A&

Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer

Conceived and designed the experiments: XFL GAC RCB. Performed the experiments: XFL MIA WM RS MSN SZ. Analyzed the data: XFL SR. Contributed reagents/materials/analysis tools: YW GAC. Wrote the paper: XFL RCB.Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 39-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells.This work was supported by the Anne and Henry Zarrow Foundation, kind gifts from Stuart and Gaye Lynn Zarrow and from Mrs. Delores Wilkenfeld, the Laura and John Arnold Foundation, the RGK Foundation, and the MD Anderson NCI CCSG P30 CA16672. G.A.C. is supported as a Fellow at the University of Texas MD Anderson Research Trust, as a University of Texas System Regents Research Scholar and by the CLL Global Research Foundation

Light regime characterization in an airlift photobioreactor for production of microalgae with high starch content

The slow development of microalgal biotechnology is due to the failure in the design of large-scale photobioreactors (PBRs) where light energy is efficiently utilized. In this work, both the quality and the amount of light reaching a given point of the PBR were determined and correlated with cell density, light path length, and PBR geometry. This was made for two different geometries of the downcomer of an airlift PBR using optical fiber technology that allows to obtain information about quantitative and qualitative aspects of light patterns. This is important since the ability of microalgae to use the energy of photons is different, depending on the wavelength of the radiation. The results show that the circular geometry allows a more efficient light penetration, especially in the locations with a higher radial coordinate (r) when compared to the plane geometry; these observations were confirmed by the occurrence of a higher fraction of illuminated volume of the PBR for this geometry. An equation is proposed to correlate the relative light intensity with the penetration distance for both geometries and different microalgae cell concentrations. It was shown that the attenuation of light intensity is dependent on its wavelength, cell concentration, geometry of PBR, and the penetration distance of light.Fundação para a Ciência e a Tecnologia (FCT

XPD codon 312 and 751 polymorphisms, and AFB1 exposure, and hepatocellular carcinoma risk

<p>Abstract</p> <p>Background</p> <p>Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of hepatocellular carcinoma (HCC) related to the exposure of aflatoxin B1 (AFB1). In this study, we have focused on the polymorphisms of xeroderma pigmentosum complementation group D (XPD) codon 312 and 751 (namely Asp312Asn and Lys751Gln), involved in nucleotide excision repair.</p> <p>Methods</p> <p>We conducted a case-control study including 618 HCC cases and 712 controls to evaluate the associations between these two polymorphisms and HCC risk for Guangxi population by means of TaqMan-PCR and PCR-RFLP analysis.</p> <p>Results</p> <p>We found that individuals featuring the XPD genotypes with codon 751 Gln alleles (namely XPD-LG or XPD-GG) were related to an elevated risk of HCC compared to those with the homozygote of XPD codon 751 Lys alleles [namely XPD-LL, adjusted odds ratios (ORs) were 1.75 and 2.47; 95% confidence interval (CIs) were 1.30-2.37 and 1.62-3.76, respectively]. A gender-specific role was evident that showed an higher risk for women (adjusted OR was 8.58 for XPD-GG) than for men (adjusted OR = 2.90 for XPD-GG). Interestingly, the interactive effects of this polymorphism and AFB1-exposure information showed the codon 751 Gln alleles increase the risk of HCC for individuals facing longer exposure years (<it>P</it>_interaction= 0.011, OR = 0.85). For example, long-exposure-years (> 48 years) individuals who carried XDP-GG had an adjusted OR of 470.25, whereas long-exposure-years people with XDP-LL were at lower risk (adjusted OR = 149.12). However, we did not find that XPD codon 312 polymorphism was significantly associated with HCC risk.</p> <p>Conclusion</p> <p>These findings suggest that XPD Lys751Gln polymorphism is an important modulator of AFB1 related-HCC development in Guangxi population.</p